排尿障礙治療中心版權所有 Medical Treatment for Lower Urinary Tract Dysfunction Hann-Chorng Kuo Department of Urology Buddhist Tzu Chi General Hospital Hualien

排尿障礙治療中心版權所有

Medical Treatment for Lower Urinary Tract Dysfunction

Hann-Chorng Kuo

Department of Urology

Buddhist Tzu Chi General Hospital Hualien


Innervation of Lower Urinary Tract

• Bladder-

cholinergic parasympathetic- contraction; beta-adrenergic & NO– relaxation

• Bladder neck – alpha-adrenergic- contration

• Urethral muscles-

cholinergic parasympathetic, NO, cholinergic somatic nerves


Neuroanatomy of Lower Urinary Tract


Treatment Goals of Voiding Dysfunction

• To increase bladder capacity – Bladder Hypersensitivity

• To reduce detrusor overactivity – Detrusor overactivity

• To increase urethral resistance – Urethral incompetence

• To reduce urethral resistance -- Bladder outlet obstruction

• To increase bladder contractility – Detrusor underactivity or acontractility

• To improve bladder compliance – Low bladder compliance


Improved Voiding Efficiency

• Increase detrusor contractility – increase detrusor muscle tone or contractility

• Reduce urethral resistance – bladder neck, urethral sphincter, prostatic urethra

• Improved bladder capacity and compliance

• Combination of all of the above


Storage of Urine

• Stable bladder

• Good compliance

• Competent urethra- mucosa, submucosa, smooth muscles, striated skeletal muscles (external sphincter)

• Good pressure transmission and hammock effect during stress


Storage Problems

• Bladder hypersensitivity

• Low bladder compliance

• Detrusor overactivity – neurogenic or idiopathic

• Low urethral resistance

• Bladder outlet obstruction

• Combination of the above


Detrusor overactivity during Bladder filling phase


Detrusor Overactivity followed by Valsalva maneuver


Empty of Urine

• Sustained detrusor contraction- cholinergic parasympathetic fibers

• Relaxation of bladder neck – alpha-adrenergic sympathetic nerves

• Relaxation of external sphincter- cholinergic pudendal nerves

• Patent non-obstructive urethra


Normal Micturition – relaxation of urethral sphincter


Empty Problems

• Bladder outlet obstruction – Bladder neck dysfunction, BPH, Urethral stricture, Dysfunctional voiding, DESD

• Bladder hypersensitivity

• Detrusor underactivity or areflexia

• Poor urethral sphincter relaxation

• Combination of the above


Dysfunctional Voiding in a girl with Bilateral Hydronephrosis


Low Detrusor Contractility


Pharmacology of Micturition- Increase storage efficiency

• Reduce detrusor overactivity• Anticholinergic agents- oxybutynine, flavox

ate, imipramine• Ganglion blocker- bentyl• Beta-adrenergic agents• Botulinum toxin• Vanilloid receptor blockers- capsaicin, resin

iferatoxin


Pharmacology of Micturition- Increase empty efficiency

• Parasympathomimetic agent- Urecholine

• Adrenergic blockers- inhibition of detrusor relaxation (?)


Pharmacology of Micturition- Increase outlet resistance

• Increase smooth muscle tone –

Imipramine, methylephedrine

• Increase striated muscle tone –

Nitric oxide synthase inhibitor

Pelvic floor muscle training


SUI & Urethral Incompetence induced Detrusor Overactivity


Pharmacology of Micturition- Decrease outlet resistance

• Decrease bladder neck & urethral resistance

• Alpha-adrenergic blockers- dibenyline, terazosin, tamsulosin, doxazosin

• Nitric oxide donors

• Botulinum toxin

• Polysynaptic blocker – baclofen, diazepam


Decreased MUCP after Botulinum Toxin Injection


Reduction of MUCP after Nitric Oxide Donors (NTG)


Combined Medication- Improved Storage Efficiency

• Detrusor Overactivity- anticholinergics, sympathomimetics, imipramine

• Intrinsic sphincter deficiency- imipramine, sympathomimetics

• DHIC- depends on voiding efficiency and grades of incontinence


Combination of Medication- Improve Voiding Efficiency

• Increased bladder sensation- intravesical capsaicin, RTX

• Detrusor overactivity- anticholinergic, intravesical RTX, botulinum toxin

• Detrusor underactivity – parasympathomimetics, alpha-blocker, NO donors, striated muscle relaxant, periurethral botulinum toxin injection


Combined Medication – Improved Voiding Efficiency

Urethral sphincter hypertonicity- alpha-blocker, NO donors, striated skeletal muscle relaxant

• Urethral sphincter overactivity- alpha-blocker, striated muscle relaxant, NO donors, botulinum toxin

• Bladder neck dysfunction- alpha-adrenergic blocker


Dysfunctional voiding in A woman with Multiple Stroke


Medication for Detrusor hyperreflexia

• Oxybutynin & anticholinergics

• Imipramine

• Intravesical capsaicin & resiniferatoxin

• Intra- detrusor botulinum toxin

• Multiple medication increases adverse effect especially in elderly with inadequate detrusor contractility (DHIC)


Anticholinergics Treatment

• Oxybutynin – the most effective and safe drug currently available

• Detrusitol – M3 antagonist, less salivary and GI side effects than Ditropan

• Flavoxate – mild effect on detrusor

• Imipramine – central and anticholinergics


Tolterodine vs Oxybutynin

• A secondary amine with competitive muscarinic receptor blocking property

• As potent as oxybutynin in inhibiting detrusor contractions

• 8 times less potent in inhibiting salivation than oxybutynin

• 2mg bid tolterodine in comparison to 5mg tid of oxybutynin

• Titration doses from 1-2 mg bid to 4mg bid


Side effects of Anticholinergic

• Post-synaptic receptors M1 and M2 are widespread in CNS, anticholinergics may have cognitive dysfunction, especially in elderly

• Dry mouth, constipation, blurred vision• Darifenacin has 11-fold higher affinity to M

3 than M2 receptors and a 5-fold lower affinity for M receptors in parotid gland


Pharmacology of Detrusor Overactivity


Extended-release system for oxybutynin & tolterodine


Intravesical Therapy for Detrusor overactivity

• Blocking efferent cholinergic fibers – intravesical oxybutynin, atropine

• Blocking neuromuscular junction – intravesical botulinum A toxin injection

• Blocking afferent fibers that mediate detrusor reflex – intravesical lidocaine

• Blocking C-fiber mediated detrusor contractions – intravesical capsaicin, resiniferatoxin


Intravesical Capsaicin Therapy

• Patients who are refractory to conventional treatment

• Capsaicin 10 -5 M in 30ml N/S instilled to bladder for 30 minutes

• Resiniferatoxin 10-8 M in 30ml N/S

• A burning sensation or urge at instillation

• Relief of pain and urge in the later days


Therapeutic Effects of Resiniferatoxin on Detrusor Overactivity

• 10 -5 to 10 -7 M RTX is effective for DH of SCI and DH of CNS origin

• 10 -8 M RTX can significantly improve voiding pattern and pain score in hypersensitive disorders and bladder pain

• RTX is safe for application in humans• Less initial irritative response in RTX treat

ment than capsaicin


Urodynamic Result after RTX Therapy in a SCI patient


Urodynamic Changes after RTX in Chronic SCI with DESD

Baseline Post-RTX Stastistics

Cystometric capacity(ml) 102.1±31 236.6±88.6 P<0.001

Bladder compliance

(ml/cmH2O)23.7±12.1 25.9±15.3 P>0.05

Voiding pressure

(Pdet, cmH2O)55.9±23.2 47.5±28.1 P>0.05

Presence of

DESD (n=20)100% 100%


Intravesical RTX in treatment of Neurogenic Detrusor Overactivity

• C-fiber mediated detrusor reflex does not predominate neurogenic detrusor overactivity in lesion above pons

• Resiniferatoxin in 10-6~-7 M can activate initial excitatory responses

• Therapeutic results are not as satisfactory as that in SCI patients

• An alternative for patients who cannot tolerate or refractory to anticholinergic agents


Therapeutic Results of RTX in Neurogenic v Non-neurogenic Voiding Dysfunction

• 22/41 patients (53.6%) with detrusor overactivity improved after RTX 10-7M instillation (initial concentration)

• 6/10 (60%) Neurogenic DH, 4/13 (31%) Idiopathic DI, 12/18 (67%) BOO related DI improved

6/7 (86%) type I, 1/3 (33%) type II, 7/16 (44%) type III, 8/15 (53%) type IV


Urodynamic Changes after RTX in Detrusor Overactivity

Baseline Post-RTX Statistics

Cystometric capacity(ml)

(n=41)216±106 302±133 P=0.000

Qmax (ml/sec) 12.7±7.6 21.8±28.9 P=0.224

Voiding pressure

(Pdet, cmH2O)33.6±11.7 34.1±19.5 P=0.923

Residual urine (ml) 41.1+52.7 49.4+98.9 P=0.725


Botulinum A toxin Injection

• Inhibition of acetylcholine (Ach) release from presynaptic cholinergic fiber

• Induce paralysis of muscle fibers• Intravesical injection can inhibit detrusor ov

eractivity• Urethral injection can reduce urethral resist

ance and sphincter spasticity• Duration of effect about 3-6 months


Mechanism of Botulinum A Toxin in Neuromuscular Junction


Botulinum A Toxin Urethral Injection in Woman


Cystoscopic Urethral Injection in Men

**

** **

**


Table 1.The Urodynamic Parameters at Baseline and after Botulinum Toxin in Effective Patients

Baseline Post-Botox Statistics*

Capacity (n=53) 331.4±148.8 333.2±155.4 0.922

Qmax (n=53) 6.7± 6.7 9.4± 5.7 0.003

Voiding pressure (n=53)

62.0± 43.1 45.9±37.8 0.000

MUCP (n=21) 97.1±31.7 51.1±23.2 0.027

FPL (n=21) 3.35±0.59 3.30±0.33 0.773

PVR (n=53) 225.4±174.4 110.1±137.6 0.000

MUCP=maximal urethral closure pressure, FPL=functional profile length,

PVR= postvoid residual volume

*Comparison between baseline and 4weeks after treatment


Therapeutic Results after Botox Urethral Injection for Voiding Dysfunction

GoodGood ImprovedImproved FailedFailed

Detrusor underactivity (n=27)Detrusor underactivity (n=27)13

(48.2%)

8

(29.6%)

6

(22.2%)

DESD (n=18)DESD (n=18)3

(16.7%)

10

(55.6%)

5

(27.8%)

Dysfunctional voiding (n=18)Dysfunctional voiding (n=18)6

(33.3%)

10

(55.6%)

2

(11%)

Poor relaxation of urethral Poor relaxation of urethral sphincter (n=12)sphincter (n=12)

3

(25%)

7

(58.3%)

2

(16.6%)

TOTAL (n=75)TOTAL (n=75)25

(33.3%)

35

(43.7%)

15

(20%)

DESD=Detrusor external sphincter dyssynergia


Botulinum Toxin Detrusor Injection for Detrusor Hyperreflexia


Btulinum A Toxin Detrusor Injection for DH


Initial Results of BotulinumToxin Detrusor Injection for Incontinence

No Sex / Age Disease DESE Capacity Dysuria Incontinence

1 M / 35 DESD 250 U Improved －＋

2 F / 10 DI 100 UNo

Change－＋＋＋

3 F / 45 DI 200 U Improved －－

4 M / 48 DHIC 200 U Improved －＋

5 F / 56 DH 200 U Improved －－


Medication for Bladder outlet obstruction

• Bladder neck – alpha-adrenergic blocker

• Smooth muscle – Nitric oxide donors (nitroglycerine, isosorbid mononitrate), anticholinergics

• Striated muscle – baclofen, diazepam, dantrolene, calcium channel blocker, NO donors, botulinum A toxin

• Enlarged Prostate – finasteride (Proscar)


Bladder neck dysfunction in woman


Spastic urethral sphincter (Dysfunctional voiding)


Medical Treatment for Female BOO

• Skeletal muscle relaxant – diazepam, baclofen, dantrolene, calcium blocker

• Alpha-adrenergic blocker – dibenylene, terazosin, doxazosin, tamsulosin

• Nitric oxide donor- nitroglycerine, isosorbid mononitrate

• Estrogen• Botulinum A toxin


Medical Therapy for BPH• Prostatic smooth muscle tension was mediate

d by alpha 1-adrenoreceptors

• Smooth muscle contractions contribute 40% of outflow obstruction

• Alpha 1- blockers can rapidly improve Qmax and relieve LUTS

• Phenoxybenzamine, terazosin, doxazosin have side effect of dizziness and hypotension


Relation of prostate and urethra


Bladder Outlet Obstruction due to Benign Prostatic Hyperplasia


Bladder outlet obstruction due to BPH in Men


Prostatic specific alpha- adrenoreceptor

• Alpha 1A- AR subtype comprises 70% of all alpha-1 receptors

• Alpha 1A-AR agonist – tamslosin has 13 x more affinity to prostatic smooth muscle than urethral muscle , 10 x than vascular smooth muscle

• Side effects are still reported• Long-acting (once daily) dose


Hormone based medical therapy

• 5-alpha-reductase catalyzes conversion of testosterone to dihydrotestosterone

• Inhibition of 5-alpha-reductase can arrest prostatic growth and relieve obstruction

• Finasteride can improve symptom score, Qmax, QOL score

• Effective especially in prostatic weight of >40 gm and effective in prostatic hematuria


Combination therapy with alpha-blocker and finasteride

• Terazosin is effective therapy, finasteride was not, combination was no more effective than terazosin alone (Lepor, N Engl J Med 1996; 335: 533)

• Combined dibenyline and finasteride has an additive effect than dibenyline or finasteride alone in improvement of Qmax and prostatic size


Nocturia

• A result of excessive amount of urine production at night

• Noctural polyuria >35% daily urine

• Abnormal lower urinary tract function

• A combination of two etiologies


Desmopressin

• The circardian rhythm of vasopressin was lost in the elderly with nocturnal polyuria

• Atrial natriureteric peptide in the elderly was higher during night time

• Use of arginine vasopressin analogue patients with nocturnal enuresis and nocturnal polyuria become dry


Therapeutic Effects of Desmopressin in Nocturnal Polyuria

BaselineBaseline PosttreatmentPosttreatmentP ValueP Value

(Paired t Test)(Paired t Test)

Nocturnal frequency Nocturnal frequency (time/night)(time/night)

5.20 ± 1.16 2.24 ± 1.12 <0.0001

Nocturnal urine volume (mL)Nocturnal urine volume (mL) 955.6 ± 255.9 255.8 ± 210.5 <0.0001

Quality of lifeQuality of life 4.47 ± 1.07 1.05 ± 0.91 <0.0001

Urine specific gravityUrine specific gravity 1.012 ± 0.007 1.016 ± 0.005 0.011

Serum Sodiun (mEq/L)Serum Sodiun (mEq/L) 139.5 ± 4.34 139.7 ± 3.84 0.761

Serum Potassium (mEq/L)Serum Potassium (mEq/L) 4.46 ± 0.35 4.31 ± 0.44 0.022


Combination therapy for geriatric Nocturnal polyuria

• Combined anticholinergics and DDAVP for detrusor overactivity and nocturnal polyuria for DI & NP

• Combined alpha-blocker and DDAVP for BOO and NP

• Combined alpha-blocker and anti-cholinergics and DDAVP for BOO & DI & NP


Difficult urination due to A Spastic Urethral Sphincter


Treatment of spastic urethral sphincter

• Behavioral therapy: hydration, laxatives, time voiding, changing voiding posture

• Physiotherapy: pelvic floor muscle exercises• Electric stimulation : interferential current stimulat

ion• Biofeedback: visual or Uroflowmetry & EMG• Medication: baclofen, alpha-adrenergic blockers, e

strogen, combination therapy• Urethral injection of botulinum A toxin


Therapeutic results of baclofen and terazosin in treatment of spastic urethral sphincter

IPSS Qmax Residual urine

Baseline Trated Baseline Treated Baseline Treated

Baclofen (n=73) 15.2±6.7 10.4±5.7 14.3±9.7 16.7±8.1 65.7±33.9 37.5±21.7

% of change 31.6±21.5 16.87±12.7 42.9±34.1

Baclofen plus 12.7±7.9 6.1.±4.5 14.8±11.0 22.677.5 58.1±21.8 31.01±31.2

Terazosin (n=64)

% of change 51.7±27.4 52.7±31.1 46.5±29.3

Statistics* P<0.05 P<0.05 NS


Medication for Dysfunctional voiding

• Oxybutynin – effective in reducing detrusor overactivity, side effects of mucosal dryness & constipation

• Ditropan XL – elimination of peak drug effect and reduce adverse effects

• Tolterodine – M3 anticholinergic• Alpha-adrenergic blocker to reduce urethral resista

nce• Phenylpropanolamine, pseudoephedrine – in ISD

with incontinence ready for CIC


Treatment of Nocturnal Enuresis

• Conditioning therapy: Alarm system or dry-bed training,effective in about 30-80%

• Medcal therapy: (1) Tricyclic antidepressant (TCA), imipramine, amitriptyline effective in 10-50% (author 24%)

(2) anti-cholinergics (3) desmopressin (DDAVP)• Side effect in combination medical therapy


DDAVP Therapy in Nocturnal Enuresis in Children

• DDAVP in dose of 10-20 ug intranasally is effective in 70% of children with PNE

• After discontinuing DDAVP for 3months, 21% remained dry without medication

• 20 ug is adequate in treating PNE, in children not responded to 20ug, 40ug did not effective

• No serious adverse effect


Treatment of Adult Nocturnal Enuresis

• DDAVP in patients proven to have nocturnal polyuria (nocturnal urine volume > 35% daily urine volume, or >900ml/N)

• Oxybutynine in patients proven to have DI• Imipramine or methylephedrine in patients s

uspicious to have urethral incompetence• Pelvic floor muscle exercises or functional

electrostimulation might be helpful


Medical treatment of Interstitial Cystitis

• Cyclosporine• Methotrexate• Tice strain BCG– 60% response rate vs 27

% in placebo• Elmiron (PPS 100mg tid) – 6.2% to 18.7% r

esponse rate• Electromotive administration of intravesical

lidocaine & dexamethasone – 62% effective


Inravesical Heparin therapy

• Patients with urgency frequency and a positive potassium test

• Intravesical Heparin 25000u/10ml saline and holding for 2 hours

• 2x or 3x per week for 12 weeks

• 67% patients have improvement in symptoms and increase in bladder capacity


Urodynamic finding before and after Heparin

Therapy


The changes of urodynamic parameters before and after

heparin treatment

Baseline 3 months Statistics

P value

FSF(ml) 96.5±46.4

146.1±55.4 0.001

US(ml) 225.4±96.2

264.9±84.2 0.009

Cystometric capacity(ml)

262.0±89.8

304.3±84.8 0.002

PdetQmax(cmH2O) 25.7±9.1 28.3±9.3 0.07Qmax (ml/sec) 12.9±5.7 15.1±7.7 0.063Residual urine(ml)

29.4±38.4

14.5±25.7 0.096

IPSS (points) 19.5±4.6 9.0±4.0 0

Nocturia (times/night)

5.7±2.0 2.3±1.1 0

Pain scale of KCl (points)

3.2±0.5 0.7±0.7 0


Thank you for your attention


Low contractility





Detrusor Overactivity and Contracted Bladder





Documents

排尿障礙治療中心 版權所有 Medical Treatment for Lower Urinary Tract Dysfunction Hann-Chorng Kuo Department of Urology Buddhist Tzu Chi General Hospital Hualien

排尿障礙治療中心版權所有 Medical Treatment for Lower Urinary Tract Dysfunction Hann-Chorng Kuo Department of Urology Buddhist Tzu Chi General Hospital Hualien