MEDICAL MANAGEMENT OF LUTS/BPH&

RECENT ADVANCES

Bikash Bk. ThapaMS – General Surgery

Introduction

Component of BOO

• A dynamic (physiologic, reversible) component – related to the tension of prostatic smooth muscle

in the prostate, prostate capsule, and bladder neck• A fixed (structural) component – related to the bulk of the enlarged prostate

impinging upon the urethra

Association of BOO

• Voiding Dysfunction– BPO- muscle hypertrophies- decompensation- reduced

expression of connexin 43- impairs synchronise contraction- contractile dysfunction

• Storage Dysfunction– cycle of urine storage and voiding causes repeated bladder

distension, raised intravesical pressure, ischemia, reperfusion– Impaired vesical blood flow results in oxidative stress, with free

radicals causing damage to the urothelium, nerves, and smooth muscle.

Pathogenesis

• Hormonal• Dysregulation of stromal growth factors• Reawakening of embryonic process• Decrease cell death• Genetic susceptibiltiy

Role of Androgen

New Hypothesis

• BPH is caused by malfunction of the valves in the internal spermatic vein manifesting as varicocele

– Elevated venous pressure causes hypertrophy and exposure to high concentration of free testosterone causes hyperplaisa of prostate

• Involvement of adrenergic nerves in prostatic hyperplasia.

• Cytokines derived from inflammatory cells also induce epithelial growth factors

Summary

Diagnosis

• History • Assessment of symptoms and QOL• Physical Examination• Urine Analysis• Uroflowmetry• PVR• PSA• Prostate Ultrasound• Case Sensitive and Elective– bladder diary, pressure-flow studies, serum creatinine

measurements,and ultrasonography of the upper urinary tract.

Severity Index

Current treatment options

• Conservative treatment • Alpha blockers • 5-alpha-reductase inhibitors (5ARIs) • Combination therapy • Phytotherapy • Minimally invasive techniques • Surgery

Goal of treatment

• Relieving LUTS• Decreasing BOO• Improving bladder emptying• Ameliorating overactive bladder activity• Reversing renal insufficiency• Preventing disease progression

Efficacy index

Watchful waiting

• Patient selection• Education,• Reassurance,

• Periodic monitoring,• Lifestyle advice

Watchful waiting

• Patient selection• Education,• Reassurance,

• Periodic monitoring,• Lifestyle advice

Life Style Advice

• Reduction in fluid intake • Avoidance of moderation of caffeine and alcohol• Double voiding technique• Urethral stripping• Distraction- mind out of bladder n toilet• Bladder retraining- Hold on• Optimising drugs• Treatment of constipation

Treatment Goals of Medical Therapy

Alpha – Blocker1a, 1b, 1d

Pharmacotherapy• Non selective alpha blockers– Phenoxybenzamine

• Selective short acting (alpha 1) – Prazosin, Alfuzosin, Indoramin

• Selective long acting (alpha1, all three type)– Terazosin, Doxazosin, Alfuzosin SR

• Partially subtype (alpha 1a)– Tamsulosin, Sildosin

• Partially subtype ( alpha 1d)– Naftopidil, Tamsulosin

Drug Saftey

• Asthenia• Diziness• Nasal congestion• Postural hypertension• Co-medication• anejaculation• Intraoperative floppy iris syndrome– Miosis, iris billowing, iris prolapse

α-blockers should be offered to men with moderate to severe LUTS.

• a1-adrenoceptor antagonists can result in a 16–25% (2.0–2.5 mL/s) increase in maximum flow rate and a 30–40% (4–6 point) reduction in the average IPSS.

5 alpha Reductase inhibitor

Dutasteride

Dutasteride

Finasteride

Prostatevolumereduced

Bartsch G et al. Eur Urol. 2000;37:367380.

DHTTestosterone

Type II 5AR

Type I 5AR

Clinical role of dual inhibition remains unclear

Reduce LUTS (IPSS) by approximately 15-30%,Decrease prostate volume by 18-28% andIncrease Qmax by 1.5-2.0 ml/sPSA dec by 50%Dec hematuriaInc apoptotic index of stromal and epithelial cellDec detrusor pressure at Qmax

Proscar Long-Term Efficacy and Safety Study (PLESS)

Terazosin lowered the symptom score and increased the peak urinary flow rate when compared with placebo.

Finasteride alone was no better than placebo.

The combination of finasteride and terazosin was no better than terazosin alone.

• In the Veterans Affairs Cooperative Study, 1229 men with BPH (mean peak urinary flow rate of 10.5 mL/sec) were randomly assigned to placebo, finasteride (5 mg/day), terazosin (10 mg/day), or both for one year

Combination Therapy &Short term Efficacy

• PREDICT trial in which 1095 men were randomly assigned to doxazosin, finasteride, or both for one year – Doxazosin was more effective than finasteride or

placebo for urinary symptoms and flow rate, but again, the combination was no more effective than doxazosin alone

Combination Therapy &Long Term Efficacy

Medical Therapy of Prostatic Symptoms (MTOPS) trial, in which 3047 men with BPH were randomly assigned to receive doxazosin, (4 to 8 mg/day), finasteride (5 mg/day), combination therapy, or placebo

CombAT vs MTOPSClinical progression CombAT MOPTS

Overall risk of disease progression %

66 44

Symptomatic progression %

64 41

AUR % 81 68

Urinary incontinence % 65 26

BPH related surgery % 67 71

Anticholinergic and OAB with BPH

• 75% of clinical BPH have concomitant urodynamic detrusor overactivity

• In concomitant BPH and DO, 65% have inadequate symptoms control

• 19% have persistent OAB symptoms after TURP

• Recurrence of OAB symptoms after TURP in long term mean follow up of 12.6 years .

Anitcholinergic agents

Anticholinergic - M1 , M3 receptor • Adverse effect

– Dry mouth (up to 16%),– Constipation(up to 4%),– Micturition difficulties (up to 2%)– Nasopharyngitis (up to 3%), – And dizziness (up to 5%).– Disorientiation, hallucination, convulsion– hyperthermia

• Contraindications– Myasthenia gravis– Glaucoma– Significant bladder outflow obstruction– Urinary retention– Severe ulcerative colitis– Gastrointestinal obstruction– Hypethyroidism– CAD– CCF

Alpha blocker n Anticholinergic

• Reducing voiding frequency, nocturia, or IPSS compared to α-blockers or placebo alone.

• Reduce urgency urinary incontinence episodes as well as urgency and significantly increased QoL

Plant Extract- Phytotherapy

• Have anti-inflammatory, antiandrogenic, or oestrogenic effects

• Decrease sexual hormone binding globulin (SHBG)

• Inhibit aromatase, lipoxygenase, growth-factor stimulated proliferation of prostatic cells

• Α-adrenoceptors, 5α-reductase, muscarinic cholinoceptors, dihydropyridine receptors, or vanilloid receptors

• Improve detrusor function

• Neutralize free radicals .

Phytotherapeutic agents

Conclusion from systemic reviews

• The plant extract beta-sitosterol improved symptoms

• Cernilton, which is prepared from the rye grass pollen, Secale cereale, has been evaluated in four clinical trials – It improved symptoms, but did not affect urinary flow rates or

residual urine or prostate volume.

• Pygeum africanum is an extract of bark from an African plum tree. – In a meta-analysis of 18 randomized controlled trials, active

treatment improved symptoms two times more frequently than placebo and increased peak urinary flow rates 23 percent

Desmopression (v1, v2 receptor)

• Desmopressin significantly reduced nocturnal diuresis by approximately 0.6-0.8 ml/min (-40%)

• Decreased the number of nocturnal voids by approximately 0.8-1.3 (-40%)

• Extended the time until the first nocturnal void by approximately 1.6 hours

• Reduced night-time urine volume as well as the percentage of urine volume excreted at night

• headache, nausea, diarrhoea, abdominal pain, dizziness, dry mouth, and hyponatraemia.

• Peripheral oedema (2%) and hypertension (5%)

Practical Consideration• Desmopressin should be taken once daily before sleeping.

• desmopressin treatment should be initiated at a low dose (0.1 mg/day)

• The maximal daily dose recommended is 0.4 mg/day.

• Patients should avoid drinking fluids at least 1 hour before using desmopressin until 8 hours thereafter.

• In men aged 65 years or older, desmopressin should not be used if the serum sodium concentration is below the normal value.

• In all other men aged 65 years or older, serum sodium concentration should be measured at day 3 and 7 as well as after 1 month and, if serum sodium concentration has remained normal, every 3-6 months subsequently.

Nitric Oxide

cGMP

activate protein kinases, ion channels, and cGMP-binding phosphodiesterases

Calcium depletion

Smooth muscle relaxation

PDE5 hydrolyses

guanylyl-cyclase

PDE- INHIBITORS

Newer AgentsPhosphodiesterase inhibitors

mean Qmax increase 3.7-4.3 mLs or 24-38%

reduced IPSS by approximately 17-35%

Side Effects of PDE5 inhibitors

• Headache, flushing, dizziness, dyspepsia, nasal congestion, myalgia,

• Hypotension, syncope, tinnitus, conjunctivitis, or altered vision (blurred, discoloration).

• Priapism or acute urinary retention is considered minimal.

New Trials• Several new drugs are currently under clinical investigation (phase

II-III trials) of which none has been licensed for male LUTS so far. These new drugs target:

– the prostate, e.g. gonodotrophin-releasing hormone antagonists, oestrogen receptor antagonists,• Chlormadinone/allylesternol• Zanoterone/Flutamide

– apoptosis-inducing agents, vaccines, vitamin D agonists, or androgen replacement therapies;

– the bladder, e.g. β3-adrenoceptor agonists;

– the nervous system, e.g. neuromuscular blocking agents, tachykinin receptor antagonists.

Is bladder diary recommended?

USG is recommended for the anatomical evaluation of Prostate

Evaluation of upper urinary tract

Is long-term therapy with a1-adrenoceptorantagonists recommended?

Approximately 18, 64, and 36–80% of patients withdrew from the studies after2, 3, and >4 years, respectively.

What urodynamic test is recommended for menundergoing surgical treatment for BPH?

What foods and dietary habits are recommended for patients with BPH?

Is a reduced alcohol intake recommended in patients with BPH

What treatments are recommended for urinary retention by BPH?

What therapeutic strategies are recommended to avoid sexual dysfunction

as an adverse event?

Referal for Surgical therapy

• Symptom assessment• Duration of therapy• Disease progression• Complication• Follow up• Cost effectiveness

AUA GUIDELINES

References

• JUA clinical guidelines for benign prostatic hyperplasia

• EUA guidelines for LUTS• AUA Guidelines• Campbell Urology- 9th edn