Approach and management of Benign enlargement of Prostate and recent advances

1. MEDICAL MANAGEMENT OF LUTS/BPH
&
RECENT ADVANCES
Bikash Bk. Thapa
MS – General Surgery

2. Introduction

3. 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

4. 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.

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

6. Role of Androgen

7. 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

8. Summary

9. 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.

10. Severity Index

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

12. Goal of treatment
• Relieving LUTS
• Decreasing BOO
• Improving bladder emptying
• Ameliorating overactive bladder activity
• Reversing renal insufficiency
• Preventing disease progression

13. Efficacy index

14. Watchful waiting
• Patient selection
• Education,
• Reassurance,
• Periodic monitoring,
• Lifestyle advice

15. Watchful waiting
• Patient selection
• Education,
• Reassurance,
• Periodic monitoring,
• Lifestyle advice

16. 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

17. Treatment Goals of Medical Therapy

18. Alpha – Blocker
1a, 1b, 1d

19. 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

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

23. 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.

24. 5 alpha Reductase inhibitor
Dutasteride
Finasteride
Type II 5AR
Testosterone DHT
Dutasteride
Prostate
volume
reduced
Type I 5AR
Bartsch G et al. Eur Urol. 2000;37:367380.

25. Clinical role of dual inhibition remains
unclear
Reduce LUTS (IPSS) by approximately 15-30%,
Decrease prostate volume by 18-28% and
Increase Qmax by 1.5-2.0 ml/s
PSA dec by 50%
Dec hematuria
Inc apoptotic index of stromal and epithelial cell
Dec detrusor pressure at Qmax

26. Proscar Long-Term Efficacy and Safety Study (PLESS)

29. Combination Therapy &
Short term Efficacy
• 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
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.

30. • 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

31. Combination Therapy &
Long Term Efficacy

33. 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

34. CombAT vs MTOPS
Clinical 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

35. 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 .

36. Anitcholinergic agents

37. 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

38. 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

39. 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 .

40. Phytotherapeutic agents

41. 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

43. 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

44. • headache, nausea, diarrhoea, abdominal pain,
dizziness, dry mouth, and hyponatraemia.
• Peripheral oedema (2%) and hypertension (5%)

45. 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.

46. Nitric Oxide
cGMP
activate protein kinases, ion
channels, and cGMP-binding
phosphodiesterases
Calcium depletion
Smooth muscle relaxation
guanylyl-cyclase
PDE5 hydrolyses
PDE- INHIBITORS

47. Newer Agents
Phosphodiesterase inhibitors
mean Qmax increase 3.7-4.3 mLs or 24-38%
reduced IPSS by approximately 17-35%

48. 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.

49. 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.

52. Is bladder diary recommended?

53. USG is recommended for the
anatomical evaluation of Prostate

54. Evaluation of upper urinary tract

55. Is long-term therapy with a1-adrenoceptor
antagonists recommended?
Approximately 18, 64, and 36–80% of patients
withdrew from the studies after2, 3, and >4 years,
respectively.

56. What urodynamic test is recommended for men
undergoing surgical treatment for BPH?

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

58. Is a reduced alcohol intake recommended
in patients with BPH

59. What treatments are recommended for
urinary retention by BPH?

60. What therapeutic strategies are
recommended to avoid sexual dysfunction
as an adverse event?

62. Referal for Surgical therapy
• Symptom assessment
• Duration of therapy
• Disease progression
• Complication
• Follow up
• Cost effectiveness

63. AUA GUIDELINES

64. References
• JUA clinical guidelines for benign prostatic
hyperplasia
• EUA guidelines for LUTS
• AUA Guidelines
• Campbell Urology- 9th edn