urology ppt

1. MEDICAL MANAGEMENT OF BPH
DR ANCHAL,DNB RESIDENT UROLOGY
MMHRC

2. 2
What is the pathology of BPH?
• Hyperplastic process
• Earliest sign : micronodule formation in transitional
zone – lateral lobes (mixture of stromal cell and
epithelial component) and in periurethral region –
median lobe within the smooth muscle collar of the
preprostatic sphincter (mainly connective tissue)
• Further coalescence and growth of micronodule
become macronodule

3. 3
Pathophysiology of BOO
• BOO cause thickening of bladder wall
• High intra-renal pressure  hydronephrosis
• Impair renal function & even renal failure
• Microscopic:
– Smooth muscle cell enlarged
– Increase in connective tissue (collagen and elastin) btw SM bundles
– Lead to poor compliance
• BOO also cause bladder overactivity
– Prolong increase intravesicle pressure during voiding
– Ischemia of bladder wall
– Damage to neurons within the bladder (denervation)

4. 4
Some clinical definition
• LUTS: Lower urinary tract symptom:
– Non-specific terms for symptom which may be attributable to lower
urinary tract dysfunction
– Storage LUTS (Frequency, Urgency, Nocturia)
– Voiding LUTS (Hesitancy, Straining, Slow stream, intermittency,
terminal dribbling, sense of incomplete voiding)
• BOO: Bladder outflow obstruction
– Urodyanmical diagnosis of an obstruction to passage of urine
• BPE: Benign prostate enlargement:
– Clinical finding of an enlarged prostate
• BPH: Benign prostatic hyperplasia:
– Histological basis of BPE leading to BOO that result in LUTS
• BPO: Benign prostatic obstruction:
– BOO cause by BPE

5. 5
Differential Diagnosis of LUTS
• Prostate1
– Obstruction (BPH, BPE, BOO) (30%)
• Bladder1
– Detrusor overactivity (50%)
– Impaired detrusor contractility (30%)
– Sensory urgency
– Sphincteric incontinence
– Polyuria/nocturnal polyuria
• Medications2
– Antihistamines
– Antidepressants
1. Chaikin DC, Blaivas JG. Curr Opin Urol. 2001;11:395-398. 2. Su L et al. J Clin Epidemiol. 1996;49:483-487.

6. 6
What are the different instrument for
measurement of LUTS in men?
• DAN (Danish Prostate Symptom Score)
• Bristol Male LUTS
• AUA
• IPSS
– Derived from AUA + 1 more QOL question
– Most commonly used
– Valid , Reliable and reproducible

7. 7
IPSS
• 7 Question + 1 QOL
• How often do you experience:
– Voiding: Straining , intermittency, slow stream, sense of incomplete voiding
– Storage: Nocturia (times), Frequency (<2 hr) , Urgency
• Frequency:
– not at all 0
– <1/5 : 1
– <1/2 2
– ½ : 3
– > ½ : 4
– all the time : 5 (except nocturia)
• 0-7 mild; 8-19 moderate, 20-35 severe
• QOL: 0:delighted > 6:terrible
• Reliable, reproducible and valid

8. 8

9. 9

10. 10
Barry et al J Urol 1995
• A 3-point absolute drop in IPSS is required for
the patient to perceive as improvement
• The required drop in score is greater in those
with higher baseline IPSS

11. 11
Any drawbacks of IPSS?
• Drawbacks
– Does not make a diagnosis, just a symptom score
– Not prostate / BPH specific – females / patients
with CPPS can have an IPSS score

13. 13
Treatments for LUTS, BPH, BOO
• Watchful waiting
• Medical therapy
– 5-reductase
inhibitors
– -blockers
– Combination therapy
– Phytotherapy
• Office-based treatment
– TUMT
– TUNA
– WIT
• Surgicenter/
hospital-based treatment
– TURP (gold standard)
– TUIP
– Open surgery
– TUVP
– ILC
– VLAP
– Prostatic stents

14. 14
What are the important factors in
treatment of LUTS/BPH??
Degree of bothersome
Risk of progression

15. 15
What is the treatment option of WW?
• Mild to moderate LUTS
• Moderate to severe symptoms without bothering
• Components for WW
– Reassurance, education and explanation to patients
– Lifestyle advice : esp for storage LUTS
• Reasonable fluid intake, timed voiding
• Reduction of fluid before bedtime (nocturia)
• Avoidance of caffeine and alcohol
• Avoiding medications like antihistamine
• Double voiding and urethral milking (sense of incomplete voiding
and post-micturition dribble)
• Distraction technique for irritative LUTS
• Avoid constipation
– Periodic reevaluation with SS, UFR and PVR to check for
Progression

16. 16
What is the evidence of WW?
• Option for many men as few, if left untreated,
will progress to acute urinary retention and
complications
• Some men’s symptoms may improve
spontaneously, while others’ symptoms
remain stable for many years
• IPSS in Placebo group from PLESS study even
decrease 1.3 after 4 years

17. 17
What is the evidence of WW?
• Ball study (AJ Ball, P Abrams et al, BJUI 1981)
• 100 men with LUTS FU 5 yrs
– 25% get better, 30% get worse, 40% same
• 2% AUR, 10% require surgery

18. 18

19. Alpha blockers 5-Alpha reductase inhibitors
19
BPH – Medical Therapy
Improve symptoms
and increase urinary
flow rate by relaxing
prostatic and bladder-neck
smooth muscle
through sympathetic
activity blockade
Improve symptoms,
increase urinary flow rate,
and prevent BPH
outcomes by reducing
prostate enlargement
through hormonal
mechanisms
Adapted from Roehrborn CG Curr Opin Urol 2001;11:17-25; National Cancer Institute. NIH Publication No. 99-4303, 1999.

21. 21
• Mechanisms
– Relaxation of the dynamic smooth muscle component in the stroma of
the prostate via competitive antagonism at the A1R
– Reduce prostate tone and bladder outlet obstruction
• It has been shown that α-blockers have little effect on urodynamically
determined bladder outlet resistance
– For female bladder neck, not supplied by adrenergic nerves
• So other proposed mechanisms
– Induction of apoptosis
• Doxazosin and terazosin have been shown in vitro to induce
apoptosis in prostate cells independent of the A1R (but contrary to
this is the lack of change in size of the prostate seen clinically)
• By working at extraprostatic sites
– Detrusor (by increasing blood flow)
– Spinal cord ?

22. 22
Djavan
• Meta-analysis 1999 of AARB [EU]
– Response rate : 30-40%
– Reduce SS by 30% (4pt)
– Improves Qmx by 16-25%
• All alpha·1-adrenoceptor antagonists (alfuzosin, terazosin,
doxazosin and tamsulosin) produce comparable
improvements in LUTS and urinary flow
• Max effect at ~4weeks
• No reason to prolong for more than 1 month if not efficacious
• 1/3 of men will not experience SS reduction

23. 23
Summary
Terazosin Doxazosin Alfuzosin Tamsulosin
Qmax rise 0.6-2 1.4-3.5 1.3 1.3-1.7
SS drop 1-2.3 2-4 1.6 2.3-3.2

24. 24
How many types of Alpha 1
receptors are you aware of?

25. 25
Alfa1-adrenoceptor (AR)
• Mediate prostates smooth muscle contraction
• Alpha 1 receptor (A1R) can be divided, based on molecular cloning and in
vitro studies
– High affinity for prazosin :
• A1aR, A1bR and A1dR
– Low affinity for prazosin :
• A1LR (may represent a functional phenotype of A1aR)
– A2R
• All three high affinity types have been demonstrated in the prostate stroma
(influence of SM tone)
– 70% predominance A1aR
• Inferred that dynamic component of the prostate smooth muscle is via
activation of the A1aR but the contribution of the other subtypes are not
clear

26. 26
AARB : Summary
• Rapid relief of symptoms and improvement of flow
rate (days)
• Effective regardless of prostate size3
– Reduces symptoms equally well in patients with
and without BOO
• Effective irrespective of patient symptom (mild ,
moderate or severe)
• Effective across all age group
• Do not reduce prostate size
• Do not prevent AROU

27. 27
Summary: -Blockers
• All alpha-blockers seen to have similar efficacy in improving
symptoms and flow
• Tamsulosin has less effect on blood pressure than alfuzosin
(especially in elderly patients) and causes less symptomatic
orthostatic hypotension
• Tolerability of alfuzosin and tamsulosin is similar and better
than other agent
• Benefit of alfa1-AR has shown to be better than placebo and
finasteride in men with LUTS by RCT
• Low risk of morbidity2
• Differences between agents with regards to
– Cardiovascular side effects
– Sexual side effects: more retrograde Ejaculation in
Tamsolusin
– More vasodilatory SE with alfulzosin

28. What are the side effects of AAR?
28

29. What are the side effects of AAR?
29
1. Asthenia, dizziness – 10%
2. Postural hypotension (1%)
– doxazosin and terazosin > alfuzosin and tamsulosin
3. Impotence (5-8%)
4. Retrograde ejaculation (8%)
– 1% with doxazosin, terazosin, alfuzosin (Djavan)
– 4% with tamsulosin 0.4mg (Djavan) – more
5. Rhinitis
– Tamsulosin
• In studies, up to 30% withdraw because
– Lack of efficacy
– Adverse effects

30. 30
What is IFIS?
• Intraoperative floppy iris syndrome
• First reported in 2005 in cataract surgery among
patients taking tamsulosin
Chang DF, Campbell JR. Intraoperative floppy-iris syndrome associated with tamsulosin (Flomax). J
Cataract Refract Surg 2005; 31:664–673
• Triad of intraoperative findings during cataract
surgery
1. Poor preoperative pupil dilation
2. Iris billowing and prolapse
3. Progressive intraoperative myosis

31. 31
How does 5ARI work?

32. 32
Two types of 5AR (testosterone to DHT)
• Type 1 : predominance in extraprostatic tissue (skin,
liver), role in BPH remains unclear
• Type 2 : predominance in prostate but also expressed
in extraprostatic tissue, for prostatic growth,
development and hyperplasia process
• Testosterone: DHT in prostate is 1:5
• Causes apoptosis and atrophy of the epithelial part
of the prostate
• Reduce the “static” component of BPH
• Prostate size reduction: 20-25%
• PSA level: ½ after 6-12m of treatment

33. 33
What is the result of dutasteride VS
finasteride?
• Finasteride: Type II inhibitor (5mg)
• Dutasterdie : Type I & II inhibitor (0.5mg))
• Both reduce prostate DHT concentration by
90%
• Indirect comparison between individual
studies and one unpublished direct
comparative trial indicate that dutasteride and
finasteride are equally effective in the
treatment of LUTS

34. 34
What are the indications of
5ARIs?

35. 35
Indications
• Men with LUTS and an enlarged prostate (> 40cc)
• Boyle meta-analysis of RCTs concluded that finasteride only
be useful if prostate gland > 40cc
• Those with risk for progression – PLESS and MTOPS can
reduce progression
• Effective treatment for refractory hematuria due to prostate
bleeding
– Suppression of VEGF
– Insufficient data to use 5AR before TURP to reduce bleeding

36. 36
What is the efficacy of 5ARIs?

37. 37
• PLESS [MaConnell NEJM 1998]
• 4 yrs of 5 AR Inhibitors vs placebo
– Increase of Qmax 1.9ml/s (placebo 0.2)
– Decrease in SS by ~3 (placebo 1.3)
– Reduce risk of AUR by ~60% (5% vs 10%)
– Reduce risk of BPHRS by ~60% (3% vs 7%)
– Reduce prostate size by 20% (vs 15% in placebo)
• AUA
– Less effective in improving LUTS than alpha-blocker

38. 38

39. 39
EAU
• Only suitable for long term treatment
• After 2-4 yr of treatment:
– Reduce symptom score by 15%
– Reduce prostate volume: 20-25%
– Increase Qmax: 2ml/s
• Symptom reduction not better than placebo if prostate size <
40cc
• Dutasteride reduce IPSS, prostate volume & AROU and
increase Qmax even if prostate 30-40cc
• Reduce symptom slower than AARB
• Reduce risk of AROU better than AARB
• Reduce blood loss during TURP (decrease vascularization)
• High PSA & large prostate seems to be most
beneficial

40. 40
What are the side effects

41. 41
PLESS
• Decreased libido 6%
• ED 8%
• Ejaculate disorder (retrograde, failure , decrease
semen volume) 4%
• Rash, breast enlargement, tenderness1%
• Most of these occur during the 1st yr and does not
increase over time
• But leads to withdrawal from PLESS in 30%

42. 42
How does 5ARI affect PSA and does
that mask the early detection of
prostate cancer?

43. 43
EAU
• 5ARI lower the PSA by ~50% after 1 yr.
• Both the PLESS Study Group & Finasteride PSA
study Group (Andriole Urology 1998 and
Oesterling Urology 1997) have verified that :
• doubling the PSA value after taking finasteride
allows appropriate interpretation of PSA and 5ARI
does not mask the detection of prostate cancer.
• Histologically it has also been shown that 5ARI
does not cause problems with interpretation of
TRUS Bx (PLESS study Group Yang Urology 1999)

44. 44
What are the role of
antimuscarinics?

45. 45
What are muscarinic receptors?
• Five muscarinic receptor subtypes (M1-M5) have been
described in humans, of which the M2 and M3 subtypes are
predominantly expressed in the detrusor
• Although approximately 80% of these muscarinic receptors
are M2 and 20% M3 subtypes, only M3 seems to be involved
in bladder contractions in healthy humans
• The role of M2 subtypes remains unclear. However, in men
with neurogenic bladder dysfunction and in experimental
animals with neurogenic bladders or bladder outlet
obstruction M2 receptors seem to be involved in smooth
muscle contractions as well

46. 46
How dose bladder contraction mediated?
• Scaral (S2-4) micturition centre connet to
bladder via pelvic nerves
• Acetlcholine stimulate post-synaptic
muscarinic receptor  G-protein mediated Ca
release  opening of Ca channels  SM
contraction
• Anticholinergic inhibitsmuscarinic receptor
stimuation  reduce SM cell contraction

47. What is the use of antimuscarinic in BPH?
47
• Muscarinic receptor antagonists might be
considered in men with moderate to severe
LUTS who have predominantly bladder
storage symptoms
• This drug should be used precautiously if
residual urine >250-300ml

48. What is the evidence of Antimuscarinic vs
48
Placebo?
• Randomized, placebo-controlled trials
demonstrated that Tolterodine can
significantly reduce:
1. Urgency incontinence
2. Daytime or 24-hour frequency
3. Urgency related voiding
– Roehrborn et al, et al. Extended-release tolterodine with or without
tamsulosin in men with lower urinary tract symptoms and overactive
bladder: effects on urinary symptoms assessed by the International
Prostate Symptom Score. BJU Int. 2008 Nov;102(9):1133-9. Epub
2008 May 26.

49. 49
What is the evidence of antimuscarinic?
• If treatment outcome was stratified by PSA,
tolterodine significantly reduced daytime frequency,
24h voiding frequency and IPSS storage symptoms in
those men with PSA concentrations below 1.3 ng/mL,
which was not the case in men with PSA of 1.3
ng/mL or more indicating that men with smaller
prostates might profit more from antimuscarinic
drugs
– Roehrborn CG, Kaplan SA, et al. Effects of serum PSA on efficacy of tolterodine extended
release with or without tamsulosin in men with LUTS, including OAB. Urology 2008
Nov;72(5):1061-7

50. 50
Urodynamic effect of Antimuscurinic
• Larger bladder volume to first detrussor
contraction
• Decrease bladder contractility index
• Qmax is unchange

51. 51
What are the side-effects of
antimuscarinic?
1. Dry mouth - 25%
2. Constipation (4%) similar to placebo
3. AROU and increase of postvoid residual urine in
men without bladder outlet obstruction is minimal
and not significantly different compared to placebo
4. Nasopharyngitis (3%)
5. Dizziness (5%)
6. Withdrawal rate – 10%
– Withdrawal due to side-effect <1% (no diff from placebo)

52. 52
Will it cause retention?
• Increase PVR is minimal and no different from
placebo
• Fesoterodine 8mg show higher PVR than
fesoterodine 4mg or placebo
• Incidence of AROU is comparable to placebo
• Men with BOO : not recommended due to
theoretical risk
• Generally recommend that not for PVR > 200ml and
Qmax < 5ml/s

53. 53

54. 54
What are the studies : antimuscarinics +
AARB?
TIMES JAMA2006
• LUTS +OAB, no prior Rx
• Tolterodine SR (Tsr) + tamsulosin (T) ,either therapy, placebo
• Tsr +T in general more efficacious than either one
• Tsr = Tsr +T in low PSA and small prostate
• Tsr +T suggested for high PSA and high prostate vol
• Exclude PVR > 40% of CC
• Conclusion: Combination therapy is more efficacious then mono therapy ,
esp in pt with high PSA + prostate volume

55. 55
ADAM Pfizer data
• On alpha1 blockers with persistent OAB
• Randomized to continue alpha-1-blockers with Tsr or placebo
• Conclusion: Pt on AARB with persistent OAB will
have improved sym when adding Tsr

56. 56
What are the recommendations of
combination therapy?
• Combination treatment with α-blocker and
muscarinic receptor antagonist might be considered
in patients
– with moderate to severe LUTS if symptom relief has been
insufficient with the monotherapy of either drug
– More effacicious with pt with high PSA + prostate volume
• Combination treatment should cautiously be
prescribed in men who are suspicious of having
bladder outlet obstruction

57. 57
What phytotherapeutic agents
are you aware of?

58. 58
Is there any role of phytotherapy?
• EAU Guidelines committee is unable to make
specific recommendations about
phytotherapy of male LUTS because of the
heterogeneity of the products and the
methodological problems associated with
meta-analyses

59. 59
Phytotherapy
• Saw Palmetto berry (Seronoa Repens)
– Anti-inflammatory , antiproliferative , oestrogenic drug
with 5ARI activity
– Previous Meta-analysis : 40% reduction in symptom score
(same as finasteride) [ Wilt JAMA 1998]
– Recent study: no difference vs placebo (see below)
• South African Star Grass (Harzol)
– Contain beta-sitosterol
– Cause apoptosis in prostate stromal cell
– RCT vs placebo: 5pt improvement of SS over placebo
• Others: African plum (Pygeum Africanum)

61. What is the evidence of Saw Palmetto for BPH?
61
• Mode of action is unknown
• Double-blind trial, randomly assigned 225 men > 49yo
• Moderate-to-severe symptoms
• One year of treatment : saw palmetto (160 mg BD) or placebo
• Result: There was no significant difference in
1. Change in AUASI scores
2. Qmax
3. Prostate size
4. Residual volume after voiding
5. Quality of life, or serum prostate-specific antigen levels
6. The incidence of side effects was similar in the two groups
• Conclusions: In this study, saw palmetto did not improve symptoms or
objective measures of benign prostatic hyperplasia
N Engl J Med 2006;354: 557-66

62. 62
Desmopressin

63. 63
What is the role of desmopressin?
• Indication: Nocturia with a polyuric background
• MOA:
– Synthetic analogue of vasopressin
– Anti-diuretic effect: increase water re-absorption & urine osmolality,
decrease water excretion & urine volume
– Only V2 affinity: No V1 effect (HT , vasoconstriction)
– Effect of reduce urine volume last 8-12 hour
• Form: IV, Nasal spray , tablet, MELT
• Dosage:
– Initiated at a low dose (0.1 mg/day) PO nocte
– Gradually increased every week until maximum efficacy is reached
– The maximal daily dose recommended is 0.4 mg/day
• Usage:
– Patients should avoid drinking fluids at least 1 hour before using
desmopressin until 8 hours thereafter

64. 64
• Effect:
– Reduced nocturnal diuresis : 1ml/min
– Reduced number of nocturia: 2x /night
– Extend time to first nocturia by: 1.6 hour
– Reduce % of urine volume excreted at night
• Side effect:
– Headache, naeusea, diarrhoea, abd pain , dizziness , dry mouth
– Hypo Na (< 130mmol/L) (5%)
– Peripheral edema & HT
• Cautions:
– Risk of Hypo Na is 8x in pt > 65yo
– 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

65. 65
PDE5 inhibitor

66. 66
LUTs and ED
• ED and LUTs strongly linked
• both highly prevalent in aging men
• co-prescription of both drugs likely to increase
• PED5-i: increase concentration of cGMP  reduce
SM tone of detrussor , prostate and urethra

67. 67
• Risk of combination therapy:
– Tadalafil : singificant drop of BP with doxazosin , hence to ↓ BP effect,
suggest alfuzosin/ tamsulosin to combine with PDE5i
– sildenafil should not be used in doses exceeding 25 mg within 4 h of
taking an α1-AR antagonist
– Tamulosin → dose dependent anejaculation
• AARB on ED:
– Would not worsen ED
– Cardura XL & Alfulzosin may improve IIEF
• Combination Tx
– Pilot study n=62 with untreated LUTS and ED
– Randomized to alfuzosin 10mg QD, Viagra 25mg QD, or both for 12
weeks.
– IPSS improvement -24% for combination (-16% for alfuzosin/ -17% for
Viagra)
– IIEF improvement +59% for combination (+17% for alfuzosin/ +50% for
Viagra)
– Combination well tolerated with no serious adverse events

68. 68
What is the practical consideration of
PDE5 inhibitor?
• PDE5 inhibitors reduce moderate to severe male
LUTS but on effect on Qmax
• Officially licensed only for the treatment of erectile
dysfunction and pulmonary arterial hypertension
• Treatment beyond this indication (e.g. male LUTS) is
still experimental and should not be used routinely in
the clinical setting
• Long-term experience in patients with LUTS is still
lacking

69. 69
What is the evidence of
combined therapy?
MTOPS
COMBAT

70. 70
Combination Therapy: Rationale
• 5ARIs and -blockers have complementary actions
– 5ARIs act on the hormonal axis
– -blockers act on the adrenergic receptors
• Main reported effects
– -blockers induce rapid symptom and flow
rate improvement
– 5ARIs reduce risk of progression to AUR or
BPH-related surgery

71. 71
Indications
• Men with moderate to severe LUTS
• Risk of disease progression (large prostate,
High PSA, Advance Age, etc)
• Only be used with long-term treatment (>12m)
is intended
• Discontinuation of AARB after 6m might be
consider in men with moderate LUTS

72. 72
Major combination therapy trials
1. VA study Lepor H et al. N Engl J Med. 1996 Aug 22;335(8):533-9.
2. PREDICT Kirby RS et al. Urology. 2003 Jan;61(1):119-26
3. MTOPS McConnell JD et al. N Engl J Med. 2003 Dec 18;349(25):2387-98
4. CombAT Roehrborn CG et al. J Urol 2008;179(2):616-21
• But 1. 2. only look at symptom improvement, no
monitoring progression
• Both only 1 yr Fu
• Also smaller prostate size

73. 73
MTOPS: Conclusion
1. Doxazosin, Finasteride and the combination all reduce the risk
of overall clinical progression. Combination more effective
than either drug alone
2. In reducing symptom score rise, combination therapy more
effective than monotherapy
3. In reducing risk of AUR and the need for BPH related surgery,
combination and finasteride equally effective
4. Doxazosin slightly delays the the time to AUR and BPH related
surgery but failed to reduce the risk of these of events over
the duration of the study
5. Combination resulted in greater improvement in AUA-SS and
Qmx than monotherapy alone

74. 74
Combination therapy (dutasteride +
tamusulosin) can
• Reduce AUR /BPHRS:
– Better than tamsulosin but not dutasteride
• Reduce BPH clinical progression/ IPSS:
– Better than both monotherapy
• Improves patient-record , disease specific QoL &
treatment satisfaction:
– Better than both monotherapy
• Controlling both storage & voiding symptoms:
– Better than both monotherapy
– Dutasteride can improve voiding symptom as from effect
of prostate volume , but also as effective as alfa-blocker in
the control of storage symptoms

75. 75

76. 76

77. 77

79. THANKS