Medical management of bph

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. Abundant in the prostate and base of the bladder, and sparse in the body of the bladder alpha-1A subtype 70 percent of adrenoreceptors in prostate tissue alpha-1B receptors prevalent in smooth muscle of the vasculature alpha-1D subtype less than 30 percent of prostatic adrenoreceptors and are located in prostatic stromal elements detrusor muscle of the bladder, bladder neck, and the sacral region of the spinal cord

20. 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

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

22. 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.

23. 5 alpha R eductase inhibitor Dutasteride Dutasteride Finasteride Prostate volume reduced Bartsch G et al. Eur Urol . 2000;37:367 380. DHT Testosterone Type II 5AR Type I 5AR

24. C linical 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

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

26. 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

27. 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

28. Combination Therapy & Long Term Efficacy

29. 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

30. Result of MTOPS Study The risk of overall clinical progression was reduced to a similar degree by doxazosin  and finasteride  (39 and 34 percent, respectively, when compared to placebo). Combination therapy reduced the risk of clinical progression by 66 percent, significantly greater than with either drug alone. Symptom scores improved with all therapies, but to a greater degree with combined therapy.

31. Combination therapy or finasteride  alone (but not doxazosin  alone) reduced the risk of acute urinary retention and the need for invasive therapy. The number needed to treat to prevent one instance of overall clinical progression was 8.4 for combination therapy, 13.7 for doxazosin , and 15.0 for finasteride . Adverse effects were similar with combination therapy and monotherapy , with the exception of abnormal ejaculation, peripheral edema, and dyspnea , which were more common with combination therapy. Breast cancer risk was not increased in the finasteride -only or combination therapy groups.

32. 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

33. 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 .

34. Anitcholinergic agents

35. Practical consideration Predominantly irritative symptoms Caution with PVR > 250 to 300 ml Preop PVR is done

36. 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

37. 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

38. 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 , 5 α- reductase , muscarinic cholinoceptors , dihydropyridine receptors, or vanilloid receptors Improve detrusor function Neutralize free radicals .

39. Herbal therapies for BPH are commonly used in Europe; these remedies comprised 70 percent of spending for drug treatment of prostatism in Germany in 1997 [ 58 ]. Saw palmetto is approved by the German Commission E for stage I and II (mild to moderate) BPH. Two herbal extracts have officially been approved for the treatment of prostatism in France. No herbal therapies have been approved by the United States Food and Drug Administration for this purpose,

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

42. 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

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

44. 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.

45. PDE5 hydrolyses guanylyl-cyclase PDE- INHIBITORS

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

47. 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.

48. contraindicated in patients using nitrates or the potassium channel opener nicorandil, due to additional vasodilatation should not be used in patients who are taking the α-blockers doxazosin or terazosin , have unstable angina pectoris retinitis pigmentosa

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.

50. Is bladder diary recommended?

51. USG is recommended for the anatomical evaluation of Prostate

52. Evaluation of upper urinary tract

53. 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.

54. There are eight long-term studies (over 3 years; range 4–10 years) for the treatment of a1-adrenoceptor antagonists in the literature.307–314 During follow-up, approximately 18, 64, and 36–80% of patients withdrew from the studies after2, 3, and >4 years, respectively. The reasons for their withdrawal included an insufficient therapeutic response (14– 54%), loss to follow-up for unknown reasons (16–48%), satisfaction with their condition (1–8%), the detection of prostate cancer (4–54%), adverse effects (1–17%) and urinary retention (3%).307,308,310–313 Eight percent of patients with treatment failure stopped medication or changed to other drugs, and 8–25% underwent surgery. The risk factors for treatment failure were severe LUTS, low urinary flow rate, large prostate (>30–40 mL ), large PVR or a history of urinary retention, concomitant OAB symptoms, urodynamically proven BOO, and insufficient effects after using shortterm therapy.311–314

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

56. It has been reported that 25–30% of men undergoing prostatectomy have an unfavorable outcome.325,326 BOO, DU, and DO are all important prognostic variables for the surgical outcomes of BPH.327 Symptom improvement is less likely for men with no or equivocal BOO compared with men with evident BOO.328,329 Both DU without BOO and DO without BOO strongly predict treatment failure for TURP.330,331 A higher degree of BOO without DO and/or DU is associated with improvements in both symptoms and QOL. urodynamic examinations, including pressure-flow studies and cystometry , are recommended to delineate BOO, DU, and DO (Grade B).329,333 In contrast, there is a view that the information obtained from pressure-flow studies does not improve the surgical outcome sufficiently to justify the cost and invasiveness of the procedure.334 Predicting BOO using simpler parameters, such as uroflowmetry and PV, may be a viable alternative.335

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?

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

62. AUA GUIDELINES

63. Recommendation Men with mild symptoms are suitable for watchful waiting. Men with LUTS should be offered lifestyle advice prior to or concurrent with treatment α-blockers should be offered to men with moderate to severe LUTS. 5α-reductase inhibitors should be offered to men who have moderate to severe LUTS and an enlarged prostate. 5α-reductase inhibitors can prevent disease progression with regard to acute urinary retention and need for surgery Muscarinic receptor antagonists might be considered in men with moderate to severe LUTS who have predominantly bladder storage symptoms.

64. No specific recommendations about phytotherapy of male LUTS Desmopressin can be used for the treatment of nocturia based on a polyuric background. Combination treatment with α-blocker together with 5α-reductase inhibitor should be offered to men with moderate to severe LUTS, enlarged prostates, and reduced Qmax (men likely to develop disease progression). Combination treatment is not recommended for short-term therapy (< 1 year). 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. PDE5 inhibitors reduce moderate to severe male LUTS.

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