1. Benign Prostatic Hyperplasia (BPH) and Prostatitis Matthew Lane, PharmD, BCPS Associate Professor University of Kentucky

2. BPH Common cause of urinary dysfunctional symptoms in elderly men Due to proliferation of stromal and epithelial cells of the prostate gland

3. BPH 75% of men who live up to age of 70 will experience symptoms No evidence disorder predisposes patients to developing prostate cancer

4. Etiology Testosterone metabolized to dihydrotestosterone (DHT) by 5-alpha reductase 5-alpha reductase contained in prostatic epithelial cells DHT is the obligate androgen responsible for normal and hyperplastic prostatic growth Overactivity of bladder (50% incidence with BPH)

5. Clinical Presentation Obstructive –Hesitancy, decrease in urinary force, urinary stream intermittency, terminal dribbling and incomplete bladder emptying Irritative –Nocturia and daytime urinary frequency, urge incontinence and pain Obstructive symptoms associated more with enlarged prostate, while irritative symptoms suggest voiding dysfunction

6. Clinical Presentation Objective findings –Abdominal tenderness –Enlarged bladder –Enlarged, firm, rubbery prostate Differential diagnosis –Urinary tract infection –Prostate CA –Hydronephrosis –  bladder contractility or outlet obstruction

7. Studies Urinalysis –Obtain urine specimen before digital rectal examination (DRE) DRE –Large, palpable prostate with smooth mucosal surface rectally appreciated

8. Prostate CA DRE –Presence of hard nodules or induration suggest prostate CA Intravenous pyelogram (IVP) warranted only if hematuria present

9. Urodynamic Evaluation Assesses urinary flow rate, bladder volume, detrusor pressure and visualization of voiding Peak urinary flow rate is noninvasive and useful monitoring parameter Cystoscopy –Used to rule out tumors and stones –Required only if hematuria or pelvic pain with voiding present

10. AUA Symptom Score

11. Complications Urinary incontinence –With advanced disease secondary to large residual volume Hydronephrosis with renal damage –Associated with abdominal discomfort and flank pain during voiding Acute urinary retention –Alcohol, anticholinergics, alpha-adrenergic agents and neuroleptics may precipitate

12. Treatment Goal is to relieve symptoms, maintain quality of life and prevent complications Nonpharmacologic strategies –Transurethral resection of the prostate (TURP) –Transurethral incision of the prostate (TUIP) –Transurethral dilation of the prostate (TUDP) –Urethral stent

13. TURP Treatment of choice for large prostate gland (> 30 g) +/- complications Significant relief of symptoms in 75-86% of patients up to 7 years after procedure Initial adverse effects include postsurgical TURP syndrome (2%), voiding problems, hemorrhage and UTIs Impotence, retrograde ejaculation and urinary incontinence may occur

14. TUIP and TUDP Reasonable alternatives for men with smaller prostates (< 30 g) that cause bladder outlet obstruction Incisions or balloon catheter relieve outlet obstruction and preserve antegrade ejaculation Good choice in high-risk surgical patients (e.g. elderly) as it can be performed under local anesthesia

15. Drug Therapy Used initially to treat mild to moderate symptoms of prostatism Alpha-blockers –Prostatic capsule, BPH adenoma and bladder neck rich with alpha 1 receptors

16. Alpha Blockers Agents reduce smooth muscle tone of prostate, bladder neck, urethra, improve voiding function and decrease symptoms Receptor alpha 1A subtype most important Relieves irritative symptoms

17. Alpha-Blockers Shown in clinical trials to improve urinary flow rate (3 mL/s) and BPH symptoms (40%) Most agents must be titrated in stepwise fashion due to postural hypotension and syncope Administer first dose at bedtime Blood pressure changes usually small in normotensive men

18. Alpha-Blockers Patients experience improvement in symptoms within several weeks –Assess initial response after 1 month Common side effects include dizziness and nasal congestion Regimens –Terazosin 1-20 mg/d –Doxazosin 1-8 mg/d

19. Alpha Blockers Tamsulosin –Higher affinity for alpha 1A receptors potentially causing less dizziness and postural hypotension (10x more specific for prostate than peripheral receptors) –Stepwise titration not necessary –0.4-0.8 mg/d (maximum benefit at 0.4mg/d) –Significant increase in ejaculatory disturbances –Not indicated for treatment of hypertension –Benefits seen over first few days/wk.

20. Alpha Blockers Alfuzosin –Uroselective alpha adrenergic selective when used in the current extended release formulation –Lowest incidence of hypotension –Low risk of sexual side effects, unlike tamsulosin –Dosing: 10mg extended release tab daily

21. Alpha Blockers Silodosin (Rapaflo®) –Alpha 1a receptor specific (minimal orthostasis effects) –Similar benefit in reducing LUTS compared to other agents – SE - Significant increase in ejaculatory disturbances –Dosing 8mg/day with meal. Dose reduce in renal insufficiency Avoid strong CYP3A4 inhibitors

22. 5-alpha Reductase Enzyme Inhibitors 2 types of receptors –Type 1 located in skin and liver –Type 2 located in prostate Blockage of DHT production leads to shrinkage of prostate and decreased LUTS Advantageous in patients with large prostate size Disadvantage – reduces PSA making cancer detection more challenging

23. Finasteride Blocks conversion of testosterone to dihydrotestosterone by inhibiting 5-alpha reductase enzyme (type II) Long-term administration (5 mg/d) causes prostate shrinkage (25%) and is detected 3-24 months after initiation Improvement in urinary flow rate (2 mL/s) and symptoms occur at 12-18 months

24. Dutasteride Inhibits both peripheral and prostate specific enzymes High protein bound, high metabolism by CYT 3A4, t ½ - approx 5 weeks Dosing - 0.5 mg daily Prostate size reduced 25.7% @ 2 yrs PSA reduced 50% @ 2 yrs SE’s similar to finasteride Dutasteride/Tamsulosin – Jalyn ®

25. VA Trial 359 Compared terazosin, finasteride, terazosin + finasteride and placebo Results –Terazosin superior to finasteride –Finasteride no more effective than placebo –Combination therapy was not synergistic Subsequent meta-analysis of 6 finasteride clinical trials show agent only effective for prostates > 40 g

26. MTOPS Evaluated combo alpha blockade and 5AREI vs single agents and placebo AUA scores declined 7 points during combo therapy over 4.5 yrs. Overall shows combo tx slows progression best Demonstrates effectiveness of alpha blockers Shows that prostate > 40g and PSA > 4 respond best to combo tx. Surgical rates similar between finasteride vs combo tx NEJM 2003; 349; 2387-2398

27. CombAT Trial 4 year trial comparing tamsulosin, dutasteride or combo for moderate/severe BPH in 4000+ men Both arms using dutasteride were better at preventing acute urinary retention and need for prostate reduction sx. Reiterates men with enlarged prostates benefit best when using 5AREI with or without alpha blocker Eur Urol. 2010;57(1):123

28. Tadalafil FDA approved for treatment of signs and symptoms of BPH 5mg daily Comparable to tamsulosin in mild symptom control Option for mild disease with concomitant erectile dysfunction Cautions –Interaction with alpha blockers –St. Johns wort may decrease effectiveness

29. Approach to Drug Therapy Patients with smaller prostates and significant symptoms should receive alpha-blocker agent alone Patients with larger prostates (> 40 g) treated with alpha-blocker + finasteride to provide prompt symptom relief Trials ongoing to assess treatment of overactive bladder (anticholinergics)

30. Other Agents Flutamide –Nonsteroidal antiandrogen that inhibits binding of DHT to receptor –Limited effectiveness –Reserved for nonsurgical candidates, finasteride failures +/- alpha blocker therapy GnRH agonists –High cost, toxicity and questionable effectiveness preclude use of leuprolide

31. Other Developments Saw palmetto Finasteride 1 mg/d –BPH prevention –Male-pattern baldness –Prostate CA prevention

32. A 56 yo male with 2 year history of increasing voiding symptoms, his main complaint being he has to wake up multiple times nightly to urinate. AUA symptom score 18 Peak flow rate: 15 ml Post Void Residual: 10 ml Prostate Volume: 25 ml PSA level: 0.9 ng/ml What would you recommend for initial treatment? A. None, recommend watchful waiting. B. Terazosin C. Finasteride D. Terazosin and finasteride

33. Bacterial Prostatitis Acute –Sudden onset of fever, tenderness and urinary/constitutional symptoms Chronic –Urinating difficulty, low back pain, suprapubic discomfort –Recurring infection with same organism Possible routes of infection are same as those of UTIs

34. Prostatitis Gram-negative, enteric organism most frequent pathogens –E. coli occurring in 75% of cases DRE reveals swollen, tender, warm, tense gland Diagnosis made when number of bacteria in expressed prostatic secretions are 10 times that of urethral and midstream sample upon voiding

35. Treatment of Prostatitis Acute –Trimethoprim-sulfamethoxazole –Fluoroquinolones –Cephalosporins –Duration of therapy 4 weeks to reduce risk of developing chronic prostatitis Chronic –Cures rarely obtained –Trimethoprim and fluoroquinolones –Treat initially for 4-6 weeks