10/9/2015. Dana A. Brown, Pharm.D., BCPS Assistant Dean for Academics, Associate Professor of Pharmacy Practice Palm Beach Atlantic University

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1 Dana A. Brown, Pharm.D., BCPS Assistant Dean for Academics, Associate Professor of Pharmacy Practice Palm Beach Atlantic University 1. Explain the pathophysiology of benign prostatic hyperplasia (BPH), including factors which can worsen BPH 2. Recognize the clinical presentation of BPH, including common signs and symptoms 3. Provide appropriate non pharmacologic and pharmacologic recommendations for a given patient with BPH based on patient specific parameters 4. Counsel a given patient on the appropriate administration and potential adverse effects of various BPH treatment modalities 5. Compare and contrast BPH treatment modalities with regards to adverse effects, role in therapy, and drug drug interaction considerations 6. Explain patient characteristics that would make various BPH treatment modalities inappropriate (contraindications) 1

2 Mr. Jones 71 yo WM Chief Complaint It feels like I have to pee all of the time. I get frustrated because I just end up dribbling until the urine comes out. Mr. Jones, cont d History of Present Illness 1 year h/o difficulty urinating that has worsened over the past month Reports dribbling, straining, weak stream, nocturia X 3 episodes/night, occasional bed wetting Denies hematuria, loss of urine with activity Mr. Jones, cont d Past Medical History Hypertension Dyslipidemia GERD Allergies Type 2 diabetes Family History Mother: age 69; + HTN, Type 2 DM Father: age 88 from CHF; + HTN, Type 2 DM, dyslipidemia Brother: age 69; + HTN, dyslipidemia 2

3 Mr. Jones, cont d Social History Married X 49 years 1 daughter aged 42 Retired Rti dcarpenter Drinks 1 beer each evening Smokes 1 pack of cigarettes/day No routine physical activity Mr. Jones, cont d Medications: Atenolol 100 mg PO Qdaily Lisinopril 10 mg PO Qdaily Pravastatin 40 mg PO HS Famotidine 20 mg PO BID Loratadine 5 mg/pseudoephedrine 120 mg PO BID Aspirin 325 mg PO Qdaily Metformin 1000 mg PO BID Glipizide XL 10 mg PO Qdaily Amitriptyline 25 mg PO QHS What is BPH? Benign Prostatic Hyperplasia 1,2 Enlargement of the prostate resulting in compression of the urethra ultimately leading to difficulty with urination American Urological Association definition 1 a histologic diagnosis that refers to the proliferation of smooth muscle and epithelial cells within the prostatic transition zone. Signs and symptoms may be regressive 3

4 Epidemiology 2 ~50% of men >60yo have microscopic findings consistent with BPH; ~90% at >85yo ~50% of men with microscopic changes will develop an enlarged prostate gland and have difficulty emptying the bladder ~50% of symptomatic patients will require treatment Functions of the Prostate Gland 2 Two major functions of the prostate gland: 1. To secrete liquefying components of semen which allow sperm to move freely 2. To produce secretions which have antibacterial effects because of high zinc concentrations Prostate Gland Growth Spurts 2 Birth Prostate weighs ~ 1 g ~40s Growth Spurt #2 Prostate doubles/triples in size Adolescence Growth Spurt #2 Prostate weighs ~15-20 g Age Prostate continues to grow until this age 4

5 Prostate Gland Tissue 2 1. Epithelial Produces ejaculate secretions 2. Stromal Containsα 1 adrenergic 1 adrenergic receptors Stromal:epithelial ratio 2:1 (normal), 5:1 (BPH) 3. Capsule Contains fibrous connective tissue & smooth muscle Contains α 1 adrenergic receptors Hormonal Influence 2 Testosterone Testosterone 5-α-reductase Dihydrotestosterone Two otpesof types of 5 α reductase α Type I DHT causes acne, facial hair, male pattern baldness Type II DHT causes prostate enlargement & growth BPH Pathophysiology 1,2 Symptoms emerge usually in 6 th decade Signs & symptoms result from static & dynamic factors Static factors Anatomical enlargement of the prostate gland leading to direct bladder outlet obstruction (BOO) Dynamic factors Excessive α adrenergic tone of the stromal tissue of the prostate 5

6 Lower Urinary Tract Symptoms (LUTS) 1,2 Obstructive Weak urine stream Urinary hesitancy Straining Dribbling Incomplete bladder emptying (feeling of fullness after voiding) Irritative Urinary frequency Urgency Nocturia Enuresis Medications and Worsening of BPH Symptoms 1,2 Testosterone replacement regimens More substrate to be converted to DHT α adrenergic agonists (pseudoephedrine) Stimulate α adrenergic receptors Anticholinergic agents (antihistamines, phenothiazines, TCAs) May bladder contractility Quiz Question #1 Which of Mr. Jones medications could be contributing to his current clinical presentation? A. Atenolol B. Amitriptyline C. Loratadine/pseudoephedrine D. A & B E. B & C 6

7 Quiz Question #2 The 5 α reductase enzyme converts dihydrotestosterone to testosterone. A. True B. False Quiz Question #3 Mr. Jones complaints of nocturia and bed wetting are examples of what type of BPH symptoms? A. Dynamic B. Irritative C. Obstructive D. Static Clinical Assessment 1,2 ALWAYS assess medications!!! Other useful parameters Prostate specific antigen (PSA) Age PSA (ng/ml) Not specific for BPH! ng/mL ng/mL ng/mL ng/mL Digital Rectal Exam (DRE) Helps determine size of prostate gland & assesses for prostate cancer Harder but still somewhat soft on palpation (nose cartilage) 7

8 Back to Mr. Jones Vital Signs: BP 106/70, P 54, RR 22, Temp 98.5 F, Pain 0/10, Wt 263 lbs PE: All WNL except GU: Normal scrotum; prostate round, mobile and firm on palpation; penis w/o discharge or curvature Mr. Jones, cont d Laboratory/Diagnostic Findings Chem 8 WNL PSA: 7.9 ng/ml U/S findings: PVR of 264 ml and prostate weight of approximately 51 g U/A: Color: yellow Leukocyte esterase: ( ) SG: Nitrites: ( ) Glucose: ( ) Ketones: ( ) Blood: ( ) Quiz Question #4 Mr. Jones PSA score of 7.9 ng/ml is considered elevated and likely indicates BPH. A. True B. False 8

9 Complications of BPH BPH Management Options 1,2 1. Watchful waiting 2. Pharmacotherapy α adrenergic antagonists 5 α reductase inhibitors Type 5 phosphodiesterase inhibitors Hormones (LHRH agonists & anti androgens) Herbals/Complementary alternative medicine (CAM) 3. Minimally Invasive/Surgical Interventions Prostatectomy Transurethral resection of the prostate (TURP) Transurethral microwave thermotherapy (TUMT) Watchful Waiting 1 Indicated for patients with mild symptoms or who are asymptomatic No specific treatment is indicated Return for reassessment Q6 12 months 9

10 Patient Education 1 Fluid restriction at bedtime Avoid caffeine & alcohol intake Limit it salt intake Frequent emptying of bladder Avoid drugs that exacerbate symptoms Categories of Drug Options 1,2,3 1. Interference with testosterone stimulatory effects on the prostate gland ( static factors) 5 α reductase inhibitors Hormones (LHRH agonists & anti androgens) 2. Relaxation of the prostatic smooth muscle ( dynamic factors) α adrenergic antagonists, PDE 5 inhibitors (?) 3. Combination therapy α adrenergic antagonist + 5 α reductase inhibitor Drug Initiation 2,3 Initiate with asingle agent α adrenergic antagonist Faster acting & more effective Less sexual adverse effects 5 α reductase inhibitor Prostates > 40g Cannot tolerate the CV effects of α antagonists PDE5 inhibitor FDA approved for BPH or BPH + ED Combination therapy Prostates 50g + PSA levels 10

11 α Adrenergic Antagonists 1,2,4,5,6,7,8,9,10 MOA: Relax prostatic smooth muscle by α 1 adrenergic receptor blockade (α 1A [tamsulosin & silodosin]) Examples: First generation: phenoxybenzamine Second generation: alfuzosin (Uroxatral ), doxazosin (Cardura /Cardura XL ), terazosin (Hytrin ) Third generation: Tamsulosin (Flomax ), silodosin (Rapaflo ) BPH symptoms but do not prostate size or volume Do not affect PSA levels Tamsulosin v. Silodosin 11 Silodosin 8 mg/d X 12 weeks 955 pts with symptomatic BPH Tamsulosin 0.4 mg/d X12 weeks Placebo X 12 weeks from baseline in total score of IPSS questionnaire Silodosin and tamsulosin significantly improved total scores of IPSS questionnaire, storage/voiding scores and QOL as compared to placebo Tamsulosin v. Silodosin, cont d 11 Only silodosin significantly nocturia v. placebo Improvements in Qmax were noted in ALL treatment t tgroups A high placebo response Most common ADR was absent or ejaculation 14% with silodosin, 2% with tamsulosin 11

12 α Adrenergic Antagonists, cont d cont d 1,2,4,5,6,7,8,9,12 Relief of symptoms usually within 3 weeks of initiation Doses Alfuzosin XR 10mg PO with same meal Qdaily Doxazosin 1mg PO QHS, up to 4 8mg/day Doxazosin XL 4mg PO Qam w/breakfast, up to 8mg PO Qam over 3 4 weeks Terazosin 1mg PO QHS, up to 2 10mg/day Tamsulosin 0.4mg PO Qdaily, up to 0.8mg/day if no resolution of symptoms within 2 weeks of initiation; Take 30 min after the same meal Silodosin 8mg PO with same meal Qdaily α Adrenergic Antagonists, cont d 9 Renal Dosage Adjustment for Silodosin CrCl > 50 ml/min: No dosage adjustment is needed. CrCl ml/min: 4 mg PO once daily. CrCl < 30 ml/min: Not recommended. α Adrenergic Antagonists, cont d 1,2,4,5,6,7,8,9 Adverse Effects Orthostatic hypotension (2nd generation) Dizziness (2nd generation) First dose syncope (2nd generation) Fatigue (3 rd generation) Ejaculatory dysfunction (3 rd generation) Nasal congestion (3 rd generation) Flu like symptoms (3 rd generation) risk for complications with cataract surgery (3 rd generation) 13 12

13 α Adrenergic Antagonists, cont d 1,2,4,5,6,7,8,9 Drug Drug Interactions Alfuzosin is a substrate for CYP 3A4 Tamsulosin clearance is by cimetidine (avoid use) Phosphodiesterase 5 inhibitors Produce systemic hypotension Coadministration: stable dose of α adrenergic antagonist before initiation of PDE5 inhibitor α Adrenergic Antagonists, cont d 1,2,4,5,6,7,8,9 Avoid use: Hepatic insufficiency (no use in severe hepatic dysfunction) Strong CYP 3A4 inhibitors (tamsulosin & silodosin) CAD/angina Vl Volume depletion Tamsulosin & Cardiac arrhythmias Silodosin are better options Multiple antihypertensives NOTE: Monotherapy with α adrenergic antagonists for the management of HTN in men with BPH is inappropriate therapy for HTN 14 α Adrenergic Antagonists, cont d 1,8,9 Monitoring Parameters Symptom improvement BP and HR checks at every visit 13

14 5 α Reductase Inhibitors Inhibitors 1,15,16,17 MOA: Blockade of 5 α reductase enzyme to inhibit conversion of testosterone to DHT (finasteride Type II only) Examples: Finasteride (Proscar ) Dutasteride (Avodart ) Best used in patients with LUTS and enlarged prostates ( 50 grams) Adequate trial is 6 12 months 5 α Reductase Inhibitors, cont d 1,15,16,17 Doses Finasteride 5mg PO Qdaily Dutasteride 0.5mg PO Qdaily Maximal reductions in prostate size seen ~12 months Adverse Effects Ejaculation disorders Erectile dysfunction/ libido Gynecomastia Nausea, abdominal pain, flatulence Rash (finasteride only) 5 α Reductase Inhibitors, cont d 1,15,16,17 Contraindications/Precautions Hepatic dysfunction (caution) Pregnancy Category X Women of childbearing age or who are pregnant should NOT Handle 5 α reductase inhibitor tablets Have contact with semen from men treated with 5 α reductase inhibitors Drug Drug Interactions Dutasteride only: cautious use with CYP 3A4 inhibitors/inducers 14

15 5 α Reductase Inhibitors, cont d 1,15,16,17 Monitoring Parameters Obtain baseline PSA & DRE PSA levels by 50% Follow up with PSA in 6 months, then PSA & DRE annually PDE5 Inhibitors 18 MOA: Inhibition of PDE5 in prostate to cause vasodilation and prostatic and bladder neck relaxation Example: Tadalafil (Cialis ) FDA approved in Oct 2011 Approved for BPH as well as BPH + ED as studies show improvement in urinary symptoms Dose 5 mg PO Qdaily Combination Therapy 19,20 5 α reductase inhibitor + α adrenergic antagonist Jalyn (0.5 mg dutasteride mg tamsulosin) Ideal for patients with Severe symptoms Enlarged prostates (>40 grams) PSA levels Has been shown to prevent symptom progression & the risk for developing urinary retention, UTIs, & need for surgery 15

16 Combination Therapy, cont d 1,19,20 adverse effects and expensive Can consider d/c ing α blocker after 6 9 mos α adrenergic antagonist + anticholinergic Considered for patients with BOO symptoms + symptoms of overactive bladder Urinary frequency, urgency, enuresis Quiz Question #5 Silodosin provides quick symptom relief in the management of BPH as well as reduces prostate size and volume. A. True B. False Quiz Question #6 As part of the management of his BPH symptoms, Mr. Jones may be counseled to: A. Avoid alcohol at bedtime B. Discontinue using loratadine/pseudoephedrine C. Limit fluid intake at bedtime D. All of the above 16

17 Quiz Question #7 A common adverse effect associated with terazosin therapy is: A. Erectile dysfunction B. Gynecomastia C. Orthostatic hypotension D. Rash Quiz Question #8 Which of the following treatment options is appropriate for initiating today to manage Mr. Jones BPH symptoms? A. Finasteride 5 mg PO Qdaily B. Tadalafil 5 mg PO Qdaily C. Tamsulosin 0.8 mg PO Qdaily D. Terazosin 10 mg PO QHS Herbals/CAM, cont d Saw palmetto 21,22,23 Earlier evidence suggests modest efficacy on treated LUTS Newer data fail to confirm a clinical important role in the management of BPH AUA 2010 guidelines do not advocate recommending saw palmetto for BPH due to a lack of evidence 1 17

18 Zinc 24 High zinc levels found in normal prostate glands Some men with BPH have low zinc concentrations ti Better conclusions seen in men with prostate cancer Adverse effects: Nausea, vomiting, abdominal cramps Surgical Intervention 1 Indications for surgery Unresponsive to drug therapy Refractory urinary retention or other BPH complications Recurrent UTIs secondary to BPH Individual preference Prostatectomy Transurethral resection of the prostate (TURP) Transurethral microwave thermotherapy (TUMT) Quiz Question #9 Saw palmetto acts similar to tamsulosin to improve the symptoms of BPH. A. True B. False 18

19 Quiz Question #10 Mr. Jones has been receiving silodosin 8 mg PO Qdaily and dutasteride 0.5 mg PO Qdaily for 6 months now. His PSA is 3.3 ng/ml. He reports significant improvement in his symptoms and is mostly symptom free. Which of the following should occur? A. He should continue both medications B. He should D/C dutasteride and continue silodosin C. He should D/C silodosin and continue dutasteride D. He should D/C both medications 19