Endocrinology: Benign Prostatic Hyperplasia Courses in Therapeutics and Disease State Management

Epidemiology Common benign neoplasm that affects the majority of elderly mean BPH occurs in approximately 60% of men over 60 years of age and 78% of men over at age 80. Peak incidence of BPH occurs between ages 63 and 65

Anatomy Review Link: Representation of the anatomy of and α-adrenergic receptor distribution in the prostate, urethra, and bladder. Normal prostate in an adult male is 15-20 grams (size of a walnut) At birth the prostate is pea size (about 1 gram) at puberty, the prostate grows to a normal size of 15-20 grams and does not begin to grow again until age 40. Can grow to upto 100grams.

Pathophysiology Stimulation of the concentrated α1-adrenergic receptors in the prostate causes smooth-muscle contraction Results in compression of the urethra, reduction of the urethral lumen, and decreased urinary bladder emptying Anatomic enlargement of the gland itself physically blocks the bladder neck Link: Table covering Medical Treatment Options for Benign Prostatic Hyperplasia Drug therapy targets these specific pathophysiologic processes often described as the “dynamic” and “static” factors contributing to symptoms.

Decreased force of stream Symptoms Obstructive Irritative Decreased force of stream Weak flow Hesitancy Straining Dribbling Prolonged voiding Incomplete voiding Retention Urgency Frequency Nocturia Dysuria Small volume Incontinence

Complications Acute urinary retention Urinary tract infections Renal impairment/Renal Failure Hematuria when tissue growth exceeds its blood supply Overflow urinary incontinence

Diagnosis and Classification American Urological Association Prostate Symptom Score Not at all = 0 Less than 1 time in 5 = 1 Less than half the time = 2 About half the time = 3 More than half the time = 4 Almost always = 5 Over the past month, How often have you had the sensation of not emptying your bladders completely? How often have you had to urinate again in less than 2 hours? How often have you stopped and started when urinating? How often have you found it difficult to postpone urinating ? How often have you had a weak urinary stream? How often have you had to push or strain to begin urinating? How many times did you most typically get up to urinate from the time you went to bed until the time you got up in the morning? None = 0 | Once = 1 | Twice = 2 | 3 times = 3 | 4 times = 4 | 5 times or more = 5 Score Mild BPH = 1 to 7 | Moderate = 8 to 19 | Severe = 20 to 35 Digital rectal exam Prostate Specific Antigen (PSA) Urinalysis BUN/Cr Post Void Residuals Urinary flow rates Medication history Assessment of the patient with suspected BPH involves ruling out other conditions that may be the cause or contributing to the patient’s symptoms. This involves a physical exam, careful history of the patient’s symptoms and current medication use The AUA’s Prostate symptom score is used to classify BPH symptoms as mild, moderate or severe; this guides the treatment plan

Treatment Approaches Goal is to reduce symptoms and prevent complications Link: Comparison Table of α1-Adrenergic Antagonists, 5α- Reductase Inhibitors, Phosphodiesterase Inhibitors, and Anticholinergic Agents for Benign Prostatic Hyperplasia Watchful waiting can be initiated for pts with mild symptoms. If bothersome or moderate or severe then drug therapy is usually nitiated

Non-Pharmacologic Watchful waiting Lifestyle changes in all patients Avoid medications which contribute to or exacerbate symptoms Testosterone replacement Adrenergic agonists (decongestants) Anticholinergics Diuretics Fluid restriction at bedtime Avoid caffeine and alcohol Scheduled toileting Watchful waiting is the preferred approach for patients with mild symptoms. All patients, regardless of severity should be counseled on the lifestyle changes and non-drug options for managing and preventing BPH symptoms

Complementary and Alternative Medicine Saw Palmetto Randomized placebo controlled trials have not demonstrated efficacy Lycopene Contradictory studies Counsel patients to maintain vegetable rich diet Phytosterols Promising, but not conclusive Diet rich in vegetables, nuts and legumes

Management Algorithm for Benign Prostatic Hyperplasia (BPH) This slide provides a general summary of the pharmacologic approach to managing BPH. Alpha-blockers are generally used first line and can be used in any and all stages of symptoms.

First Line Therapy: Alpha 1 Blockers Relax prostatic smooth muscle tissue, bladder neck, and urethra Equally efficacious within a few days All are metabolized by CYP 450 3A4 Selection of agent based on age, side effect profile, and cost

2mg titrate to 8mg, XL start at 4mg Alpha 1 Blockers Doxazosin Terazosin Tamsulosin Alfuzosin Silodosin Brand Name Cardura® Hytrin® Flomax® Uroxatrol® Rapaflo® Uroselective No Yes Dosing 2mg titrate to 8mg, XL start at 4mg 5mg titrate to 10mg 0.4mg (can try 0.8mg) 10mg QD 8mg (renal dose 4mg) Timing Bedtime After meals* After meals Hypotension ++ - + Ejaculation Disorders +++ Rhinitis Floppy iris syndrome Generally, Alpha 1 Antagonists should not be used as sole treatment of hypertension in men with BPH. Retrograde ejaculation is most common with the uroselective agents and can be a troubling adverse effect. This symptom can be managed by educating men to void after ejaculation. Can typically avoid hypotension and syncope with non-selective agents by using slow weekly titrations and continued adherence. Geriatric men are more sensitive to hypotension

5-Alpha Reductase Inhibitors Shrinks enlarged prostate by blocking conversion of testosterone to dihydrotestosterone Equally efficacious, but require at least 6 months of therapy Effectiveness has been best demonstrated in men with significantly enlarged prostates (>40 grams)

5-Alpha Reductase Inhibitors Finasteride Dutasteride Brand Name Proscar® Avodart® Dosing 5mg QD 0.5mg QD Decreased Libido + Erectile Dysfunction Gynecomastia Cost/day $0.87 $3.93 Pregnant women should avoid coming into contact with tablets or the semen of men taking them Reduce PSA by 50%, must interpret PSA in light of this. Most effective when used in combination with alpha 1 blockers. Use results in a 25% reduction in risk of prostate cancer; but a 27% increase in number of highly aggressive tumors among those detected

Other Therapies Phosphodiesterase-5 Inhibitors Antimuscarinics October 2011, the FDA approved tadalafil (Cialis®) for the treatment of symptoms related to BPH. Not first line, but option for men with BPH and ED Hypotension risk? Antimuscarinics Adjunctive for some men with urge incontinence Not for patients with high post-void residuals Small crossover studies in combo with tamsulosin or afluzosin demonstrate improvement in both BPH and ED and did not show increased risk of hypotension. However, these studies were conducted with younger men. Caution is warranted in their combined use in geriatric men.

Surgical Therapy Typically reserved for men with complications, severe symptoms unresponsive to optimal pharmacotherapy, or those who prefer surgery Greatly improves symptoms but high complication rates Transurethral resection of the prostate (TURP) Open prostatectomy Both procedures can result in retrograde ejaculation, urinary incontinence, and erectile dysfunction. These procedures are generally ineffective towards the irritative voiding symptoms.

The Role of the Pharmacist Selecting an agent and appropriate dose Patient education on lifestyle modifications Counseling on correct administration and management of adverse effects Monitoring use of OTC and prescription drugs that may exacerbate BPH Link: Table on Monitoring of Drugs Used in Treatment of Benign Prostatic Hyperplasia Link: Table on Dosing of Drugs Used in Treatment of Benign Prostatic Hyperplasia