Benign Prostatic Hyperplasia 5th stage Bootan Abdulqader MSc. Clinical pharmacy

PROSTATE PHYSIOLOGY Located anterior to the rectum, the prostate is a small heart-shaped, gland located below the urinary bladder. It surrounds the proximal urethra. Soft, symmetric, and mobile on palpation, a normal prostate gland in an adult man weighs 15 to 20 g.

How common is Benign Prostatic Hyperplasia? BPH is a prevalent condition associated with the aging process in men. As a man matures, the prostate goes through two main periods of growth. The first occurs early in puberty, when the prostate doubles in size. The second one, at around age 25, the gland begins to grow again and this often will result, years later, in BPH. More than half of all 60-year-old American men have BPH, but only 10% of them need medical or surgical intervention. This rate levels up with age. Though the prostate continues to grow during most of a man's life, the enlargement usually starts provoking problems late in life. BPH rarely causes symptoms

The prostate has two major functions: 1. To secrete fluids that make up a portion (20%–40%) of the ejaculate volume . 2. To provide secretions with antibacterial effect possibly related to its high concentration of zinc. Prostate size increases from 25g to 30g for men in 40s 30g to 40g in 50s 35g to 45g in 60s.

The prostate gland comprises three types of tissue: epithelial tissue, stromal tissue, and the capsule. Epithelial tissue, also known as glandular tissue , produces prostatic secretions. Stromal tissue, also known as smooth muscle tissue , is embedded with α 1-adrenergic receptors. The capsule, or outer shell of the prostate, is composed of fibrous connective tissue and smooth muscle,

PATHOPHYSIOLOGY The pathogenesis of BPH is often described as resulting from both static and dynamic factors. Static factors relate to anatomic enlargement of the prostate gland, which produces a physical block at the bladder neck and thereby obstructs urinary outflow. Dynamic factors relate to excessive α -adrenergic tone of the stromal component of the prostate gland, bladder neck, and posterior urethra, which results in contraction of the prostate gland around the urethra and narrowing of the urethral lumen.

MEDICATION-RELATE SYMPTOMS Testosterone replacement regimens α -Adrenergic agonists, used as oral or intranasal decongestants (e.g. pseudoephedrine, ephedrine, or phenylephrine), can stimulate α -adrenergic receptors in the prostate. Drugs with significant anticholinergic adverse effects (e.g., antihistamines, phenothiazines, tricyclic antidepressants, or anticholinergic drugs used as antispasmodics or to treat Parkinson disease) may decrease contractility of the urinary bladder detrusor muscle.

CLINICAL PRESENTATION All symptoms of BPH can be divided into two categories: obstructive and irritative. Obstructive symptoms, also known as prostatism or bladder outlet obstruction , result when dynamic and/or static factors reduce bladder emptying. The force of the urinary stream becomes diminished, urinary flow rate decreases, and bladder emptying is incomplete and slow. Patients report urinary hesitancy and straining and a weak urine stream. Urine dribbles out of the penis, and the urinary bladder always feels full, even after patients have voided.

Approximately 50% to 80% of patients have irritative voiding symptoms, which typically occur late in the disease course. Irritative voiding symptoms result from long-standing obstruction at the bladder neck. Symptoms Urinary frequency, urgency, intermittency, nocturia, decreased force of stream, hesitancy, and straining

Diagnosis 1.Medical History Should focus on: Urinary tract symptoms UTI, Hematuria Previous surgery Family history of prostate carcinoma Co-morbidities/general health issues Medications (Anti-cholinergics & sympathomimetics)

2.Investigations: laboratory findings: GUE: to exclude infection or hematuria. Renal function test to asses renal function. Prostate Specific Antigen (PSA)(if appropriate) International Prostate Symptom Index DER

Complications of bladder outlet obstructions: acute retention of urine urinary tract infection. vesicle stone. Hematuria. Renal failure.

Treatment: ↓ symptoms (IPSS/AUA) ↓ bother (bother score) and ↑ QOL Goals of Therapy for BPH ↓ symptoms (IPSS/AUA) ↓ bother (bother score) and ↑ QOL ↓ prostate size or arrest further growth ↑Increase in peak flow rate / Relieve obstruction Prevention of long-term outcomes/complications Acceptable adverse events profile

Treatment Options Lifestyle Measures Watchful Waiting Medical Management Alpha blockers 5-alpha reductase inhibitors (5 ARI’s) PDE5 inhibitors (Tadalafil 5mg po qDay) Surgical Management

Lifestyle Measures Fluid modification Timed voiding Modify medications Reduce fluid intake in the evening Avoid caffeine, alcohol Timed voiding Regular timed voiding of the bladder Modify medications I.e: change time of dosing diuretics Avoid cold remedies (anti-histamines) Avoid anti-cholinergics Avoid alpha-agonists (i.e. decongestants)

Watchful Waiting Watchful Waiting: Patient monitored by physician without active intervention for LUTS Safe in patients with mild, stable symptoms Intervene when symptoms worsen or complications arise such as acute retention, recurrent hematuria, recurrent UTI, hydronephrosis, bladder calculi

Medical Treatment: Long-acting Non-selective 1-blockers Dosage is increased in a stepwise fashion at weekly intervals Does not affect PSA Acts to relax prostatic/bladder neck smooth muscle (& vascular smooth muscle - non selective) Doxazosin (Cardura) Dosage: 1-2 mg qDay, titrate up to 4-8 mg OD Terazosin (prostanor) Dosage: 1 mg OD, titrate up to 2, 5, or 10 mg Not usually first line anymore

Role of a1-Adrenoreceptors a1-ARs and Human LUTS Smooth muscle contraction a1A Lumbosacral a1D Instability Irritative symptoms a1D>a1A Resistance vessels a1A Aging effects a1B>a1A Prostate Spinal cord Detrusor Vessels • a1-Adrenoreceptors are expressed in a variety of tissues and they play an important role in the dynamic component of BPH.1 There are four major a1-adrenoreceptor subtypes, a1A, a1B, a1D, and a1L. These subtypes have different patterns of expression. a1A-adrenoreceptors are the dominant subtype in prostatic stromal tissue, accounting for approximately 85% of the a1-adrenoreceptor messenger RNA (mRNA) in this tissue. These receptors play a key role in contraction of this muscle mediated by noradrenergic input from the sympathetic nervous system. a1-adrenoreceptors in the lumbrosacral spinal cord are also involved in control of urinary function, and the a1D subtype predominates in this tissue. The clinical significance of these receptors in the treatment of LUTS remains to be determined. The action of norepinephrine at a1D- and a1A-adrenoreceptors in the detrusor muscle is thought to be involved in irritative symptoms associated with BPH. In young individuals, a1A-adrenoreceptors are the dominant subtype in resistance vessels, but a1B-adrenoreceptors become the most highly expressed subtype in older individuals.2,3 While the most advantageous subtype selectivity profile for an a1-adrenoreceptor antagonist used for the treatment of BPH has not yet been determined, the concept of clinical uroselectivity, as defined by the International Consultation on BPH, remains a valid concept.2 1. Schwinn DA. Novel role for alpha1-adrenergic receptor subtypes in lower urinary tract symptoms. BJU Int. 2000;86:11-22. 2. Jardin A, Andersson K-E, Chapple C, et al. a1-adrenoreceptor antagonists in the treatment of BPH. In: Benign Prostatic Hyperplasia. 5th International Consultation on Benign Prostatic Hyperplasia (BPH). Eds: Chatelain C, Denis L, Foo KT, et al. World Health Organization–International Union Against Cancer. Paris, France. June 25-28, 2000:459-477. 3. Rudner XL, Berkowitz DE, Booth JV, et al. Subtype specific regulation of human vascular a1-adrenergic receptors by vessel bed and age. Circ. 1999;100:2336-2343.

Long-acting selective 1-blockers Specifically relaxes the smooth muscle of the prostate and bladder neck Does not interfere with bladder contractility Does not affect PSA Alfuzosin (Xatral) Dosage: 10 mg qDay Tamsulosin (Flomax) Dosage: 0.4 mg qDay Silodosin (Rapaflo) Dosage: 8mg qDay

Side effects include: Postural hypotension, dizziness, tiredness, rhinitis, retrograde ejaculation, and headache Use of alpha-1a receptor blocker lead to les systemic side effects (Postural hypotension, dizziness, tiredness, rhinitis, headache).

5--reductase Inhibitors Regulate androgen available to prostate by blocking conversion of testosterone to dihydrotestosterone (DHT) Slow the rate of prostate enlargement Reduce prostate volume and relives “static” compression by BPH Reduce PSA by ~50% Takes 3-6 months to exert clinical effect

Dihydrotestosterone (DHT) Action Testosterone is converted to DHT by two 5-reductase isoenzymes The target for DHT is the androgen receptor DHT has approximately 5 times greater affinity for the androgen receptor than testosterone The greater affinity makes DHT a more potent androgenic steroid at physiologic concentrations The DHT/androgen receptor complex alters gene expression

Men with larger prostates (> 40 g) respond most favorably Finasteride (Proscar) Dosage: 5 mg OD – type II inhibitor Dutasteride (Avodart) Dosage: 0.5 mg OD – type I and II inhibitor

PDE5 Inhibitor Tadaladfil 5mg qDay: Improves male LUTS Exact mechanism unknown Helps concurrent erectile dysfunction May potentiate hypotension in men taking concurrent alpha-blockers

Rationale for Combination Therapy 5-Reductase Inhibitors: Arrest Disease Progression Alpha- Blockers: Relieve Symptoms Rapidly The use of combination therapy for BPH is based on the rationale that alpha blockers and 5-reductase inhibitors have complementary pharmacologic and clinical properties and that the combination of the two can provide the complementary benefits of both classes of therapy. Alpha-adrenergic blockers block alpha1-adrenergic receptors on prostate and bladder smooth muscle to relax the muscle and provide symptomatic relief.1 On the basis of data collected to date, they do not appear to alter prostate volume or serum PSA. Furthermore, they have not been shown to significantly alter the risk of acute urinary retention or BPH-related surgery. 5-reductase inhibitors act by preventing the conversion of testosterone to dihydrotestosterone, which is a primary contributor to prostatic enlargement in BPH.2,3 DHT contributes to cellular proliferation and inhibition of apoptosis in the prostate, and 5-reductase inhibitors counteract the actions of DHT. 5-reductase inhibitors thus act at the pathophysiologic substrate of BPH. They do not provide fast relief of LUTS. However, they do retard or prevent disease progression as reflected in reduced prostate volume and serum PSA values as well as reduced risks of acute urinary retention and BPH-related surgery. Thus, the combination of a 5-reductase inhibitor and an alpha blocker can in theory provide both the disease-arresting efficacy and rapid symptom relief. References 1. Clifford GM, Farmer RDT. Medical therapy for benign prostatic hyperplasia: A review of the literature. Eur Urol. 2000;38:2–19. 2. Ekman P. Finasteride in the treatment of benign prostatic hypertrophy: An update. Scand J Urol Nephrol. 1999(Suppl 203):15–20. 3. Bartsch G, Rittmaster RS, Klocker H. Dihydrotestosterone and the concept of 5α-reductase inhibition in human benign prostatic hyperplasia. World J Urol. 2002;19:413–425. Combination Therapy: Arrest Disease Progression and Rapidly Relieve Symptoms

Finasteride and doxazocine combination In selected patients, combination therapy is most effective in Reducing risk of clinical progression Improving AUA symptom score Improving maximum urinary flow rate Monotherapy significantly reduces risk of clinical progression of BPH Finasteride (5ARI) and combination therapy significantly reduce the risk of AUR and invasive therapy Doxazosin (-adrenergic blocker) prolongs time to progression of AUR and invasive therapy, but does not reduce overall risk Both long-term monotherapy and combination therapy are safe and effective

Combination Treatment with An -Blocker Plus An Anticholinergic for Bladder Outlet Obstruction: Efficacy Improved QoL Increased bladder capacity Safety No acute urinary retention was observed Did not affect quality of urinary flow Did not affect postvoid residual urine volume “The proposed combination of Detrol® and tamsulosin appears to be an effective and relatively safe treatment option in patients with bladder outlet obstruction and detrusor overactivity”

Indications for Surgery Bothersome symptoms despite treatment BPH-related complications Urinary Retention (inability to void) Bladder calculi Recurrent UTI Recurrent hematuria from the prostate Upper tract dysfunction (hydronephrosis, renal dysfunction) Surgical approach will depend on: Patient’s prostate size Surgeon’s judgment Patient’s co-morbidities

Transurethral resection of the prostate (TURP) Standard of care Uses electrosurgery to “core” out the obstructive tissue

Treatment of BPH: Summary Watchful Waiting Patients with mild symptoms Alpha Blocker Relaxes prostatic smooth muscle Rapid relief of symptoms (within 2 weeks) May not address eventual progression 5--reductase inhibitor Decreases prostate volume “Slower” acting (3-6 months) May reduce risk of progression More suitable for larger prostates Combination Therapy