Lec. 5 BPH 2024-2025 PDF

Department of Clinical Pharmacy/Fifth stage Therapeutic I Lec. 5 BPH 2024-2025 Dr. Dunya Habeeb Shnain B.Pharm. FIBMS Clinical pharmacy Benign prostatic hyperplasia (BPH): Is a non-cancerous condition in which an enlarged prostate compresses...

Department of Clinical Pharmacy/Fifth stage Therapeutic I Lec. 5 BPH 2024-2025 Dr. Dunya Habeeb Shnain B.Pharm. FIBMS Clinical pharmacy Benign prostatic hyperplasia (BPH): Is a non-cancerous condition in which an enlarged prostate compresses the urethra, blocking the outflow of urine. Epidemiology: Benign prostatic hyperplasia (BPH) is the most common benign tumor in men and its prevalence increase with age. It is responsible for urinary symptoms in the majority of males older than 50 years. By the age of 80 years, virtually all men experience one or more of the symptoms associated with BPH. Etiology of BPH: Two chief etiologic factors for BPH include advanced patient age and the stimulatory effect of androgens. Within the prostate, testosterone is converted by 5α-reductase to dihydrotestosterone (DHT). DHT is five times more potent than testosterone and is responsible for stimulating growth factors that influence cell division, leading to prostatic hyperplasia and enlargement. Pathophysiology: The precise pathophysiologic mechanisms that cause BPH are not clear. Both intraprostatic dihydrotestosterone (DHT) and type II 5α-reductase are thought to be involved. BPH commonly results from both static (gradual enlargement of the prostate) and dynamic (agents or situations that increase α-adrenergic tone and constrict the gland’s smooth muscle) factors. Clinical Presentation: In early stages of disease, the patient may complain of obstructive voiding symptoms. Obstructive signs and symptoms result when dynamic and/or static factors reduce bladder emptying due to obstruction of the urethra by the enlarged prostate. Patients experience urinary hesitancy, urine dribbles out of the penis, and the bladder feels full even after voiding, besides weak urinary flow and intermittent stream. If BPH untreated, the disease may progress, and the patient may complain of irritative voiding symptoms [sometimes called storage symptoms] and So the Patients experience urinary frequency, urgency, and nocturia.  Obstructive and irritative voiding symptoms are referred to as lower urinary tract symptoms (LUTS) which is not limited to BPH but may also be caused by neurogenic bladder or urinary tract infections or prostatitis or even prostate cancer. Patients may also present with chronic urinary retention. Here, the bladder slowly distends due to inadequate emptying over a long period of time. Some patients present suddenly with acute urinary retention, when they are unable to micturate and develop a painful, distended bladder. This is often precipitated by excessive alcohol intake, constipation, or prostatic infection. Examples of drugs that can exacerbate symptoms include: 1-Testosterone 2-α-adrenergic agonists (eg, decongestants) 3-Those with significant anticholinergic effects (eg, antihistamines, phenothiazines, tricyclic antidepressants, antispasmodics, and antiparkinsonian agents). Severity of Symptoms: Severity of symptoms should be assessed by the patient using a standardized instrument (eg, the American urology association (AUA) Symptom Scoring Index). According to this instrument: BPH is mild if score≤7; moderate if score 8-19; and severe if score ≥20. Signs of BPH: Distended urinary bladder and enlarged prostate on digital rectal examination (DRE). Complications of BPH: BPH progression may produce complications including chronic kidney disease, gross hematuria, urinary incontinence, recurrent urinary tract infection and bladder stones. Some patients develop acute urinary retention. Erectile dysfunction commonly develops in patients with BPH. Diagnosis: 1- Careful medical history: especially the presence of diabetes mellitus, or medications that may cause or worsen voiding symptoms) 2- Physical examination: digital rectal examination On digital rectal examination, the prostate is usually but not always enlarged (>20 g), soft, smooth, and symmetric. 3- Objective measures of bladder emptying (eg, peak and average urinary flow rate and postvoid residual [PVR] urine volume). If PVR is greater than 50 mL, patients have an increased risk of infection. 4- Laboratory tests (eg, urinalysis and prostate-specific antigen [PSA]). Treatment: The goals are to control symptoms, prevent progression of complications, and delay need for surgical intervention and Maintaining or improving quality of life. The range of treatment options for the management of BPH includes watchful waiting/lifestyle advice, medical therapies and surgical interventions. The choice depends on severity of signs and symptoms. If the AUASI score is 0–7 (mild), use watchful waiting. Patients with moderate disease (scores 8–19) are candidates for medical treatment. Patients with high AUASI scores of 20 and more (severe disease) should be assessed for prostatectomy. Non-Pharmacological Treatment: Surgery (Prostatectomy) is indicated for patients: 1- who are at risk of disease progression (ie, those with large prostates > 30 g), 2-have moderate-severe symptoms and 3-who are unresponsive to or intolerant of drug treatment, 4-or have complications of BPH disease. Patients who present with acute retention require urgent treatment and should undergo immediate catheterization to relieve the obstruction. ‫يحتاج املرضى الذين يعانون من االحتباس الحاد إلى عالج عاجل ويجب عليهم‬.‫يخضع للقسطرة الفورية لتخفيف االنسداد‬ Behavioral Modification (Lifestyle Advice): 1. Fluid restriction before bedtime 2. Minimizing caffeine and alcohol intake 3. Frequent emptying of the bladder 4. Avoiding drugs that exacerbate voiding symptoms, like antihistamines and decongestants. Patients who take a diuretic should avoid taking it in the evening. 1- Watchful Waiting: If this option was chosen then, patients are reassessed at 6–12 month intervals and educated about behavior modification. 2- Pharmacological Therapy: Treatment options are: 1-α-adrenoceptor blocking drugs 2-5α-reductase inhibitors 3-antimuscarinic antagonists 4-β3 agonists 5-phosphodiesterase inhibitors (tadalafil) and combination therapies.  The first-line treatments are α1A-adrenoceptor blockers such as tamsulosin. α1- adrenergic antagonists are preferred over 5α-reductase inhibitors because(α1- adrenergic antagonists ) have a faster onset of action (days to a few weeks) and improve symptoms independent of prostate size, while 5 α -Reductase inhibitors have a delayed onset of peak clinical effect of 6 months. Besides that, 5α-reductase inhibitors cause more sexual dysfunction. So, they are considered second-line therapy in sexually active males. In general, α1-Adrenergic antagonists are preferred for patients with LUTS, who also have a small prostate (30gm) or a prostate- specific antigen (PSA) level of more than 1.4 ng/mL. Because of the delay in clinical effect, a 5αreductase inhibitor is often taken with an α1-adrenergic antagonist. Combination medication regimens are reserved for patients who have voiding symptoms that do not respond to an adequate trial of single drug treatment or patients who are at high risk of developing complications of BPH. It is usually used for symptomatic patients with a prostate gland more than 40 g and PSA of 1.4 ng/mL (1.4 mcg/L) or more. Consider monotherapy with a phosphodiesterase inhibitor (PI) or use in combination with an α-adrenergic antagonist when erectile dysfunction and BPH are present. A- α-Adrenergic Antagonists: α-Adrenergic antagonists relax smooth muscle in the prostate and bladder neck; so they are increasing urinary flow rates and reducing PVR urine volumes. These agents do not decrease prostate volume or PSA levels. These agents are best for managing acute symptoms but have no impact on reducing the risk of complications such as acute urinary retention or progression to prostate surgery. a. Nonspecific α-adrenergic blockers such as doxazosin and terazosin also lower blood pressure significantly. b. Newer agents are uroselective antagonists of α1-adrenergic receptors (tamsulosin, silodosin) and selective antagonists of postsynaptic α1-adrenergic receptors (alfuzosin) in the prostate and bladder. They may have less associated hypotension.  Prazosin is the first generation α1 antagonists. Current guidelines do not recommend prazosin due to multiple doses/day and significant cardiovascular adverse effects. Doxazosin ,Terazosin, and alfuzosin are second-generation α1-adrenergic antagonists. They antagonize peripheral vascular α1- adrenergic receptors in addition to those in the prostate. Adverse effects include first-dose syncope, orthostatic hypotension, and dizziness. Alfuzosin is less likely to cause cardiovascular adverse effects than other second generation agents and is considered functionally and clinically uroselective Tamsulosin and silodosin, third generation α1-adrenergic antagonists, are selective for prostatic α1A-receptors. Therefore, they do not cause peripheral vascular smooth muscle relaxation and associated hypotension. Uroselective agents (Tamsulosin, silodosin and alfuzocin) are preferred in patients who usually have low blood pressure or those taking multiple antihypertensives. However, selectivity lost at high doses. The onset of action is days to weeks, with peak clinical effects observed in several weeks. So, patients should be advised that it may take 2–6 weeks before symptomatic treatment relief is seen. α1-Adrenergic antagonists are hepatically metabolized. Side Effects: Which includes postural hypotension, dizziness, fatigue, headache, drowsiness, nasal congestion, and ejaculatory dysfunction. Hypotension is most commonly associated with immediate-release terazosin and doxazosin; is less commonly associated with extended- release alfuzosin and doxazosin; and least commonly associated with tamsulosin and silodosin. Hypotensive adverse effects of terazosin and doxazosin can be additive with those of diuretics, antihypertensives, and phosphodiesterase type 5 inhibitors (eg, sildenafil). Alfuzosin has the least effect on ejaculatory function. B- 5α-Reductase Inhibitors: They inhibit 5 α –reductase enzyme, which is responsible for intraprostatic conversion of testosterone to dihydrotestosterone, the active androgen that stimulates prostate tissue growth. So, they result in shrinkage of an enlarged prostate by approximately 15% to 25% after 6 months of continuous treatment. 5α-reductase inhibitors have little impact on short-term acute symptoms but reduce prostate size and improve urinary low and obstructive symptoms in the long-term and These agents slow disease progression and decrease the risk of complications. The two agents currently available in this group are finasteride and dutasteride which are considered to be therapeutically equivalent. 5α-Reductase inhibitors may be preferred in patients with uncontrolled arrhythmias, poorly controlled angina, requirement for multiple antihypertensives, or intolerance to the hypotensive effects of α1-adrenergic antagonists. Measure PSA at baseline and again after 6 months of therapy. If PSA does not decrease by 50% after 6 months of therapy in an adherent patient, evaluate the patient for prostate cancer. Side Effects of 5 Alpha Reeducates Inhibitors: Sexual dysfunction, including decreased libido, erectile dysfunction, ejaculation disorders, and gynecomastia, occurs in 5% to 15% of treated patients with reductase inhibitors. the incidence is higher with dutasteride than for finasteride. Dutasteride has been shown to increase insulin resistance in adipose tissue and may be associated with an increased risk of congestive heart failure. The 5 alpha reductase inhibitors are associated with a dose-related increased risk of osteoporosis. 5α-Reductase inhibitors are in FDA pregnancy category X and are therefore contraindicated in pregnant women. As the drugs may cause feminization of a male fetus. Women who are pregnant or seeking to become pregnant should not handle the tablets [unless wearing gloves] or have contact with semen from men taking 5αreductase inhibitors. C- Phosphodiesterase Inhibitors: They increase intracellular cyclic guanosine monophosphate, thus reducing smooth muscle tone (relaxes smooth muscle) of the detrusor, prostate, and urethra. Tadalafil is preferred over other PIs because of its longer plasma half-life, which is beneficial in chronic diseases. It improves voiding symptoms but does not increase urinary flow rate or reduce PVR urine volume. May be used in practice to treat both BPH and erectile dysfunction Tadalafil should be avoided if the creatinine clearance is less than 30 mL/min. Tadalafil is contraindicated in patients on nitrates by any route of administration and in some medical conditions (eg. unstable angina), heart failure, MI, persistent hypotension. To minimize an additive blood pressure lowering effect, a uroselective alpha 1Aadrenergic antagonist may be preferred when combined with tadalafil D- Anticholinergic Agents: Irritative voiding symptoms are due to involuntary detrusor muscle contraction in response to small volumes of urine in the bladder. The detrusor muscle is innervated with muscarinic receptors. Anticholinergic agents are indicated when a patient has aggravating irritative voiding symptoms despite treatment with an alpha 1-adrenergic antagonist. The following agents are currently available for treating storage symptoms (irritative voiding symptoms): darifenacin, fesoterodine, oxybutynin, propiverine, solifenacin, tolterodine and trospium. Start with lowest effective dose to determine tolerance of CNS adverse effects and dry mouth.  If irritative symptoms do not improve after starting an anticholinergic agent, up titrating the dose, or switching to another anticholinergic agent may be helpful. Anticholinergic adverse effects, including dry mouth, tachycardia, constipation, confusion, and drowsiness. Finally, elderly patients have a high risk of cognitive impairment from anticholinergic agents. The adverse effects of anticholinergics are dose-related and may be poorly tolerated and require drug discontinuation. Consider transdermal (eg, oxybutynin) or extended-release formulations (eg, tolterodine) or uroselective agents (eg, darifenacin or solifenacin) if systemic anticholinergic adverse effects are poorly tolerated. E- Mirabegron: Mirabegron is a β3-adrenergic agonist that relaxes the detrusor muscle [but not reduce bladder contractility] and thus reducing irritative voiding systems, increases urinary bladder capacity, and increases the interval between voiding. It does not cause anticholinergic adverse effects and is an alternative to anticholinergic agents in patients with LUTS. Common adverse effects of mirabegron include headache, hypertension, tachycardia, constipation, and nasopharyngitis. So should be avoided in those with uncontrolled hypertension and if Cr clearance less than 15 ml/min. Thank you