BPH Treatment PDF

Therapeutics II BENIGN PROSTATIC HYPERPL ASIA D r. M o h a m m e d Z a w i a h Learning Objectives 1. Understand the basic pathophysiology of BPH. 2. Identify pharmacological treatment options for BPH. 3. Recognize criteria for selecting appropriate treatment based on disease severity. 4....

Therapeutics II BENIGN PROSTATIC HYPERPL ASIA D r. M o h a m m e d Z a w i a h Learning Objectives 1. Understand the basic pathophysiology of BPH. 2. Identify pharmacological treatment options for BPH. 3. Recognize criteria for selecting appropriate treatment based on disease severity. 4. Evaluate common adverse effects associated with BPH medications. 5. Discuss combination therapies and alternative treatment strategies for BPH. References 1. Stuart T. Haines, 2023, DiPiro’s Pharmacotherapy: A Pathophysiologic Approach, 12th Edition, McGraw Hill. 2. Terry L. Schwinghammer, 2023, Schwinghammer’s Pharmacotherapy Casebook: A Patient-Focused Approach, 12th Edition, McGraw Hill. 3. Marie A. Chisholm-Burns, 2022, Pharmacotherapy Principles & Practice, 6th Edition, McGraw Hill. 4. Caroline S Zeind, Applied Therapeutics: 2023, The Clinical Use of Drugs, 12th Edition, North American, LWW. 5. ACCP Updates in Therapeutics® 2023: The Pharmacotherapy Preparatory Review and Recertification Course.  Definition Benign prostatic hyperplasia (BPH), is a nonmalignant condition in which an enlarged prostate compresses the urethra, blocking the outflow of urine. Stages: I. BPH: Initial growth. II. Benign Prostatic Enlargement (BPE): Continued growth. III. Benign Prostatic Obstruction (BPO): Advanced obstruction of urine flow (at the level of the bladder neck)  Epidemiology Prevalence of BPH: ∼20% in men aged 41–50 ∼50% in men aged 51–60 > 90% in men over age 80  Pathophysiology Prostate Tissue Types: ▪Stromal (smooth muscle, and collagen). ▪Epithelial (glandular). ▪Capsule (fibrous). Pathophysiology cont.. The pathophysiology of BPH remains incompletely understood but is likely multifactorial. Increased risk of BPH may be related to inflammation and metabolic factors. However, LUTS thought to be due to: Static factor: Prostate growth leading to mechanical obstruction of bladder neck. Dynamic factor: Smooth muscle contraction via α1A-adrenergic receptors. Detrusor factor: Bladder muscle (Detrusor) hypertrophy as well as collagen deposition due to obstruction. Pathophysiology cont.. Hormonal Influence in Static Component: ◦ The development of benign prostatic hyperplasia requires testicular androgens as well as aging. Pathophysiology cont.. Adrenergic Receptors & Phosphodiesterase Type 5 (PDE5) in adynamic factor Smooth muscle cells in the prostate—at the bladder neck and in the prostatic capsule— are richly populated with α-adrenergic receptors. Contraction of the prostate and bladder neck are mediated by α1-adrenergic receptors. 98% of α-adrenergic receptors in the prostate are in stromal tissue. 70% are α1A subtype, with the remainder being α1B and α1D. Stimulation of these receptors results in a dynamic increase in prostatic urethral resistance. The PDE5 enzyme has been found throughout the urinary tract, where it works to break down the intracellular smooth muscle relaxant, cyclic guanosine monophosphate (cGMP). Pathophysiology cont.. Bladder Response to Obstruction (Detrusor factor). Many of the clinical symptoms of benign prostatic hyperplasia are related to obstruction-induced changes in bladder function rather than to outflow obstruction per se.  Pathophysiology Bladder Response to Obstruction (Detrusor factor). Obstruction-induced changes in bladder function are of two basic types. I. First, there are changes that lead to detrusor overactivity (instability). These are clinically manifested by frequency and urgency. Thus, treating the bladder overactivity may have more impact than treating the obstruction. II. Second, there are changes that lead to decreased detrusor contractility. These are clinically manifested by symptoms of decreased force of the urinary stream, hesitancy, intermittency, increased residual urine, and, in a minority of cases, detrusor failure.  Medication-related Symptoms Medication Category Examples Reason for Avoidance in BPH Testosterone Replacement Increases DHT production in the prostate, potentially Testosterone regimens Therapy worsening prostate enlargement and urinary retention. Stimulates α-adrenergic receptors in the prostate, causing Pseudoephedrine, Ephedrine, α-Adrenergic Agonists muscle contraction and narrowing the urethral lumen, Phenylephrine compromising bladder emptying. Causes relaxation of the bladder detrusor muscle, β-Adrenergic Agonists Terbutaline preventing proper bladder emptying. In large doses, can cause polyuria, leading to urinary Diuretics Various diuretic medications frequency similar to BPH symptoms. Antihistamines, Phenothiazines, Decreases contractility of the bladder detrusor muscle, Tricyclic Antidepressants, Anticholinergic Medications impairing bladder emptying and worsening urinary Antispasmodics, Parkinson’s retention. disease drugs  Risk Factors The risk factors for BPH include ▪Age ▪Race ▪Genetic susceptibility ▪Metabolic syndrome ▪Diabetes ▪Obesity ▪hypertension ▪Beverage consumption ▪sex hormone levels ▪Dietary factors (Dietary lycopene, beta-carotene, total carotenoids) Clinical Presentation  AUA/IPSS Score American Urological Association (AUA); International Prostate Symptom Score (IPSS), BPH Severity  BPH Complications When BPH progresses, it can produce complications that include the following: 1. Acute, painful urinary retention, which can lead to acute renal failure. 2. Persistent or intermittent gross hematuria when tissue growth exceeds its blood supply. 3. Overflow urinary incontinence or unstable bladder. 4. Recurrent urinary tract infection that results from urinary stasis. 5. Bladder diverticula. 6. Bladder stones. 7. Chronic renal failure from long-standing bladder outlet obstruction  Treatment The goals of treatment: 1. To control symptoms, as evidenced by a minimum of a three-point decrease in the AUA symptom index. 2. To delay progression. 3. To prevent complications and need for surgery. Treatment Treatment options: 1. Watchful waiting 2. Drug therapy 3. Surgery Treatment “Watchful waiting” Initial treatment for patients with mild disease (asymptomatic or have mildly bothersome symptoms) and have no complications of BPH disease. Include: 1. Reassessment at intervals of 6 to 12 months for symptoms (IPSS) and sings (urinary flow rate and PVR urine volume). 2. Patient education about disease. 3. Behaviour modification. 4. Avoiding drugs that can exacerbate BPH. Treatment Behavior modification includes: 1. Restricting fluids close to bedtime. 2. Minimizing caffeine and avoiding alcohol intake. 3. Frequent scheduled voiding. 4. Voiding from the sitting rather than standing position (PLoS One 2014;9:e101320). 5. Increased physical activity and weight loss. 6. Avoiding constipation. Treatment Drug options Treatment Treatment Mild: ◦ In a patient with BPH, BPE, or BPO, if symptoms are mild, watchful waiting is recommended. Moderate to Severe: ◦ If symptoms are moderate-to-severe with a small prostate and low PSA, an α-adrenergic antagonist is recommended. ◦ If symptoms are moderate-to-severe with a large prostate and increased PSA, consider a 5α- reductase inhibitor plus an α-adrenergic antagonist. ◦ If symptoms are moderate-to-severe with predominant irritative voiding symptoms, consider an α-adrenergic antagonist plus an anticholinergic agent, or an α-adrenergic antagonist plus B3 agonist. ◦ If symptoms are moderate-to-severe with erectile dysfunction, a phosphodiesterase inhibitor, an α-adrenergic antagonist or both are recommended. Severe: ◦ If symptoms are severe and the patient has complications of BPH or is not responding to medication therapy, surgical intervention is indicated. Treatment α1-Adrenergic Antagonists αAdrenergic antagonists relax smooth muscle in the prostate and bladder neck. In general, they improve the AUA Symptom Score by 30% to 40%, decreasing the AUA Symptom Index by three to six points, within 1 to 6 weeks. Increase urinary flow rates by 2–3 mL/sec in 60%–70% of patients Reduce PVR urine volumes. Do not decrease prostate volume or PSA levels. Second and third generations α1 adrenergic antagonists are considered equally effective for treatment of BPH. With continued use, durable clinical benefit has been demonstrated for years. Treatment α1-Adrenergic Antagonists o α1 -adrenergic blockers and erectile dysfunction In patients with erectile dysfunction who develop LUTS/BPH, alpha-1 antagonists may be added to treatment with PDE-5 inhibitors, though this combination may cause significant hypotension in some patients. We do not use PDE-5 inhibitors and alpha-1 antagonists for the purposes of combination therapy in patients with isolated LUTS without erectile dysfunction, due to lack of additional efficacy. oalpha blockers and predominant irritative symptoms Beta-3 adrenergic agonists and antimuscarinics may be added to alpha-1 antagonists for persistent LUTS, especially when irritative symptoms predominate. Treatment α1-Adrenergic Antagonists α1 -adrenergic blockers and (hypertension + BPH) An α1 -adrenergic antagonist is not preferred as single- drug therapy for treatment of both BPH and hypertension in a patient. It is recommend that patients with BPH and hypertension be treated with separate and appropriate drug treatment for each medical condition. In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) of 24,000 patients with hypertension, doxazosin produced more congestive heart failure than amlodipine, lisinopril, or chlorthalidone. Treatment α1-Adrenergic Antagonists Non Uroselective: Prazosin (Minipress) is not recommended because of multiple daily dosing, quick onset, and lipophilic structure (increases orthostatic hypotension and syncope). Terazosin (Hytrin) and doxazosin (Cardura) are second- generation α1-adrenergic receptor antagonists. o Immediate-release (IR) terazosin and doxazosin require dose titration to prevent orthostatic hypotension and syncope, thus delaying the time to reach an effective dose. o Doxazosin is available as an extended-release (ER) formulation which may improve tolerability. Treatment α1-Adrenergic Antagonists ◦ Two sample titration schedules for terazosin are as follows: ◦ Schedule 1: Slow titration Days 4 to 14: 2 mg at bedtime Weeks 2 to 6: 5 mg at bedtime Weeks 7 and on: 10 mg at bedtime ◦ Schedule 2: Quicker titration Days 1 to 3: 1 mg at bedtime Days 4 to 14: 2 mg at bedtime Weeks 2 to 3: 5 mg at bedtime Weeks 4 and on: 10 mg at bedtime Treatment α1-Adrenergic Antagonists Uroselective: Tamsulosin (Flomax) and silodosin (Rapaflo) are uroselective based on their affinity for α1A-receptors. Alfuzosin (Uroxatral) is functionally “or clinically” uroselective based on its ER formulation preventing peaks in serum concentrations. These agents target α1A-receptors in the prostate and are less likely to cause hypotension or syncope. These agents improve urinary symptoms within 1 week because they do not require dose titration. Treatment α1-Adrenergic Antagonists Treatment α1-Adrenergic Antagonists Adverse Effects ◦ Hypotensive effects: Can cause dizziness, syncope, and hypotension, especially with immediate-release terazosin and doxazosin. Slow dose titration and bedtime administration can minimize these effects. ◦ Ejaculation disorders (retrograde ejaculation) : Delayed or absent ejaculation is common, especially with tamsulosin and silodosin. This is generally not harmful and often does not require discontinuation. However, if the patient is sexually active and ejaculatory dysfunction is problematic, switching the patient from a third-generation to a second-generation α1 - adrenergic antagonist has been effective. ◦ Flu-like symptoms, nasal congestion and malaise: Tolerance often develops over time, and they rarely require discontinuation of treatment. ◦ Floppy iris syndrome: Primarily with associated with, silodosin, tamsulosin, and doxazosin use, although the number of reported cases is highest with tamsulosin which can complicate cataract surgery. Patients should inform their surgeon about α1-adrenergic antagonist use before surgery. ◦ Patients with severe sulfa allergy should avoid tamsulosin. Treatment α1-Adrenergic Antagonists How to minimize first-dose syncope from terazosin and doxazosin immediate-release? A slow up-titration from a subtherapeutic dose of 1 mg/day to a therapeutic dose is essential. The first dose should be given at bedtime so that the patient can sleep through the peak serum concentration of the drug when the adverse effect is most likely to occur. A 3- to 7-day interval between each dosage increase should be allowed, and the patient should be maintained on the lowest effective dose of the α1- adrenergic antagonist. Treatment α1-Adrenergic Antagonists What should be done If the patient is noncompliant with his regimen or he skips or interrupts treatment with terazosin and doxazosin immediate-release? It should be restarted using the usual starting dose and then re-titrated up. What about the missed does? The patient should not be instructed to simply double up on missed doses or resume treatment with the currently prescribed daily dose, as this can lead to significant hypotension or syncope Treatment α1-Adrenergic Antagonists Should patients with poorly controlled angina, serious cardiac arrhythmias, reduced circulating volume, untreated hypertension, or those taking multiple antihypertensives use immediate-release formulations of second-generation α1- adrenergic antagonists? Why? No, should be avoided. Because those patients poorly tolerate hypotension and these formulations are more likely to cause cardiovascular adverse effects like syncope, dizziness, and hypotension. Which alternatives are recommended for them? In such cases, alternatives like alfuzosin, extended-release doxazosin, or third-generation α1-adrenergic antagonists are preferred. Treatment α1-Adrenergic Antagonists Patients who are taking α1 -adrenergic antagonists and who plan to undergo cataract surgery? Should inform their ophthalmologist that they are taking this medication so that appropriate measures can be taken during eye surgery, for example, use of iris retractors, pupillary expansion rings, or potent mydriatic agents. No benefit has been demonstrated with holding the α1 -adrenergic antagonist preoperatively. For patients who are scheduled to have cataract surgery, and who have not yet started an α1 -adrenergic antagonist? They should be advised to delay the start of the α1 -adrenergic antagonist until surgery has been completed. Treatment α1-Adrenergic Antagonists Drug Interactions with α1-Adrenergic Antagonists (Metabolism) CYP 3A4 Inhibitors (e.g., cimetidine, diltiazem): Can decrease the metabolism of α1-adrenergic antagonists. Increases risk of drug accumulation and adverse effects. CYP 3A4 Stimulators (e.g., carbamazepine, phenytoin): May increase hepatic catabolism of α1-adrenergic antagonists. Leads to reduced therapeutic efficacy. Treatment α1-Adrenergic Antagonists Drug Interactions with Phosphodiesterase Inhibitors Phosphodiesterase Inhibitors (e.g., sildenafil, tadalafil): Can cause hypotension when used in large doses with α1-adrenergic antagonists. Risk is higher due to the vasodilatory effects and susceptibility of elderly patients. Clinical Considerations: Tadalafil with third-generation α1A-adrenergic antagonists is the least likely to cause significant hypotension. Ensure blood pressure is stabilized on the α1-adrenergic antagonist before initiating a phosphodiesterase inhibitor. Close monitoring of blood pressure is essential when combining these drugs. Treatment 5α-Reductase Inhibitors 5-α-reductase converts testosterone to dihydrotestosterone (DHT), stimulating prostate growth.5ARIs inhibit this enzyme, They reduce prostate size and PSA levels. They also increase peak urinary flow rate by 1.6 to 2.0 mL/s. They slow disease progression and decrease the risk of disease complications, thereby decreasing the ultimate need for surgical intervention. ◦ A 5ARI trial lasts 6-12 months to achieve results; they do not provide immediate symptom relief. ◦ For patients with severe disease, these agents generally should be used with a 6- month short course of an α1 -adrenergic antagonist; the latter will provide fast symptom relief until the 5α-reductase inhibitor starts to work. Treatment 5α-Reductase Inhibitors 5α-Reductase inhibitors may be preferred for patients with BPH and an enlarged prostate gland who have uncontrolled arrhythmias, have poorly controlled angina, are taking multiple antihypertensive agents, or are unable to tolerate hypotensive adverse effects of α1 -adrenergic antagonists. 5α-Reductase inhibitors also reduce or stop prostate-related bleeding by inhibiting prostatic vascular endothelial growth factor. Thus, the prevalence of gross hematuria in patients with BPH may be reduced with treatment of 5α-reductase inhibitors. Treatment 5α-Reductase Inhibitors Disadvantages Delayed clinical effect: 5α-reductase inhibitors take longer to show effects, making them less suitable for patients with bothersome symptoms. Long-term treatment: Requires 6 to 12 months for an adequate clinical trial and sustained benefit. Less improvement: Provides less improvement in AUA Symptom Score and urinary flow rate compared to α1-adrenergic antagonists. More sexual dysfunction: Higher incidence of sexual dysfunction (e.g., decreased libido, erectile dysfunction) than with α1-adrenergic antagonists. Often considered second-line for BPH in sexually active males due to these disadvantages. Treatment 5α-Reductase Inhibitors Medications: ◦ Finasteride (Proscar): Inhibits type II 5-α-reductase. ◦ Dutasteride (Avodart): Inhibits both type I and II 5-α- reductase, leading to faster and more complete DHT reduction, but no clear clinical advantage over finasteride. Treatment 5α-Reductase Inhibitors PSA Considerations: 5α-reductase inhibitors produce a median reduction of serum PSA levels of 50% at months 6 to 12 after the start of treatment. Baseline PSA should be measured before starting therapy. After 6 months of therapy, the patient should have a repeat PSA. When compared to the pretreatment PSA, if the during-treatment level does not decline by 50% but the patient has been adherent to the 5α- reductase inhibitor regimen, he should be evaluated for prostate cancer. Treatment 5α-Reductase Inhibitors Side Effects: Common: Reduced libido. Rare: Gynecomastia. Prostate Cancer and 5α-Reductase Inhibitors??? ASSINGMENT Pregnancy Category X: Pregnant women should not come in contact with semen from men taking 5- ARIs. Contraindication: Men taking 5-ARIs should not donate blood until at least 6 months after their last dose to avoid transfer to pregnant women. Treatment 5α-Reductase Inhibitors Treatment Phosphodiesterase Type 5 Inhibitors According to the 2021 AUA guidelines, can be used as initial therapy if a patient has concomitant erectile dysfunction (ED) or as an alternative treatment in those with a lack of or incomplete response to α1-antagonist therapy Tadalafil 5 mg/day was FDA approved for the treatment of BPH and BPH/ED. It improves irritative and obstructive voiding symptoms (2 point decrease in AUA score), but doesn’t increase urinary flow rate or reduce PVR urine volume. The starting dose is 2.5 mg/day for patients with reduced CrCl (30–50 mL/minute/1.73 m2 ); tadalafil is not recommended for patients with a CrCl less than 30 mL/minute/1.73 m2. Treatment Phosphodiesterase Type 5 Inhibitors Product labeling for tadalafil and the AUA guidelines recommend against the use of combination α1-antagonist and PDE-5 inhibitor therapy for the treatment of BPH because of a lack of data and the risk of hypotension. If concomitant therapy is initiated, uroselective α1-antagonists would be preferred, and patients taking both PDE-5 inhibitors and α1-antagonists should make sure to separate the doses by at least 4 hours, if possible, to help prevent hypotension. Using a phosphodiesterase type 5 inhibitor with a 5α-reductase inhibitor is reasonable as the former will effectively treat erectile dysfunction, a side effect of the latter. Treatment Phosphodiesterase Type 5 Inhibitors Common adverse effects of tadalafil: Headache Flushing Gastroesophageal reflux Sinusitis Visual disturbances Back pain These side effects are generally mild, reversible, and usually do not require stopping therapy. Back pain: Linked to tadalafil's inhibition of phosphodiesterase type 11 and can be managed with acetaminophen or NSAIDs. Treatment Phosphodiesterase Type 5 Inhibitors In patients using α1-adrenergic antagonists (for blood pressure control): ◦ Stabilize blood pressure before starting tadalafil. ◦ Separate tadalafil and α1-adrenergic antagonist doses by 4 hours. ◦ Prefer tamsulosin, silodosin, or alfuzosin over other α1-adrenergic antagonists. Drug Interactions Nitrates by any route of administration are contraindicated in patients taking tadalafil. Treatment Antimuscarinic agents These agents are recommended by current AUA guidelines as a treatment alternative for men with irritative lower urinary tract symptoms who do not have an elevated post-void residual (PVR). Addition of oxybutynin and tolterodine to αadrenergic antagonists relieves irritative voiding symptoms Start with lowest effective dose to determine tolerance of CNS adverse effects and dry mouth. Measure PVR urine volume before initiating treatment (should be less than 150 mL). 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. Trospium or fesoterodine have a lower propensity to cross the blood brain barrier making them an option for older adults at risk of sedation and confusion.  Treatment Antimuscarinic agents Treatment Antimuscarinic agents Treatment B3 Adrenergic Agonist ◦ Approximately 95% of the β-adrenergic receptors in the urinary bladder are of the β3 subtype. When stimulated, β3 -adrenergic receptors increase production of cyclic adenosine monophosphate (cAMP), which relaxes the detrusor muscle. Reducing irritative voiding symptoms Increasing urinary bladder capacity, Increasing the interval between voidings. Used as an alternative to anticholinergic agents in patients with LUTS, when irritative symptoms persist despite treatment with an α1 - adrenergic antagonist or 5α-reductase inhibitors. Treatment B3 Adrenergic Agonist Treatment Combination therapy: All combinations are summarized in the table next slide. Common example is (α1 -adrenergic antagonist plus a 5α-reductase inhibitor), Commonly used as (finasteride and doxazosin, or dutasteride and tamsulosin) When this combination is used to prevent BPH progression, patients must continue both medications. Studies have shown if the 5α-reductase inhibitor is discontinued, L recurs, and the prostate size may increase. UTS However, when the combination is used for LUTS in patients who are not at risk of BPH complications, the α1 -adrenergic antagonist may be discontinued after 6 or 9 months of continuous treatment with the 5α-reductase inhibitor. Treatment Combination therapy: Treatment Surgical Intervention Prostatectomy (transurethral or suprapubic) is the gold standard for treating: 1. Patients with moderate-to-severe symptoms of BPH (benign prostatic hyperplasia). 2. Those unresponsive or intolerant to drug therapy. 3. Patients who are noncompliant with drug therapy. 4. Prefer surgery. 5. For patients with complications. Complications of transurethral prostatectomy: 1. Retrograde ejaculation in up to 75% of cases. 2. Bleeding, urinary incontinence, and erectile dysfunction in 2%–15% of patients. Treatment Phytotherapy Phytotherapy for BPH is widely used in Europe, but data is inconclusive and conflicting. Herbal products are not regulated by the FDA for efficacy, safety, or quality. Common herbal agents like such as saw palmetto berry (Serenoa repens), stinging nettle (Urtica dioica), and African plum (Pygeum africanum) are not recommended for BPH treatment.  Evaluation Of Therapeutic Outcomes The primary therapeutic outcome of BPH therapy is restoring adequate urinary flow with minimal treatment related adverse effects. Assess efficacy 6–12 weeks after starting treatment. Outcome depends on the patient’s perception of effectiveness and acceptability of therapy. The American Urological Association Symptom Score is a validated standardized instrument that can be used to assess patient quality of life. Objective measures of bladder emptying (eg, urinary flow rate and PVR urine volume) are useful measures in patients considering surgery. Monitor laboratory tests (eg, blood urea nitrogen, creatinine, and PSA) and urinalysis regularly. An annual digital rectal examination and PSA are recommended if life expectancy is at least 10 years. Evaluation Of Therapeutic Outcomes