I have nothing to disclose Men s Health 2016 Mindi Miller, Pharm. D., BCPS Topics Benign Prostatic Hyperplasia Erectile Dysfunction Learning Objectives Describe common lower urinary tract symptoms (LUTS) seen in patients with benign prostatic hyperplasia. Describe the medical treatment options for BPH. Identify common risk factors for ED along with measures for risk reduction Describe medical treatment options for ED Discuss the controversy of testosterone replacement therapy and connection to heart disease The Prostate Gland The prostate is a heart-shaped gland located below the bladder It also surrounds the urethra The normal adult prostate weighs 15-20Gm It is composed of three types of tissue: Epithelial Stromal (contain alpha-1 receptors) The capsule (contain alpha-1 receptors) Two major functions of the prostate: Secreting fluids that contribute to the seminal fluid Secreting fluids that have an antibacterial effect Benign Prostatic Hyperplasia describes a proliferative process of both epithelial and stromal cells in the prostate. BPH is a benign neoplasm. BPH Definition
Epidemiology Risk Factors for BPH BPH is the most common benign neoplasm of men Disease prevalence is dependent on age: 50% of men have BPH by age 60 90% of men have BPH by age 80 Known Risk Factors Age Major Risk Factor Family history Possible Risk Factors Obesity Hypertension Low HDL Diabetes High insulin levels BPH Pathophysiology BPH Pathophysiology Symptoms of BPH (LUTS) are caused by Enlarged prostate tissue Contraction of the prostate capsule Testosterone, the primary androgen in males, is converted by 5 alpha reductase to dihydrotestosterone (DHT). DHT binds to the androgen receptor, initiating a cascade of events that lead to prostate growth. Enlarged Prostate Tissue (Static Component) Physically blocks the bladder neck to obstruct urine outflow Due to the effects of dihydrotestosterone (DHT) Contraction of the Prostate Gland (Dynamic Component) Narrows urethral lumen Due to excessive alpha adrenergic tone Symptoms of BPH (LUTS*) Obstructive Symptoms Due to mechanical obstruction from enlarged prostate Weak urine stream Incomplete bladder emptying Dribbling Hesitancy Need to strain to urinate Irritative Symptoms Due to excessive alpha receptor stimulation and involvement of the detrusor muscle Urgency Frequency Nocturia Complications of Untreated BPH Acute urinary retention Urinary tract infection Bladder stones Damage to the bladder Renal Impairment Hematuria *Lower urinary tract symptoms
Diagnosis of BPH AUASI History and Physical Digital Rectal Exam American Urological Association Symptom Index (AUASI) Laboratory Studies Urinalysis Prostate Specific Antigen (PSA) BUN/Scr Scoring of the AUASI Treatment of BPH BPH Symptom Severity Score 0-7 Mild BPH Score 8-19 Moderate BPH Score 20 Severe BPH General Guidelines Main goal of therapy is to improve symptoms Secondary goals Halt disease progression Prevent complications Quality of Life and Patient Choice is most important consideration Treatments Lifestyle Modifications Alpha-adrenergic antagonists 5-Alpha Reductase Inhibitors PDE-5 Inhibitors Combination Therapy Phytotherapy Surgery Minimally Invasive Therapy Lifestyle Modifications Alpha-1 Adrenergic Antagonists Fluid restriction at night Avoidance of caffeine, alcohol, and drugs that worsen symptoms Scheduled or frequent bladder emptying Smoking cessation Increased physical activity Terazosin (Hytrin ) Doxazosin (Cardura ) Alfuzosin (Uroxatral ) Tamsulosin (Flomax ) Silodosin (Rapaflo )
Alpha Blockers Comparison of Alpha-1 Blockers Work to relax smooth muscle tone and resistance in the prostate and bladder neck 3 alpha-1 receptor subtypes Alpha 1a Alpha 1b Alpha 1d 80% of all receptors in the prostate gland are alpha-1a subtype Drug Dosing Titration Uroselective Terazosin 1mg, 2mg + No 5mg, 10mg Doxazosin 1mg, 2mg, + No 4mg, 8mg Tamsulosin 0.4mg + 1a=1d>1b 0.8mg Alfuzosin 10mg - No Silodosin 8mg - 1a>1d>1b Alpha Blockers: Adverse Effects Drug Interactions Fatigue Orthostatic hypotension Dizziness Vertigo Syncope Sexual Dysfunction Edema Retrograde ejaculation Rhinitis Dyspnea/wheezing Headache Angina Floppy Iris syndrome during cataract surgery Possible lengthening of QT interval with Alfuzosin Use with antihypertensive drugs can cause additive hypotensive effects Doxazosin Terazosin Cimetidine decreases clearance Tamsulosin Contraindicated with potent CYP3A4 inhibitors Ketoconazole Itraconazole Ritonavir Benefits of Treatment with Alpha Blockers Rapid improvement of urinary flow Reduce symptoms of LUTS Similar efficacy with all drugs Modest effect on sexual function (except Tamsulosin) 5 Alpha-Reductase Inhibitors Finasteride (Proscar ) Dutasteride (Avodart )
5-ARIs Reduce the size of the prostate gland Slow progression of BPH Decrease the need for surgery Ideal for patients with large prostate volumes (>40gm) Symptom reduction may take 6-12 months Serum PSA levels are decreased by approximately 50% Finasteride Dutasteride 5AR inhibition Type II Types I and II Serum DHT 70% 90% Testosterone 14-20% 14-20% PSA 50% 50% Prostate size 20-30% 15-26% Comparable between finasteride and dutasteride Adverse Effects Erectile Dysfunction Altered Libido Ejaculatory Dysfunction Gynecomastia and Breast Tenderness Dose 5mg QD 0.5mg QD Phosphodiesterase Type-5 Inhibitors Sildenafil (Viagra) Tadalafil (Cialis)* Vardenafil (Levitra) Avanafil (Stendra) Combination Therapy: Alpha Antagonist and 5ARI Dual mechanism of action Reduce clinical progression of BPH Improved LUTS symptoms Improved urine flow rates MTOPS trial results comparing placebo, finasteride 5mg, doxazosin 4mg or 8mg, and placebo *has FDA approval for treatment of BPH
Phytotherapy For BPH Surgery for BPH Saw palmetto (Serenoa repens) African plum (Pygeum africanum) Pumpkin (Cucurbitae peponis semen) South African star grass (Hypoxis rooperi) Stinging nettle (Urtica dioica) Surgery (TURP) remains the gold standard for treatment of BPH Most reliable and immediate subjective and objective improvement Surgery is recommended in BPH patients who also have Renal insufficiency Urinary retention Recurrent UTI Bladder stones Hydronephrosis Post void residual (PVR)* volume>500ml *Amount of urine left in the bladder after the patient voids Types of Surgery for BPH Learning Assessment Open Prostatectomy Transurethral resection of the prostate (TURP) Minimally Invasive Techniques Transurethral needle ablation (TUNA) Transurethral microwave therapy (TUMT) Laser resection or ablation Transurethral incision of the prostate (TUIP) Water-Induced Thermotherapy Ethanol Invection Which class of medication provides the quickest relief of LUTS associated with BPH? Which class of medication provides the best relief for patients with large prostate glands? Erectile Dysfunction (ED) Pathophysiology Definition Inability to achieve or maintain an erection sufficient for satisfactory sexual performance. Usually the problem persists for 6 months or longer. Prevalence 12% in men < 59 22% in men 60-69 30% in men >69 ED may result from Organic causes Vascular Atherosclerotic plaques Trauma Radiation Neurogenic Stroke Seizures Diabetes Hormonal Increased prolactin Decreased testosterone Hormonal Increased prolactin Decreased testosterone Anatomic Medical Conditions Angina Asthma, COPD Drug-Induced Psychological causes Performance anxiety Depression Combination
Normal Sexual Response Risk Factors for ED Normal sexual response results from an interaction between neurotransmitter, biochemical, and vascular smooth muscle responses initiated by parasympathetic and sympathetic neuronal triggers that integrate physiologic stimuli of the penis with sexual perception and desire. Process of arousal Parasympathetic activity cause a release of Nitric Oxide (NO) NO is a potent vasodilator which causes smooth muscle relaxation and arterial influx of blood into the corpus carvernosum in the penis NO increases cgmp which enhances smooth muscle relaxation This is followed by compression of venous return, which promotes an erection Advancing age Cardiovascular disease Cigarette smoking Diabetes mellitus History of pelvic irradiation or surgery Hormonal disorders Hypercholesterolemia HTN Illicit drug use Medications Neurologic conditions Obesity Peyronie disease* Psychological conditions Sedentary lifestyle Venous leakage Peyronie disease is characterized by scar formation under the skin of the penis. The condition causes curvature and pain during erection. Medications that contribute to ED Diagnosis of ED Opiates Anticonvulsants Phenytoin Phenobarbital Antidepressants Lithium MAO inhibitors SSRIs TCA Antihistamines Antihypertensives Anti-Parkinson agents Cardiovascular agents Digoxin Disopyramide Gemfibrozil Methotrexate Diuretics Hormones Illicit drugs (cocaine, marijuana), alcohol, nicotine Sedatives Patient History Medical Social Interview of patient s partner Complete Drug List Physical Exam General Cardiovascular exam Lab Tests Fasting blood glucose Lipid profile Testosterone* Thyroid panel At least two early morning serum testosterone levels should be obtained. Treatment for ED Identify and Reverse Underlying Causes Psychotherapy Treatment of Disease Lifestyle Modifications Pharmacotherapy Nonpharmacologic Treatment Surgical Procedures Lifestyle Modifications Smoking cessation Treat hyperlipidemia Treat HTN Decrease alcohol intake Discontinue illicit drugs Weight reduction Exercise Medication changes
Pharmacotherapy Phosphodiesterase 5 inhibitors Sildenafil (Viagra) Tadalafil (Cialis) Vardenafil (Levitra) Avanafil (Stendra) First line treatment of ED Inhibit phosphodiesterase type 5 in the penile tissue, which prevents the breakdown of cgmp Increase smooth muscle relaxation in the corporus cavernosum and enhance penile rigidity The drugs are considered to be equally effective Comparison of PDE-5 Inhibitors Common Side Effects of PDE5 Inhibitors Contraindications/Cautions PDE5 Inhibitors should not be used in men taking nitrates due to a possible serious (or fatal) drop in blood pressure Patients with CAD should undergo cardiovascular risk stratification; low risk patients may receive low dose ED medication Patients with a prior diagnosis of nonarteritic ischemic optic neuropathy (NAION) should not take PDE5 inhibitors PDE5 inhibitors are metabolized by cytochrome P450 3A4 and may affect metabolism of protease inhibitors and antifungal medications Pharmacotherapy: Testosterone Therapy (TT) 12% of patients with ED have hypogonadism Patients may be treated with testosterone therapy or a combination of TT and a PDE5 inhibitor Patients with a normal testosterone level should not receive TT Testosterone Replacement Therapy (TT) Transdermal patch (Androderm, Testoderm) Placed daily Topical Gel (Testim, AndroGel, Fortesta) Applied once daily Topical Solution (Axiron) Apply under arms once daily Buccal Tablets (Striant) Applied to gum region above the incisor tooth twice daily Implantable pellet (Testopel) Implanted every 3-4 months IM injections Given every 2-3 weeks Intranasal (Natesto) Given 3 times daily in each nostril
Potential Adverse Effects Associated with TT Irritation at skin application site (transdermal patch and topical gel) Acne Worsening BPH Elevated PSA Increase in RBC, Hct Lipid abnormalities LFT abnormalities Secondary exposure with gel (women and children) Suppression of spermatogenesis Edema Gynecomastia Sleep apnea Monitoring of Patients on TT Baseline Document symptoms Physical exam Blood tests Serum testosterone and PSA 1 month after initiating therapy Assessment of symptom improvement Blood test Serum testosterone 6 months after initiating therapy (and every 6-12 months) Assessment of symptom improvement Physical exam Blood tests Serum testosterone PSA CBC Lipid panel Hepatic panel Learning Assessment Pharmacotherapy: Alprostadil True or False: Testosterone Therapy is associated with a higher risk for prostate cancer. Alprostadil (prostaglandin E 1 ) increases camp which relaxes smooth muscle and causes an erection Available as an intracavernosal injection (Caverject and Edex) and as an intraurethral insert (medicated urethral system for erection or MUSE) Adverse effects Penile pain Cavernosal scarring Priapism Drug interactions Do not use with PDE5 inhibitors Pharmacotherapy: Yohimbine Not FDA approved and not recommended by the AUA Derived from the bark of the Central African tree Pausinystalia yohimbe Competitive antagonist for alpha 2 adrenergic receptors Peripheral effects increase parasympathetic action and decrease sympathetic action Increases blood flow to the penis In a meta-analysis of several trials, yohimbine was marginally superior to placebo Contraindicated with renal dysfunction Adverse reaction were infrequent CNS excitation Increased heart rate Increased blood pressure Nervousness Irritability Skin flushing Headache Nonpharmacologic Treatment: Vacuum Erection Devices (VED) Used in patients who are not candidates or fail pharmacologic treatment Effective in 35-90% of patients The device uses negative pressure to draw blood into the penis A restrictive band is used to maintain the erection Low patient acceptability Contraindication Use of anticoagulants Sickle cell anemia Blood dyscrasias
Surgical Procedure for ED Penile Prosthesis Invasive Two types of prostheses Malleable Inflatable Associated with 90% satisfaction rate Success rate 82-98% Adverse effects: Infection Mechanical failure of the prosthesis Other Treatments for ED Shockwave therapy Endovascular treatment Apomorphine Ginseng Papaverine Phentolamine Trazodone