Urinary Incontinence and BPH

Urinary Incontinence and BPH Fred Farris, PhD Ground Plan What is Urinary Incontinence Relative Anatomy Background Information Main Forms Causes Benign Prostatic Hyperplasia General Information Treatments Micturition Micturition The process by which the urinary bladder empties when it becomes filled. Involves two main steps The bladder fills progressively until the tension in its walls rises above a threshold level. The tension produced in step one elicits the second step. A nervous reflex called the micturition reflex. The micturition reflex empties the bladder or, if this fails, at least causes a conscious desire to urinate. The micturition reflex is an autonomic spinal cord reflex, but it can also be inhibited or facilitated by centers in the cerebral cortex or brain stem. Anatomy of the Urinary System Innervation of the Bladder Bladder Anatomy Hollow, distensible, muscular ,organ Storage Capacity = 500 mL Desire = 200 mL Normal Void = 300 mL Location Behind symphysis pubis Female: Against anterior wall of uterus Male: Above prostate Anatomy of the Bladder Brain Control of Micturition Micturation is the act of urinating It can be inhibited or facilitated by higher centers in the brain. These provide 3 types of controls: Keep micturition partially inhibited, except when micturition is desired Can prevent micturition even if micturition reflex occurs, by tonic contraction of the external bladder sphincter When it is time to urinate, cortical centers can facilitate the sacral micturition centers to help initiate a micturition reflex and also inhibit the external urinary sphincter Innervation of the Bladder Stretch Receptors and Micturition Sensory (afferent) pelvic nerve (stretch) Detrusor muscle – M3 and Beta-3 receptors Internal sphincter – Alpha1 receptor External Sphincter – Nicotinic receptor Prostate Urethra Pons – Micturation Center Empty Bladder Empty bladder means little bladder distension, or stretching Little stretching means sensory pelvic nerve sends slow, infrequent impulses to spinal cord The slow impulses from the pelvic nerve stimulates release of sympathetic impulses via the hypogastric nerve to activate: Alpha-1 receptor on internal sphincter causing contraction Beta-3 receptor causing relaxation of detrusor muscle There are signals that will stimulate the pudendal nerve which is under our voluntary control When the pudendal nerve is stimulated the nicotinic receptors on the external sphincter will contract, to hold our urine in voluntarily Efferent signals to the pelvic nerve are inhibited, relaxing the detrusor muscle Full Bladder Full bladder means stretching of detrusor muscle Pelvic sensory nerve fires rapidly to spinal cord but they continue on to micturition center Hypogastric sympathetic nerve is inhibited No relaxation of detrucor muscle Relaxation of internal sphincter (Alpha-1 receptors) Pelvic efferent nerve is stimulated – causes contraction of detrusor muscle (M3 receptor) Pudendal nerve inhibited – no contraction of external spincter Micturation Transport of Urine from Kidneys to Bladder Cysotometrogram Urinary Incontinence Urinary Incontinence: Definition The involuntary loss of urine which is objectively demonstratable Urinary Incontinence: Statistics An estimated 25 million men and women in the U.S. suffer from urinary incontinence 25% males (6 million) 75% females (19 million) 19 million, represents over 10% of the women in the USA Major impact on patients’ quality of life Estimated that more pads and diapers are sold for adult urinary incontinence than for pediatric use Plays an important role in prompting nursing home admission Risk Factors Advanced Age Neurologic Illness Multiple sclerosis Stoke Parkinson’s Diabetes Obesity Urinary Tract Infections Prostate Enlargement Prior Pelvic Surgeries Bowel Resection Prostatectomy Consequences of Incontinence Decreased Quality of Life Social Withdrawal, Depression Embarrassment, Interference with Activities Contributes to Institutionalization Impacts of Clinical Outcomes Cellulitis, Pressure Ulcers, UTI Falls and Fractures Sleep Deprivation Costs > $19 Billion Incontinence: Three Main Forms Stress Urge Overflow Urge Incontinence The involuntary Associated Overactivity Caused by tumors, with (spasms) detrusor lossinfections, ofis characterized trauma, by neurological involuntary disorders, detrusoretc muscle overactivity contractions urine in association during bladder withfilling and inability of sphincter to retain and/or urine decreased underapressure strong desire to void compliance or “urgency” The involuntary loss of urine in association with a strong desire to void or “urgency” Associated with detrusor muscle overactivity and/or decreased compliance Overactivity (spasms) is characterized by involuntary detrusor muscle contractions during bladder filling and inability of sphincter to retain urine under pressure Caused by tumors, infections, trauma, neurological disorders, etc Stress Incontinence The involuntary loss of urine in the absence of contraction of the detrusor muscle Occurs when the intravesical (intrabladder) pressure exceeds that of the urethra Caused is weakened external sphincter muscles and/or increased intra-abdominal pressure Can often be initiated by a cough, or a sneeze, or a change in position Gravitational pressure may stimulate stress incontinence, especially when standing or walking Overflow Incontinence The involuntary loss of urine in association with blockage of normal excretory route The bladder fills but the patient is unable to urinate because of blockage (usually of the urethra) As pressure increases, urination or leakage finally occurs Blockage may be cause by scar tissue, inflammation, benign prostatic hyperplasia (in men), or unknown causes Causes of Incontinence in Men: Nerve Damage Conditions Diabetes Stroke, Parkinson’s, Multiple Sclerosis Overactive Bladder Spinal Cord Injury Causes of Incontinence in Men: Prostate Problems Benign Prostatic Hyperplasia Prostate Cancer and Treatments Prostatectomy Radiation Basic Evaluation of Male Urinary Incontinence General Health History International Prostate Symptom Score Voiding Diary Physical Examination Genitourinary Neurologic Bowel Movements Basic Evaluation of Male Urinary Incontinence Tests Urinalysis, Urine Culture if Indicated Post-Void Residual Renal Function Studies Imaging Studies, Renal Ultrasound Cystoscopy Urodynamic Study Important Signs and Symptoms Recurrent Urinary Tract Infections > 3 times per year Blood in Urine – Gross or Microscopic Incomplete emptying of bladder with post-void residual Benign Prostatic Hyperplasia Benign Prostatic Hyperplasia (BPH) The most frequently diagnosed neoplasticism disease in aging men Affects 85% of males over the age of 50 By age 90, 50% of males require treatment Clinically characterized by prostatic enlargement sometimes associated bladder outlet obstruction or Lower Urinary Tract Symptoms (LUTS) Bladder outlet obstruction is associated with both urinary incontinence and urinary retention Prostate Anatomy and Physiology • Male genital organ Lying below the bladder neck, between pubic symphysis and rectum • Walnut sized, weighing 10 - 20 g • Contains fibromuscular and glandular tissue and surrounds the prostate urethra • Receives ejaculatory ducts in posterior superior region • Anatomically divided into 4 zones • Peripheral Zone: The largest; representing 70% of mass • Transition Zone: Site of most hyperplasias • Central zone • Anterior Zone: Mostly fibromuscular, with little glandular tissue Prostate Anatomy and Physiology 1. 2. 3. 4. Peripheral Zone – Where most cancers propagate Central Zone Transition Zone – Zone most afflicted by BPH Anterior Zone Prostate Anatomy and Physiology • Prostate contains 30 - 50 branched tubuloalveolar glands, lined by columnar secretory cells • Columnar cells lie on basal layer of cuboidal epithelium, which form small papillary folds • Gland are surrounded by fibromuscular stroma (fibroblasts and smooth muscle) • Glandular ducts empty directly into prostatic urethra • Prostate is also covered by two capsules: • Fibroelastic layer that directly covers the gland • Extraperitoneal fascia • Between them lies the prostate venous plexus Hormones and Prostate Development • Prostate development occurs during the second and third trimesters of intrauterine life and completely depends on the androgens produced by fetal testes • The main androgen responsible for development is dihydrotestosterone (DHT), which results from intracellular conversion from testosterone. • Testosterone conversion into DHT requires mediation of 5-α-reductase, which is mainly found in stromal cells. • Two types of 5-α-reductase convert testosterone into DHT: • Type-1 is in skin, hair follicles and liver, as well as the prostate • Type-2 prevails in prostate but is also found in skin, follicles and liver • Other steroids, such as estrogen and retinoids, also play a role in prostate development Androgens and Prostate Growth • Prostate goes through two phases of growth • Phase one: Development from embryo to maturity • Phase two: Hyperplasia of prostate during aging • In phase one, androgens play a primary role in development • In phase two, androgens play a permissive role • Dihydrotestosterone plays a primary role in prostate growth • Synthesized in prostate from testosterone by enzyme 5𝛼 -reductase, type 2 • Binds to nuclear androgen receptors to stimulate mitogenesis • 10 times more potent than testosterone • Testosterone may also be converted to estrogen by enzyme aromatase but apparently a minor factor Production and Action of DHT Pathophysiology of BPH • In men, aromatase and 5-alpha reductase activity increase with age, leading to decreased testosterone but increased DHT and estrogen • Earliest microscopic signs of BPH begins between 30 and 50 yoa • DHT binds to nuclear androgen receptors to stimulate mitogenicity • Both glandular and stromal tissues undergo hyperplasia in BPH • Of the two, stromal hyperplasia predominates • Anatomically the anterior zone (AZ) is seldom enlarged • The majority of growth occurs in the transition zone (TZ) • The peripheral zone (PZ) is involved to a lesser extent • In rare cases the prostate may reach 200 to 500 g Synthesis of Dihydrotestosterone Synthesis of Estradiol Synthesis of Estrone from Androstenedione Treatment of Urinary Incontinence and Benign Prostatic Hyperplasia Treatment Options Behavioral Pharmacological Intravesical Botox Functional Electrical Stimuli Surgery Pharmacological Treatment Pharmacological Options Anticholinergic Drugs Alpha Receptor Antagonists Type II 5-Alpha Reductase Inhibitors Pharmacological Treatment Of Urge Incontinence Anticholinergic Drugs Block the action of acetylcholine (antimuscarinic) release by parasympathetic nerves that trigger bladder contractions Can be useful in treating overactive bladder and urge incontinenece Limitations: At doses only slightly higher than those needed for benefit, antimuscarinic can produce bladder paralysis and/or urinary retention First generation antimuscarinic are not selective and produce antagonism at other muscarinc receptors throughout the body Dry mouth, difficulty speaking and swallowing Antimuscarinic Drugs Prototype Antimuscarinic Agents Atropine Hyoscine Antimuscarinic Drugs for Urge Incontinence Oxybutynin (Ditropan XL, Oxytrol) Tolterodine (Detrol) Darifenacin (Enablex) Solifenacin (Vesicare) Trospium Chloride Fesoterodine (Toviaz) Prototype Antimuscarinics • Both atropine and hyoscine have been used to treat urge incontinence in the past, but not common today Atropine Hyoscine Oxybutynin • One of the most commonly used drugs to treat overactive bladder and urge incontinence • Belongs to the group of medicines called antispasmodics. Helps decrease muscle spasms of the bladder and the frequent urge to urinate. Oxybutynin Efficacy is well established in several placebo-controlled studies Has smooth muscle relaxant properties that occur at 500 times the concentration that produce antimuscarinic effects At therapeutic concentrations effects appear to be antimuscarinic Five subtypes of muscarinic receptors (M1 - M5) Oxybutynin shows some selectivity (tenfold) for M1 and M3 M3 receptors found in bladder and salivary glands Oxybutynin Pharmacokinetics A tertiary Amine that is well absorbed following po dosing Extensive hepatic first-pass metabolism and low bioavailability (6%) This accounts for large inter- and intrapatient response variability Half-life is 2 hours, necessitating 3 times a day dosing with standard release formulations Primary metabolite, N-desethyl oxybutynin is found at much higher plasma levels that parent drug and probably contributes to overall activity Most patients experience classical antimuscarinic side effects: Dry mouth, constipation, blurred vision, drowsiness Tolterodine • Used to treat symptoms of an overactive bladder, such as urge incontinence. • An antispasmodic, the same as Oxybutynin • Acts at the M2 and M3 receptors • Produces side effects similar to those of Oxybutynin Darifenacin • Used to treat symptoms of an overactive bladder, such as incontinence. • Is an antispasmodic • More selective for the M3 subtype receptor than either Oxybutynin or Tolterodine Solifenacin • Used to treat bladder problems, including neurogenic detrusor overactivity and overactive bladder, such as incontinence. • Is an antispasmodic • A competitive antagonist with selectivity for the M3 subtype receptors Solifenacin Used for urge incontinence and neurogenic detrusor overactivity Binds to the M3 receptors in the bladder Peak plasma levels are reached 3 to 8 hrs after po dosing Drug is 98% bound to plasma proteins in the blood Metabolism is mediated by CYP3A4 There are 3 inactive metabolites and 1 active metabolite; 4R-hydroxysolifenacin Half-life is 45 to 68 hours Of the administered drug, 69% is excreted renally as both parent and metabolites; 23% is excreted in the feces Trospium Chloride • Used to treat symptoms of overactive bladder, such as incontinence. • Belongs to the group of medicines called antispasmodics. Helps decrease muscle spasms of the bladder and the frequent urge to urinate. Fesoterodine • Used to treat symptoms of overactive bladder, such as incontinence. • Is an antispasmodic • Is a prodrug, metabolized to its active form desfesoterodine by plasma esterases Fesoterodine. Desfesoterodine Pharmacological Treatment of BPH Pharmacological Classes 5𝛼-Reductase Inhibitors • 𝛼 Adrenergic Antagonists 5α-Reductase Also known as 3-oxo-5α-steroid-4-dehydrogenases Enzymes involved in steroid metabolism Participate in 3 metabolic pathways Bile Acid Biosynthesis Androgen metabolism Estrogen metabolism Three isozymes of the enzyme: SRD5A1, SRD5A2, SRD5A3 vary from tissue to tissue and with age 5𝛼 -Reductase Inhibitors (Prostate Shrinkers) Fenasteride (Proscar) Dutasteride (Avodart) Finasteride (Proscar) A Type II 5-Alpha Reductase Inhibitor Competitiv irreversible inhibitor of 5-Alpha Reductase Type 2 and 3 (involved in conversion of testosterone to 2Dihydrotestosterone) Has been shown to reduce circulating DHT by 65% to 70% Finasteride (Proscar) • Several studies show reduction in prostate size in BPH patients treated with Finasteride for periods of a year or more • In these studies, surgery and urinary retention reduced by 50% • Observations are consistent with the effect of Finasteride on Gland size and/or growth • Disappointingly, in most studies, Finasteride had little effect on BPH symptoms • Major adverse effect is reduction in libido in up to 15% of patients • Three forms of 5𝛼-reductase; Type 1 (skin, liver, prostate), Type 2 (prostate), and Type 3 (ubiquitous) • Finasteride inhibits only Types 2 and 3 • Argued that DHT produced ny Type 1 may maintain prostate growth Dutasteride (Avodart) Competitive irrevesible inhibitor of 5𝛼-reductase Inhibits all three Types of 5-Alpha Reductase and reduces circulating DHT by 98% Adrenergic Antagonists Tamsulosin (Flowmax) Doxazosin (Cardura) Terazosin (Hytrin) Silodosin (Rapaflo) Alfuzosin (Uroxatral) Mirabegron (Myrbetriq) Tamsulosin (Flomax) Higher selectivity to α1A receptors than 𝛼1B and α1D Antagonism at 𝛼1A receptors in prostate and bladder appear to be responsible for prostatic tone Antagonism of these receptors results in relaxation of smooth muscle in prostate and bladder, increased urinary flow, and alleviation of lower urinary tract symptoms (LUTS) Once a day dosing (Half-life of 16 hr) Doxazosin (Cardura, Cardura XL) An α1 adrenoreceptor antagonist Equal affinity for three subtypes of alpha receptors in the prostate; 𝛼1A, 𝛼1B, and 𝛼1D α1A appears to be the primary determinant of prostatic tone and reduction of LUTs Longest half-life of all blockers (16 - 22 hr) Terazosin (Hytrin) Pharmacologic and clinical profile almost identical to that of Doxazosin Binding to α1A receptors in prostate and vasculature to reduce LUTs At one time was used as part of hypertension treatment Silodosin (Rapaflo) An α1 adrenoreceptor antagonist Has high affinity for α1A receptors in prostate and bladder to relax smooth muscle and increase urinary flow Absolute bioavailability of 32% after po dosing Primary metabolite is the glucuronide 97% bound to plasma proteins in blood Half-life of parent drug is 11 hrs Alfuzosin (Uroxatral) Equal affinity for 𝛼1A, 𝛼1B, and 𝛼1D receptor subtypes α1A receptor binding in prostate appears to be primary determinant of prostatic tone and reduction of LUTS Available in immediate-release and extended-release formulations with half-lives between 3 and 11 hours Mirabegron (Myrbetriq) An 𝛽3-adrenergic receptor agonist Stimulation of 𝛽3-receptors in the prostate relaxes smooth muscle during the storage phase • 5ARI blocks the pathway through which testosterone is transformed into dehydrotestosterone and thereby suppresses the proliferation of interstitial cells and epithelial cells in the prostate gland.