Worksheet for PHAR 840 (Farris)

Cindy Vo Worksheet for PHAR 840 (Farris) Spring 2025 – (Week 1) Upon completion of this exercise, you will be able to: Incontinence 1. Identify the two primary steps in the Micturition process. a. Bladder fills progressively until tension in walls rises above threshold level b. Tension in step 1 elicits step 2 → nervous reflex called “micturition reflex” i. Micturition reflex empties bladder 1. If fail, at least causes conscious desire to urinate ii. Micturition reflex is an autonomic spinal cord reflex 1. Can be inhibited or facilitated by centers in cerebral cortex or brainstem 2. Identify the major structures of the urinary system. a. Kidney – urine production b. Ureter c. Bladder i. Store urine ii. Empty urine d. Urethra 3. Name the parasympathetic, sympathetic, and somatic nerves that innervate the bladder and urethra. a. Parasympathetic – pelvic nerve i. Receptor: M3 receptor (+) ii. Neurotransmitter: ACh iii. Effect of stimulation: stimulates urination; ACH innervates M3 receptor causing contraction of detrusor muscle to eliminate urine from bladder b. Sympathetic – hypogastric nerve i. Receptor(s): 1. β3 receptor (-) 2. α1 receptor ii. Neurotransmitter: NE (norepinephrine) iii. Effect of stimulation: 1. β3 receptor (-): causes relaxation of detrusor muscle retaining urine in bladder 2. α1 receptor: causes contraction of internal urethral sphincter to prevent urination (retaining urine in bladder) c. Somatic – pudendal nerve i. Receptor: Nicotinic receptor (+) ii. Neurotransmitter: Ach iii. Effect of stimulation: stimulates contraction of the external urethral sphincter to prevent urination 4. For each of the nerves in question 3, explain the effects of stimulation of that nerve on the bladder or urethra. Cindy Vo 5. For each of the nerves in question 3, identify the type of receptor that is activated on stimulation. 6. For each of the nerves in question 3, identify the neurotransmitter that is released on stimulation. a. #4-6 answered in #3 7. For the average bladder, state the “capacity”. “desire”, and “normal void” volumes 8. If shown a diagram of the bladder and associated structures, identify the “Detrusor Muscle”, “Trigone”, “Internal Urethral Sphincter”, “External Urethral Sphincter”, “Prostate Gland”. 9. Name the segments of the spinal cord where the “Hypogastric”, “Pelvic” and “Pudendal” nerves emanate. a. Hypogastric: T11 – T12, L1 – L2 b. Pelvic: S2 – S4 c. Pudendal: S2 – S4 Cindy Vo 10. 11. 12. 13. 14. Explain how stretch receptors in the bladder influence the micturition response. Explain the nervous system response when the bladder is empty. Explain the nervous system response when the bladder is full. Explain the effect of “benign prostatic hyperplasia” on micturition and incontinence. Interpret a Cystometrogram Cindy Vo 15. 16. 17. 18. 19. a. As volume increases, intravesical pressure increases b. Micturition contractions are waves of pressure occurring within bladder State the relative numbers of males and females affected by incontinence in the US. a. 25% males (6 million) b. 75% females (19 million) Explain the 3 most common types of incontinence in men. a. Stress: involuntary loss of urine in absence of contraction of the detrusor muscle i. Intravesical (intrabladder) pressure exceeds that of urethra b. Urge: involuntary loss of urine in association with a strong desire to void or “urgency” i. Detrusor muscle overactivity and/or decreased compliance 1. Overactivity: involuntary detrusor muscle contractions during bladder filling and inability of sphincter to retain urine under pressure c. Overflow: involuntary loss of urine in association with blockage of normal excretory route i. Bladder fills but patient unable to urinate due to blockage (usually of the urethra); as pressure increases, urination or leakage finally occurs Name the single most common source of incontinence in men. a. Nerve damage i. Due to conditions such as diabetes, stroke, Parkinson’s, MS, overactive bladder, spinal cord injury Explain the mechanisms of action for the three most common classes of pharmacological treatments for urinary incontinence in men. a. Anticholinergic b. Alpha Receptor Antagonists c. Type II 5-Alpha Reductase Inhibitors Identify the pharmacological class for each of the following drugs. • • • • Prototype Antimuscarinic (not common) • Atropine • Hyoscine Antimuscarinic • Oxybutynin (Ditropan XL, Oxytrol) • Tolterodine (Detrol) • Darifenacin (Enablex) • Solifenacin (Vesicare) • Trospium Chloride • Fesoterodine (Tovia) • Soleneferin (Vesicare) Adrenergic Antagonists • Tamsulosin (Flomax) • Doxazosin (Cardura) • Terazosin (Hytrin) • Silodosin (Rapaflo) • Alfuzosin (Uroxatral) • Mirabegron (Myrbetriq) 5α-Reductase Inhibitors (Prostate shrinkers) • Dutasteride (Avodart) • Finasteride (Proscar) Cindy Vo Erectile Dysfunction 1. Define “Erectile Dysfunction”. a. Consistent inability to achieve and/or maintain an erection sufficient for satisfactory intercourse 2. Name the three classes into which Erectile Dysfunction are normally categorized. a. Psychogenic b. Organic c. Mixed 3. Explain the roles of NO, guanylate cyclase, and Protein Kinase G in smooth muscle relaxation. a. NO i. Nitric oxide (NO) stimulates guanylate cyclase b. Guanylate cyclase i. Increases cGMP levels c. Protein Kinase G i. Activates myosin phosphatase → dephosphorylates myosin → decreasing contraction → smooth muscle relaxation 4. Describe the basis of the six primary pathophysiological causes of erectile dysfunction. a. Vasculogenic i. Most frequent organic cause of ED is disturbance of blood flow to and from penis 1. Atherosclerotic or traumatic arterial disease 2. Excessive outflow thru veins even with adequate inflow 3. Structural alterations in fibroelastic components of corpora b. Neurogenic i. Disorder affecting sacral spinal cord or autonomic fibers to penis preclude relaxation of smooth muscle and increased blood flow ii. Serious or complete lesions to lower spinal cord c. Endocrinologic i. Elevated prolactin levels = ↓ libido in males by suppressing gonadotropin releasing hormone ii. Elevated prolactin levels = ↓ testosterone levels d. Diabetic i. Pathologic mechanisms primarily associated with diabetic vascular and neurological complications ii. ↓ levels or nitric oxide synthase in both endothelial and neural tissues e. Psychogenic i. Most common is excess sympathetic stimulation = ↑ smooth muscle tone rather than relaxation in penis 1. Performance anxiety 2. Depression 3. Relationship conflict, etc. f. Medication Related 5. Identify which of the pathophysiologic causes listed in question 4 is quantitatively most important. a. See #4 6. Explain the function of the enzyme Phosphodiesterase Type 5 (PDE5). a. PDE5 function: hydrolyzing cGMP into its inactive form, 5′-GMP b. Regulation of Vascular Smooth Muscle Tone: i. PDE5 is highly expressed in vascular smooth muscle cells, particularly in the corpus cavernosum of the penis and pulmonary vasculature. It degrades cGMP, which is produced in response to nitric oxide (NO) signaling. Since cGMP Cindy Vo promotes smooth muscle relaxation and vasodilation, PDE5 activity reduces these effects, leading to vasoconstriction. c. Role in Erectile Function: i. In penile erection, nitric oxide (NO) stimulates guanylate cyclase, increasing cGMP levels, which leads to smooth muscle relaxation and increased blood flow. d. PDE5 breaks down cGMP, terminating the vasodilatory signal. PDE5 inhibitors (e.g., sildenafil, tadalafil) block this degradation, prolonging cGMP activity and enhancing erectile function. 7. Explain the mechanism of action of PDE5 inhibitors. a. PDE5 inhibitors i. MOA: inhibits PDE type 5 (responsible for degradation of cGMP) = prolonged cGMP activity = smooth muscle relaxation 8. Identify four important PDE5 Inhibitors. a. Sildenafil b. Tadalafil c. Vardenafil d. Avanafil 9. Identify the primary structural features shared by Tadalafil, Sildenafil, and Vardenafil. a. Competitive reversible PDE5 inhibitors i. Compete w/ cGMP b. All have purine-ring structure 10. Characterize the general bioavailability of the PDE5 inhibitors and name the family of enzymes responsible for their metabolism. a. All have only limited oral bioavailability because of extensive gastric and hepatic first pass metabolism by the CYP3A family: i. Tadalafil 80% (Catechol metabolite) ii. Sildenafil 40% (N-desmethyl Sildenafil) iii. Avanafil 18% (Two major metabolites) iv. Vardenafil 15% (N-desethyl Sildenafil) Cindy Vo Gout 1. Define Gout a. Gout: inflammatory condition of arthritis type resulting from deposition of urinary acid crystals in joint spaces that lead to inflammatory reaction causing intense pain, erythema, and joint swelling 2. Describe the pathophysiology of gout. a. Gout is caused by abnormality in uric acid metabolism i. Solubility depends on concentration and temperature 1. High serum concentrations + low body temperature → uric acid can precipitate as mono sodium urate (MSU) a. Crystals (microtophi) can collect in joint spaces in distal extremities ii. Urate crystals can activate several pro inflammatory mediators: (tumor necrosis factor α [TNF-α], interleukin 1 [IL-1], interleukin 8 [IL-8]) 1. Stimulates influx of neutrophils into joint space 2. Ingests uric acid crystals, lysed, and release proteolytic enzymes triggering onset of acute gout attack 3. Repeated attacks can lead to cartilage and joint destruction 3. Identify the origin of uric acid. a. Breakdown of purines from DNA of degraded body cells and dietary proteins 4. Explain how fructose consumption can contribute to the onset of gout. a. ATP reduced to AMP b. AMP reduced to hypoxanthine c. Fructose consumption contributes to gout by increasing uric acid levels, leading to crystal formation in joints i. Increased Uric Acid Production: Cindy Vo 5. 6. 7. 8. 9. 10. 1. Fructose metabolism depletes ATP, increasing AMP degradation into uric acid via xanthine oxidase. ii. Reduced Uric Acid Excretion: 1. Fructose competes with uric acid for renal excretion, worsening hyperuricemia. iii. Insulin Resistance & Metabolic Syndrome: 1. Chronic fructose intake promotes insulin resistance, impairing uric acid clearance. iv. Inflammation Activation: 1. Uric acid triggers NLRP3 inflammasome, leading to gout flares. Describe the conditions known as “Uric Acid Nephrolithiasis” and “Tumor Lysis Syndrome”. a. Uric acid nephrolithiasis (kidney stones) can occur in up to 25% of patients with persistently acid urine and hyperuricemia i. In rare cases, uric acid stones can cause nephropathy and renal failure b. Tumor lysis syndrome (TLS) i. Metabolic complications resulting from extreme hyperuricemia due to rapid tumor cell destruction in patients undergoing chemotherapy for certain types of cancer List the drugs that cause hyperuricemia and precipitate gout. a. Thiazide and loop diuretics b. Niacin c. Pyrazinamide d. Calcineurin inhibitors e. Occasionally Aspirin (Dose Dependent) List the four classes of drugs used to treat gout. a. Nonsteroidal Anti-inflammatory Drugs b. Colchicine c. Corticosteroids d. Urate Lowering Therapy Explain the mechanism of action of colchicine. a. Colchicine does not lower plasma levels of uric acid, but retards the inflammation process (anti-inflammatory) i. Acts on polymorphonuclear leukocytes to diminish their phagocytosis ii. Acts by penetrating inflammatory cells, disrupting tubulin (fibers), and impairing ability of inflammatory cells to move to the site of inflammation iii. Inhibits release of lysosomal enzymes during phagocytosis that contributes to production of inflammation Define “Uricosuric Agent” and list drugs that act via this mechanism. a. Uricosuric Agents: compounds that increase the clearance of uric acid from the body i. block the reabsorption of filtered and secreted uric acid in the renal tubules, resulting in: 1. Increased clearance of uric acid 2. Lowered plasma levels of uric acid ii. Drugs 1. Probenecid 2. Sulfinpyrazone Describe the mechanism of action of Allopurinol a. Allopurinol i. MOA: purine analog and is an inhibitor of Xanthine Oxidase ii. It is a competitive reversible inhibitor Cindy Vo iii. Xanthine Oxidase is responsible for the successive oxidation of hypoxanthine and xanthine in the production of uric acid in the body iv. Although an inhibitor of Xanthine oxidase, allopurinol is metabolized by aldehyde oxidase v. The metabolite oxipurinol also inhibits Xanthine oxidase