Week 1 Worksheet (2025) - Turn In

Asal Ardalan 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. The bladder fills progressively until the tension in its walls rises above a threshold level. b. 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 2. Identify the major structures of the urinary system. 1. Kidney urine production 2. Ureter 3. Urethra 4. Bladder a. Stone urine b. Empty urine 3. Name the parasympathetic, sympathetic, and somatic nerves that innervate the bladder and urethra a. Parasympathetic pelvic nerve 1. 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. 33 receptor (-) 2. a1 receptor ii. Neurotransmitter: NE (norepinephrine) iii. Effect of stimulation: 1. 83 receptor (-): causes relaxation of detrusor muscle retaining urine in bladder 2. a1 receptor: causes contraction of internal urethral sphincter to prevent urination (retaining urine in bladder) c. Somatic pudendal nerve 1. 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-The answer is in question 3 5. For each of the nerves in question 3, identity the type of receptor that is activated on stimulation-The answer is in question 3 Asal Ardalan 6. For each of the nerves in question 3, identify the neurotransmitter that is released on stimulation-The answer is in question 3 7. For the average bladder, state the "capacity". "desire", and "normal void" volume Bladder capacity: 400-600 ml. Desire to urinate: 150-200 ml. Normal void volume: 200-400 mL These values can vary based on individual factors like fluid intake, bladder health, and age, but these are the typical ranges for a healthy adult bladder. 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 10. Explain how stretch receptors in the bladder influence the micturition response Asal Ardalan stretch receptors in the bladder detect the filling and stretching of the bladder, which triggers the micturition reflex, and the brain then coordinates the voluntary control over urination. The balance between involuntary reflex and voluntary control allows for proper and timely urination. 11. Explain the nervous system response when the bladder is empty when the bladder is empty, the nervous system maintains a state of relaxation by reducing stretch receptor activity, increasing sympathetic nervous activity to inhibit bladder contraction, and keeping the sphincters closed. This ensures that the bladder remains ready to fill again without involuntary urination occurring. 12. Explain the nervous system response when the bladder is full When the bladder is full, the stretch receptors detect the increased volume and activate the micturition reflex. The spinal cord and brain communicate to initiate bladder contraction, relax the internal urethral sphincter, and give you the conscious urge to urinate. The external urethral sphincter can be voluntarily relaxed, allowing urination to occur. The coordinated effort between the autonomic (involuntary) and somatic (voluntary) nervous systems ensures that urination is both a reflexive and controlled process. 13. Explain the effect of "benign prostatic hyperplasia" on micturition and incontinence BPH affects micturition by obstructing urine flow through the urethra, leading to increased bladder pressure, urinary retention, and symptoms like hesitancy, weak stream, and incomplete emptying. These changes can contribute to incontinence (eg, overflow incontinence) and urinary urgency due to bladder overactivity. Treatment options, including medications, surgery, and lifestyle changes, are aimed at relieving the obstruction and restoring normal urination. function. 14. Interpret a Cystometrogram a. As volume increases, intravesical pressure increases b. Micturition contractions are waves of pressure occurring within bladder 100 300 15. State the relative numbers of males and females affected by incontinence in the US a. 25% males (6 million) b. 75% females (19 million) 16. 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" Asal Ardalan 1. 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 17. Name the single most common source of incontinence in men Nerve damage 1. Due to conditions such as diabetes, stroke, Parkinson's, MS, overactive bladder, spinal cord injury 18. 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 19. 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) 50-Reductase Inhibitors (Prostate shrinkers) Dutasteride (Avodart) Finasteride (Proscar) Erectile Dysfunction 1. Define "Erectile Dysfunction" 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 3. Explain the roles of NO, guanylate cyclase, and Phosphokinase G in smooth muscle relaxation b. Organic c. Mixed a. NO i. Nitric oxide (NO) stimulates guanylate cyclase b. Guanylate cyclase i. Increases cGMP levels Asal Ardalan 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 1. 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 1. Disorder affecting sacral spinal cord or autonomic fibers to penis preclude relaxation of smooth muscle and increased blood flow il. 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 causses listed in question 4 is quantitatively most important Same answer as question number 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: 1. 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 cGMPCindy 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 (eg.. sildenafil, tadalafil) block this degradation, prolonging cGMP activity and enhancing erectile function. 7. Explain the mechanism of action of PDE5 inhibitors 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 Asal Ardalan 9. Identify the primary structural features shared by Tadalafil, Sildenafil, and Vardenafil a. Competitive reversible PDE5 inhibitors 1. 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 All have only limited oral bioavailability because of extensive gastric and hepatic first pass metabolism by the CYP3A family: 1. Tadalafil 80% (Catechol metabolite) ii. Sildenafil 40% (N-desmethyl Sildenafil) iii. Avanafil 18% (Two major metabolites) iv. Vardenafil 15% (N-desethyl Sildenafil) Gout 1. Define Gout 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 o [TNF-a], 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 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 1. Increased Uric Acid Production: Cindy Vo 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. 5. 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 Asal Ardalan 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 6. 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) 7. List the four classes of drugs used to treat gout. a. Nonsteroidal Anti-inflammatory Drugs.b. Colchicine.c . Corticosteroids .d. Urate Lowering Therapy 8. 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 9. 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 10. Describe the mechanism of action of Allopurinol MOA: purine analog and is an inhibitor of Xanthine Oxidase ii. It is a competitive reversible inhibitor 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