Clinical Pharmacy iI CHP233 Pathophysiology Ii

1. Clinical Pharmacy iICHP233Pathophysiology Ii

2. Course Description • Provide a thorough knowledge of the pathology of various conditions that produce alteration in human physiology. • Get a baseline knowledge of its application in other subject of pharmacy such as pharmacotherapy and clinical practice.

3. Objectives • Describe the etiology of the human diseases. • Outline the mechanisms leading to the disease. • Correlate pathophysiology to clinical manifestations in diseases.

4. Textbooks and References • Pocketcompanion to pathologic basis of disease: by Robbins and Cotran. (7th edition). • Pathophysiology: clinical Concepts of Disease Process: By Sylvia Price and Lorraine Wilson. (5th edition). • Essentials of Pathophysiology for Pharmacy: by Martin Zdanowicz.

5. Lectures/Practical (week) • Sunday: → 11-12 AM (1 hour) • Monday: → 8-11AM (3 hours)

6. Course Contents • Urinary tract disorders • Gastrointestinal disorders • Endocrine system disorders • Musculoskeletal disorders • Pulmonary disorders • Neurological and psychological disorders

7. Evaluation Quiz 1 week 6…….15 points Quiz 2 week 12 …….15 points Practical Ex. week 14……20 points Activities and attendence…….10 points Final Ex………..40 points

8. Urinary System Dr. amalabd el moneim

9. Gross Anatomy • Consist of six organs • Kidneys (2) • Ureters (2) • Urinary bladder • Urethra • Right slightly lower than left due to space occupied by liver • Retorperitoneal (lie between the peritoneum and body wall) at the level of T12-L3

10. Surface anatomy of the Kidney • Each kidney is bean-shaped and weight about 160g and measures 12cm long by 5-6cm wide and 2.5-3cm thick • Lateral surface convex, medial surface concave and has a slit called the hilum where it receives the renal artery, vein, ureter and lymphatic vessels Hilum is located on the medial surface 12 cm 3cm 6 cm

11. Internal Structure of the Kidney • Cortex: the outer granular layer (containing many corpuscles) • Medulla: the inner layer that is formed of renal pyramids ending with a papilla and separated by renal columns from the cortex • Pelvis: expanded proximal ureter Renal papilla

12. Microscopic structure of the Kidney • Each kidney contains 1.2 million functional units called nephrons • A nephron consist of two principal parts • Renal corpuscle- (glomerulus) where the blood plasma is filtered • Renal tubule- processes the filtrate into urine

13. Renal Corpuscle contains: • Bowman’s capsule • Part of collecting system • Glomerulus • Afferent arteriole • Efferent arteriole • Renal Tubules 1. Proximal convoluted tubule 2. Loop of Henle 3. Distal convoluted tubule 4. Collecting tubule

14. Two Types of NephronsCortical and JuxtamedullaryNephrons • Cortical Nephrons (85%)-nephrons close to the kidney surface • Have shorter nephron loops that dip only slightly into the outer medulla before turning back (Forming standered urine)---- the blood flow through cortex is rapid • Juxtamedullarynephron (15%)-nephrons close (juxta) to the medulla • Have very long loops that extend to the apex of the renal pyramid • Responsible for maintaining the osmolality and acid-base balance (concentereted urine due to ADH) in addition to blood filteration ----- the blood flow in medulla is slow

15. The renal corpuscle composed of glomerulus and Bowman’s capsule • Consist of a ball of capillaries called a glomerulusenclosed in a two-layered glomerular (Bowman’s) capsule • The parietal layer is a simple squamous epithelium. • The visceral layer consist of cells called podocytes wrapped around the capillaries. • The fluid that filters from the glomerular capillaries, called glomerular filtrate, collects in the capsular space between the parietal and visceral layer and then flows into the renal tubule.

16. Juxtaglomerular (JG) Apparatus • Glomerular Filteration pass through three barriers: • Capillary endothelium • Basement membrane • Glomerular epithelium (visceral layer of Bawman’s capsule) slit pores between pedicles of bodocytes. • Juxtaglomerular Apparatus = Macula densa + JG cells (smooth muscle fibers from afferent arterioles). • Macula densa monitors BP through renin release, also macula densa produce erythropoietin.

17. Blood supply to the kidneyReceives 20% of the cardiac output

18. Control of blood pressure

19. Urine collection • From each renal papilla , collecting ducts collect the urine and released it into minor calyx then to major calyx then to renal pelvis to ureter

20. ureter • Are muscular retroperitoneal tubes that extends from kidney to the urinary bladder at the angle Trigone. • The mucosa has transitional epithelium that is continuous with that of the pelvis and bladder • Urine stretches tube causing the muscularisms. to contract in paristaltic waves, milking urine down to the bladder

21. Nephrolithiasis (stone) • It occurs when the urine becomes too concentrated and substances crystallized. • The symptoms arise when stones begin to move down ureter causing an intense pain. • Kidney stones may formed in the pelvis or calyces of the kidney or in the ureter.

22. Urinary Bladder • Retroperitoneal. • Have internal wrinkles (rugae) that permit expansion (capacity ~ 1 L ) • Trigone: is area at the base delinated by openings of ureters and urethera without muscle • It has internal (involuntary) and external sphincter (voluntary). • Its muscularis, called the detrusor muscle, • The mucosa has transitional epithelium

23. Female urethra • It extended from the base of the bladder to the vestibula (3 – 5 Cm) • External urethral sphincter is voluntary at the pelvic floor. • UTIs (esp. E.coli)

24. Male urethra Male: 18 – 20 Cm • Prostatic urethra: from the base of the bladder through the prostatic gland • Membranous urethra: between the prostatic gland and the penis base • Penile (spongy ) urethra: traverses penis to orifice

25. Major kidney functions • Regulation of: • Body fluid osmolarity and volume • Electrolyte balance • Acid-base balance • Blood pressure 2. Excreation of: • Metabolic product • Foreign substances (pesticides, chemicals, ) • Secretion of: • Erythropoitin • 1,25-dihydroxy vitamin D3 (activation of vitamin D) • Renin • Prostaglandin

26. Nephron Functional Mechanisms • Filtration (from glomeruli). • Reabsorption (from renal tubules). • Secretion (from the blood directly to the tubules). • Excretion (elimination from the body).

27. Nephron function • Filtration: (the first step in urine formation) • It is bulk transport of fluid from blood to kidney tubules ( isosmotic filtrate which is free from blood cells and protein ). • Result of hydraulic pressure (i.e. increased water content of filterate) • GFR = 180 L/day. • The higher molecular weight of plasma constituent, the lower the rate of its filtration e.g. serum albumin and hemoglobin in comparison with glucose or urea).

28. Glomerular Filtration • The mechanism of filtrationis Bulk Flow • Direction of movement: from glomerular capillaries to capsular space • Driving force:pressure gradient (net filtration pressure; NFP) • Types of pressure that affect the filtration: • Favoring force: Capillary Blood Pressure (BP) • Opposing force: blood colloid osmotic pressure (COP) and Capsule Pressure (CP).

29. Glomerular Filtration Forces

30. Glomerular filtration rate (GFR) • Amount of filtrate produced in the kidneys each minute is 125 mL/min. = 180 L/day. • Factors that alter filtration pressure and change GFR, include: • Increased renal blood flow--------increased GFR • Decreased plasma protein------increased GFR causes edema. • Hemorrhage -----------------decreased capillary BP decreased GFR

31. GFR regulation: adjusting blood flow • GFR should be finely controlled to avoid excessive loss of fluid or decreased filtration with subsequent increased accumulation of waste products. • GFR is regulated through three mechanisms: • Renal autoregulation (renin -Ang. -Aldosterone) • Neural regulation: (sympathetic) • Hormonal regulation (ADH, NO, Endothellin, Prostaglandin E2 and prostacyclins) All these mechanisms adjust renal blood pressure and resulting blood flow.

32. Measurement of GFR • Inulin: (it is polysaccharides from Dhalia plant) • Freely filterable at the glomerulus. • Does not bind to plasma proteins. • Biologically inert. • Non-toxic , neither synthesized nor metabolized in kidney. • Neither absorbed nor secreted. • Does not alter renal function. • Can be accurately quantified. • Low concentration are enough (10-20 mg/100 ml plasma) and taken by injection.

33. Measurement of GFR 2- CREATININE: • End product of muscle creatine metabolism • Used in clinical sitting to measure GFR but less accurate than inulin method (because 10 % secreated from renal tubules).

34. Serum Creatinine(0.6 to 1.2 mg/dL) • Creatinine is a break-down product of creatine phosphate in muscle, and • Creatinine is usually produced at a constant rate by the body (depending on muscle mass). • Is mainly filtered by the kidney, though a small amount is actively secreted. • There is no tubular reabsorption of creatinine. • If the filtering of the kidney is deficient, blood levels rise • Measuring Serum Creatinine is a simple test and it is the most commonly used indicator of renal function.

35. A rise in blood creatinine levels is observed only with markeddamage to functioning Nephrons. • Therefore, this test is NOT suitable for detecting early stage kidney disease. • A better estimation of kidney function is given by the creatinine clearance test

36. The Typical Reference Ranges 0.5 to 1.0 mg/dL for Women 0.7 to 1.2 mg/dL for Men

37. Female has less serum level of creatinine than male. • Elderly persons, on the other hand, may have less serum level of creatinine than the adult. • In patients with malnutrition, severe weight loss, and long standing illnesses the muscle mass tends to diminish over time and, therefore, their creatinine level may be lowerthan expected for their age.

38. Creatinine Clearance • Creatinine clearance which represents the rate at which creatinine is removed from the body by the kidneys • Roughly approximates the GFR. • Its value is given in units of milliliters per minute. • Normal Range for male 75-125ml/min

39. Nephron function 2- Reabsorption: it is the process of returning filtered material ( 99 % of what filtered) to the bloodstream. • May involve transport proteins. • Normally glucose is totally reabsorbed. • Two pathways of reabsorption: • Transcellular pathway (I.e. through the cell membrane) • Paracellular transport (i.e. through junctions between cells)

41. Nephron function 3-Secretion: • Material secreted to lumen of the kidney tubules from blood. • Active transport (usually) of toxins and foreign substances (e.g. saccharine and some drugs as penicillin).

42. Nephron function 4- Excretion: • loss of fluid from the body in form of urine • Amount excreted = (amount filtered + amount secreted) - amount of solute reabsorbed

43. An overview of urine formation • Podocytes • Bawman’s space • Proximal tubules • Loop of Hennel • Distal tubules • Collecting duct. • Renal caylex • Renal pelvis • Ureter • urethera

44. Urine concentration and dilution • Importance: • When there is excess water in the body and body fluid osmolarity is reduced; the kidney can excrete urine with an osmolarity as low as 50 mosm/Liter ( a concentration that is only about one sixthe osmolarity of normal extracellular fluid). • conversely, when there is a deficient of water and extracellular fluids osmolarity is high, the kidney can excrete urine with a concentration of about 1200 to 1400 mosm/Liter ( 4-5 times the osmolarity of normal extracellular fluid).

45. Requirements for forming a concentrated or diluted urine • The controlled secretion of antidiuretic hormone (ADH), which regulates the permeability of the distal tubules and collecting ducts to water. • A high osmolarity of the renal medullary interstitial fluid, which provides the osmotic gradient necessary for water reabsorption to occur in the presence of high level of (ADH).

46. The Counter-Current Mechanism Produces a Hyperosmotic Renal Medullary Interstitium

47. Hyperosmotic gradient in the renal medulla interstitium

48. The role of ADH: • There is a high osmolarity of the renal medullary interstitial fluid, which provides the osmotic gradient necessary for water reabsorption to occur. • Whether the water actually leaves the collecting duct (by osmosis) is determined by the hormone ADH. • Osmoreceptors by the hypothalamus detect the low level of water (high osmolarity), to send an impulse to the pituitary gland which releases ADH into the bloodstream. • ADH makes the wall of the collecting duct more permeable to water. • Therefore, in the presence of ADH more water is reabsorbed and less is excreted.

50. Regulation of Renin Secretion • Renal mechanism: • Tension of the afferent artery (stretch receptor). • Macula densa (stimulated by the content of Na ions in the distal convoluted tubule) • Nervous mechanism: sympathetic nerve • Humoral mechanism: E, NE, PGE2, PGI2