Introduction to Diuretics in Pharmacology II - Study Guide m | HSCI 302, Study notes of Pharmacology

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Chapter 21: Diuretics HSCI 302: Pharmacology II Drexel University: Summer Quarter 2014 Exam 1 Review  Overview of the Kidney o Nephron: is the functional unit of the kidney o Glomerulus: the tuft of capillaries where filtration occurs o Bowman’s Capsule: cup like sac at the beginning of the tubular component of the nephron o Pathway: Glomerulus in the Bowman’s Capsule Proximal Convoluted TubuleDescending Limb of the loop of Helne Loop of Helne Ascending Limb of the Loop of Helne Distal Convoluted Tubule Collecting Duct o What is not filtered/what doesn’t enter the filtrate  Red blood cells, proteins (large plasma proteins), all other formed elements o What is filtered into the filtrate  H2O, glucose, small proteins, solutes, metabolic wastes o Diuretics Definition: Induce a state of diuresis which increases urine flow and increases excretion  Terminology Review: o Filtration: occurs at the glomerulus in the Bowman’s capsule o Reabsorb: from filtrate back into blood * very specific  Through peritubule capillaries o Secrete: from blood into tubule  Through peritubular capillaries o Excrete: what is urinated  Normal Regulation of Fluid and Electrolytes by the Kidneys: Review o Proximal Convoluted Tubule  Functions: Secretion and Reabsorption out of and into lumen  Reabsorption: o 100% of amino acids, water soluble vitamins and glucose o 80-90% of bicarbonate ions o 60-70% of water, Na+, K+  Majority in the PCT  Water follows passively from the lumen to the blood to maintain osmotic equilibrium o 50% of Cl-  Secretion: o H+, urea, ammonia and creatine are secreted into the tubular lumen o Carbonic Anhydrase: is found in the PCT cells and catalyzes the reaction to CO2 and H2) leading to Carbonic Acid which then spontaneously ionizes to H+ and HCO3-  The H+ from this reaction is then pumped out of the cell back into the lumen of the tubule by the Na+/H+ Exchange pump and the sodium is returned to the plasma with water passively following it  CO2 + H@)H2CO3- (bicarbonate) + H+  SITE OF ACTION for  Carbonic Anhydrase Inhibitors o Loop of Henle  Site of reabsorption of 20-25% of the Na+, water and Cl- in the original filtrate  Descending Loop of Henle  IMPERMEABLE TO SOLUTE REABSORPTION BUT PERMEABLE TO WATER REABSORPTION o Only passive H2O reabsorption occurs here o Filtrate is becoming hypertonic here because filtrate is loosing blood o NO glucose and amino acid reabsorption because 100% reabsorption should occur in the PCT  Ascending Loop of Henle  Relatively impermeable to both water and solute  CONTAINS ACTIVE TRANSPORT MECHANISMS FOR SOLUTE TRANSPORTATION o Pumps Na+, K+ and CL- from tubular fluid into peritubular fluid of medulla for reabsorption into peritubular capillaries and vasa recta o Filtrate is becoming hypotonic o Distal Convoluted Tubule  “fine tuning”fine tuning”  SELECTIVE REABSORPTION: or secretion, primarily along the DCT, makes final adjustments in solute composition and volume of tubular fluid  Reabsorption of a variable amount of water (usually around 5%) o This is under the control of ADH (AKA vasopressin) which is from the posterior pituitary  THIS IS DIRECT WATER REGULATION  Reabsorption of variable amount of NA+ ion under control of Aldosterone (from adrenal cortex) o THIS IS INDERECT WATER CONSERVATION  Reabsorption of Ca++ (PASSIVE)- regulated by the parathyroid hormone (PTH) o Osmoregulation: the movement of water thru semi-permeable membrane  H2O follows Na+ First Diuretic Drug Class: Ion- (Na+) Transport- Inhibitor Diuretics o Overview of MOA:  Inhibit ion transport by antagonizing membrane proteins  Which alters solute concentration and osmotic pressure  In turn inducing water movement o Thiazide Drugs  MOA: Act mainly in the DCT to decrease the Reabsorption of Na+ thru the…  INHIBITION OF NA+/CL_ COTRANSPORTER on the luminal membrane of the DCT—keeping sodium in the tubule o Overall giving an increased concentration of Na+ and Cl- in the tubular fluid which water passively follows increasing diuresis  NOTE: the most widely used of the Diuretic Drugs  Affect: DCT  ASSOCIATED DRUGS:  Chlorthiazide (Duril)  Hydrochlorothiazide-HCTZ (Microzide)  All have equal maximum diuretic effects- called ceiling diuretics b/ c increasing the dose above normal does not promote increased diuresis  Side Effects:  Hypokalemia a. Increased delivery of sodium to the collecting ducts causes increased cellular uptake of Na+ from the lumen by apical Epithelial Na+ channels i. This then causes the BASOLATERAL Na+/K+ Exchange Pump to more actively exchange Na for K—which is then passively secreted into the lumen thru apical channels 1. LOSS OF K+ LOW POTASSIUM b. Increased urination and lower BV—activates the Angiotensin- aldosterone system by the diuretic hypovolemia i. Body responds to hypovolemia by opposing diuresis one effect of which is to produce aldosterone sitmulating the Na+/K+ Exchange Pump resulting in FURTHER LOSS OF POTASSIUM 1. For this reason ACE inhibitors which inhibit angiotensin II production and therefor aldosterone activation are frequently used in combination with thiazides to combat hypokalemia o Can also use serum potassium monitoring and supplementation important with Thyizyde diuretics  Hypercalcemia o Thyazide diuretics promote the reabsorption of Ca+ + and decrease the Ca++ content of urine—useful for treatment in kidney stones  Volume Depletion and hypotension o Loop Diuretics  MOA:  INHIBIT NA+/K+/CL- COTRANSPORTER in luminal membrane  Lower the reabsorption of these ions and increasing tubular concentrations o Water passively enters the tubuleexcretion  ASSOCIATED DRUGS:  Furosemide –the prototype (Lasix)  Bumetamide (Bumex) o 1 mg of Bumetanide is approx. equivalent to 40 mg of furosemide o strong diuretic reaction can lead to large amts of body water loss leading to dehydration as well as the loss of electrolytes  carefule medical supervision is necessary during treatment  Compared to Thiazide Diruretics  Loop diuretics increase the Ca++ content of urine and CAN TREAT HYPERCALCEMIA  Area of Effect: Ascending Loop of Henle- b/c that is where the membrane proteins are  DRUG OF CHOICE IN EMERGENT SITUATIONS (IV)- for pulmonary edema  NOTE: these are the most POTENT diuretics  Adverse Effects:  Ototoxicity: hearing can be affected-ringing in ears  Hyperuricemia-increase in uric acid and gouty attacks  ALSO HAVE SAME CONCERNS ABOUT POSSBLE HYPOKALEMIA o Via the same 2 mechanisms for Thiazide Diuretics (a and b above) o Overview of Diruretics: Benefits and Appropriate Applications  Calcium Sparing Diuretic is used to identify agents that result in a relatively low rate of excretion of calcium  The reduced concentration of calcium in the urine can lead to increased rate of calcium in the serum o The sparing (retention) effect on calcium can be beneficial in hypocalcemia or unwanted in hypercalcemia  Thiazides and potassium sparing diuretics are considered to be Ca++ sparing diuretics  Thizides create net decrease in Ca++ loss in urine and are beneficial in patients with hypocalcemia  The potassium sparing diuretics cause a net increase in calcium lost in urine but the increase is much smaller than the increase associated with Loop diuretics  Loop Diuretics promote significant increase in calcium excretion and are more beneficial in patients with hypercalcemia  This can increase the risk of reduced bone density Second Diuretic Drug Class: Aldosterone Antagonists  Overview of Aldosterone: o Aldosterone is secreted from adrenal cortex o Rennin is secreted from the kidneys that ultimately leads to aldosterone secretion  RenninAngiotensinogenAngiotensin IAngiotensin II Adrenal Cortex Aldosterone o Affects what areas of the nephron  DCT and Collecting Duct  Eventually causing an increasing in Na+ reabsorption o SOOOO…. antagonizing Aldosterone will  Decrease Na+ Reabsorption  Affecting the Sodium Potassium Pump  ALSO decreases K+ secretion  Helps hypokalemia  Potassium Sparring Diuretics o MOA: antagonist of aldosterone—acting thru competitive binding of receptors at the aldosterone- dependent Na+/K+ Exchange pump in the DCT and Collecting Tubule  DECREAE Na+/WATER REABSORPTION AND ALSO DECREASE K+ SECRETION  Leading to potassium retention o ASSOCIATED DRUGS:  SPIRONOLACTONE (Aldactone) o Affect: Na+/K+ Exchange pump (which is dependent on aldosterone)  Where: in the DCT and Collecting Duct o Major Uses: