2. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Diuretic Agents

3. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Pharmacy Pharmacology: Diuretics

4. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. WARNING!!!!!! WARNING!!!!!!! DEPENDENCE on these slides ALONE, without ADEQUATE note-taking and use of other Resources, WILL result in ADVERSE CONSEQUECES to your ACADEMIC HEALTH.DEPENDENCE on these slides ALONE, without ADEQUATE note-taking and use of other Resources, WILL result in ADVERSE CONSEQUECES to your ACADEMIC HEALTH.

5. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Diuretic Agents Drugs that accelerate the rate of urine formation.Drugs that accelerate the rate of urine formation. Result: removal of sodium and waterResult: removal of sodium and water

6. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Background Primary effect of diuretics is to increase solute excretion, mainly as NaClPrimary effect of diuretics is to increase solute excretion, mainly as NaCl Causes increase in urine volume due to increased osmotic pressure in lumen of renal tubule.Causes increase in urine volume due to increased osmotic pressure in lumen of renal tubule. Causes concomitant decrease in extra-cellular volume (blood volume)Causes concomitant decrease in extra-cellular volume (blood volume) Certain disease states may cause blood volume to increase outside of narrowly defined limitsCertain disease states may cause blood volume to increase outside of narrowly defined limits –Hypertension –Congestive heart failure –Liver cirrhosis –Nephrotic syndrome –Renal failure Dietary Na restriction often not enough to maintain ECF and prevent edema  diuretics neededDietary Na restriction often not enough to maintain ECF and prevent edema  diuretics needed

7. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Review of Kidney Structure

8. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Functions of the Nephron Filtration Reabsorption Secretion Excretion

9. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. HUMAN RENAL PHYSIOLOGY Four Main Processes: –Filtration –Reabsorption –Secretion –Excretion

10. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. HUMAN RENAL PHYSIOLOGY Functions of the Kidney: –Filtration: –First step in urine formation –Bulk transport of fluid from blood to kidney tubule »Isosmotic filtrate »Blood cells and proteins don ’ t filter –Result of hydraulic pressure –GFR = 180 L/day

11. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. HUMAN RENAL PHYSIOLOGY Functions of the Kidney: –Reabsorption: Process of returning filtered material to bloodstream 99% of what is filtered May involve transport protein(s) Normally glucose is totally reabsorbed

12. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. HUMAN RENAL PHYSIOLOGY Functions of the Kidney: –Secretion: –Material added to lumen of kidney from blood –Active transport (usually) of toxins and foreign substances »Saccharine »Penicillin

13. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. HUMAN RENAL PHYSIOLOGY Functions of the Kidney: –Excretion: –Loss of fluid from body in form of urine Amount = Amount + Amount -- Amount of Solute Filtered Secreted Reabsorbed Excreted

14. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Nephron sites of action of diuretics

15. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Sodium Where sodium goes, water follows.Where sodium goes, water follows. 20 to 25% of all sodium is reabsorbed into the bloodstream in the loop of Henle, 5 to 10% in the distal tubules, and 3% in collecting ducts.20 to 25% of all sodium is reabsorbed into the bloodstream in the loop of Henle, 5 to 10% in the distal tubules, and 3% in collecting ducts. If it is not absorbed, it is excreted with the urine.If it is not absorbed, it is excreted with the urine.

16. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Diuretic Agents Carbonic anhydrase inhibitorsCarbonic anhydrase inhibitors Loop diureticsLoop diuretics Osmotic diureticsOsmotic diuretics Potassium-sparing diureticsPotassium-sparing diuretics Thiazide and thiazide-like diureticsThiazide and thiazide-like diuretics

17. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Carbonic Anhydrase Inhibitors (CAIs) acetazolamide (Diamox)acetazolamide (Diamox) methazolamidemethazolamide dichlorphenamidedichlorphenamide

18. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Carbonic Anhydrase Inhibitors: Mechanism of Action The enzyme carbonic anhydrase helps to make H+ ions available for exchange with sodium and water in the proximal tubules.The enzyme carbonic anhydrase helps to make H+ ions available for exchange with sodium and water in the proximal tubules. CAIs block the action of carbonic anhydrase, thus preventing the exchange of H+ ions with sodium and water.CAIs block the action of carbonic anhydrase, thus preventing the exchange of H+ ions with sodium and water.

19. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Carbonic Anhydrase Inhibitors: Mechanism of Action Inhibition of carbonic anhydrase reduces H+ ion concentration in renal tubules.Inhibition of carbonic anhydrase reduces H+ ion concentration in renal tubules. As a result, there is increased excretion of bicarbonate, sodium, water, and potassium.As a result, there is increased excretion of bicarbonate, sodium, water, and potassium. Resorption of water is decreased and urine volume is increased.Resorption of water is decreased and urine volume is increased.

20. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Mechanisms of Action: Carbonic anydrase inhibitors CAIs work on cotransport of Na +, HCO 3 - and Cl - that is coupled to H + countertransportCAIs work on cotransport of Na +, HCO 3 - and Cl - that is coupled to H + countertransport Acts to block carbonic anhydrase (CA),Acts to block carbonic anhydrase (CA), 1.CA converts HCO 3 - + H + to H 2 O + CO 2 in tubular lumen 2.CO 2 diffuses into cell (water follows Na + ), CA converts CO 2 + H 2 O into HCO 3 - + H + 3.H + now available again for countertransport with Na+, etc) 4.Na + and HCO 3 - now transported into peritubular capillary CA can catalyze reaction in either direction depending on relative concentration of substratesCA can catalyze reaction in either direction depending on relative concentration of substrates

21. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Carbonic Anhydrase Inhibitors: Therapeutic Uses Adjunct agents in the long-term management of open-angle glaucomaAdjunct agents in the long-term management of open-angle glaucoma Used with miotics to lower intraocular pressure before ocular surgery in certain casesUsed with miotics to lower intraocular pressure before ocular surgery in certain cases Also useful in the treatment of:Also useful in the treatment of: –Glaucoma –Edema –Epilepsy –High-altitude sickness

22. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Carbonic Anhydrase Inhibitors: Therapeutic Uses Acetazolamide is used in the management of edema secondary to CHF when other diuretics are not effective.Acetazolamide is used in the management of edema secondary to CHF when other diuretics are not effective. CAIs are less potent diuretics than loop diuretics or thiazides—the metabolic acidosis they induce reduces their diuretic effect in 2 to 4 days.CAIs are less potent diuretics than loop diuretics or thiazides—the metabolic acidosis they induce reduces their diuretic effect in 2 to 4 days.

23. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Carbonic Anhydrase Inhibitors: Side Effects Metabolic acidosisDrowsiness AnorexiaParesthesias HematuriaUrticaria PhotosensitivityMelena

24. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Loop Diuretics bumetanide (Bumex)bumetanide (Bumex) ethacrynic acid (Edecrin)ethacrynic acid (Edecrin) furosemide (Lasix)furosemide (Lasix)

25. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Loop Diuretics: Mechanism of Action Act directly on the ascending limb of the loop of Henle to inhibit sodium and chloride resorption.Act directly on the ascending limb of the loop of Henle to inhibit sodium and chloride resorption. Increase renal prostaglandins, resulting in the dilation of blood vessels and reduced peripheral vascular resistance.Increase renal prostaglandins, resulting in the dilation of blood vessels and reduced peripheral vascular resistance.

26. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Mechanisms of Action: Loop diuretics No transport systems in descending loop of HenleNo transport systems in descending loop of Henle Ascending loop contains Na + - K + - 2Cl - cotransporter from lumen to ascending limb cellsAscending loop contains Na + - K + - 2Cl - cotransporter from lumen to ascending limb cells Loop diuretic blocks cotransporter  Na +, K +, and Cl - remain in lumen, excreted along with waterLoop diuretic blocks cotransporter  Na +, K +, and Cl - remain in lumen, excreted along with water

27. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Loop Diuretics: Drug Effects Potent diuresis and subsequent loss of fluidPotent diuresis and subsequent loss of fluid Decreased fluid volume causes:Decreased fluid volume causes: –Reduced BP –Reduced pulmonary vascular resistance –Reduced systemic vascular resistance –Reduced central venous pressure –Reduced left ventricular end-diastolic pressure Potassium depletionPotassium depletion

28. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Loop Diuretics: Therapeutic Uses Edema associated with CHF or hepatic or renal diseaseEdema associated with CHF or hepatic or renal disease Control of hypertensionControl of hypertension

29. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Loop Diuretics: Side Effects Body SystemEffect CNSDizziness, headache, tinnitus, blurred vision GINausea, vomiting, diarrhea

30. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Loop Diuretics: Side Effects Body SystemEffect HematologicAgranulocytosis, neutropenia, thrombocytopenia MetabolicHypokalemia, hyperglycemia, hyperuricemia

31. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Osmotic Diuretics mannitol (Resectisol, Osmitrol)mannitol (Resectisol, Osmitrol)

32. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Osmotic Diuretics: Mechanism of Action Work in the proximal tubuleWork in the proximal tubule Nonabsorbable, producing an osmotic effectNonabsorbable, producing an osmotic effect Pull water into the blood vessels and nephrons from the surrounding tissuesPull water into the blood vessels and nephrons from the surrounding tissues

33. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Osmotic Diuretics: Drug Effects Reduced cellular edemaReduced cellular edema Increased urine production, causing diuresisIncreased urine production, causing diuresis Rapid excretion of water, sodium, and other electrolytes, as well as excretion of toxic substances from the kidneyRapid excretion of water, sodium, and other electrolytes, as well as excretion of toxic substances from the kidney Reduces excessive intraocular pressureReduces excessive intraocular pressure

34. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Osmotic diuretics No interaction with transport systemsNo interaction with transport systems All activity depends on osmotic pressure exerted in lumenAll activity depends on osmotic pressure exerted in lumen Blocks water reabsorption in proximal tubule, descending loop, collecting ductBlocks water reabsorption in proximal tubule, descending loop, collecting duct Results in large water loss, smaller electrolyte loss  can result in hypernatremiaResults in large water loss, smaller electrolyte loss  can result in hypernatremia

35. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Osmotic Diuretics: Therapeutic Uses Used in the treatment of patients in the early, oliguric phase of ARFUsed in the treatment of patients in the early, oliguric phase of ARF To promote the excretion of toxic substancesTo promote the excretion of toxic substances Reduction of intracranial pressureReduction of intracranial pressure Treatment of cerebral edemaTreatment of cerebral edema

36. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Osmotic Diuretics: Side Effects ConvulsionsConvulsions ThrombophlebitisThrombophlebitis Pulmonary congestionPulmonary congestion Also headaches, chest pains, tachycardia, blurred vision, chills, and fever

37. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Potassium-Sparing Diuretics amiloride (Midamor)amiloride (Midamor) spironolactone (Aldactone)spironolactone (Aldactone) triamterene (Dyrenium)triamterene (Dyrenium)

38. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Potassium-Sparing Diuretics: Mechanism of Action Work in collecting ducts and distal convoluted tubulesWork in collecting ducts and distal convoluted tubules Interfere with sodium-potassium exchangeInterfere with sodium-potassium exchange Competitively bind to aldosterone receptorsCompetitively bind to aldosterone receptors Block the resorption of sodium and water usually induced by aldosteroneBlock the resorption of sodium and water usually induced by aldosterone

39. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Potassium-sparing diuretics Have most downstream site of action (collecting tubule)Have most downstream site of action (collecting tubule) Reduce K loss by inhibiting Na/K exchangeReduce K loss by inhibiting Na/K exchange Not a strong diuretic because action is furthest downstreamNot a strong diuretic because action is furthest downstream Often used in combination with thiazide diuretics to restrict K lossOften used in combination with thiazide diuretics to restrict K loss

40. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Potassium-Sparing Diuretics: Drug Effects Prevent potassium from being pumped into the tubule, thus preventing its secretionPrevent potassium from being pumped into the tubule, thus preventing its secretion Competitively block the aldosterone receptors and inhibit its actionCompetitively block the aldosterone receptors and inhibit its action The excretion of sodium and water is promotedThe excretion of sodium and water is promoted

41. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Potassium-Sparing Diuretics: Therapeutic Uses spironolactone and triamterene HyperaldosteronismHyperaldosteronism HypertensionHypertension Reversing the potassium loss caused byReversing the potassium loss caused by potassium-losing drugspotassium-losing drugsamiloride Treatment of CHFTreatment of CHF

42. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Potassium-Sparing Diuretics: Side Effects Body SystemEffect CNSDizziness, headache GICramps, nausea, vomiting, diarrhea OtherUrinary frequency, weakness **hyperkalemia

43. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Potassium-Sparing Diuretics: Side Effects spironolactone gynecomastia, amenorrhea, irregular mensesgynecomastia, amenorrhea, irregular menses

44. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Thiazide and Thiazide-Like Diuretics hydrochlorothiazide (Esidrix, HydroDIURIL)hydrochlorothiazide (Esidrix, HydroDIURIL) chlorothiazide (Diuril)chlorothiazide (Diuril) trichlormethiazide (Metahydrin)trichlormethiazide (Metahydrin) Thiazide-likeThiazide-like chlorthalidone (Hygroton)chlorthalidone (Hygroton) metolazone (Mykrox, Zaroxolyn)metolazone (Mykrox, Zaroxolyn)

45. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Thiazide and Thiazide-Like Diuretics: Mechanism of Action Inhibit tubular resorption of sodium and chloride ionsInhibit tubular resorption of sodium and chloride ions Action primarily in the ascending loop of Henle and early distal tubuleAction primarily in the ascending loop of Henle and early distal tubule Result: water, sodium, and chloride are excretedResult: water, sodium, and chloride are excreted Potassium is also excreted to a lesser extentPotassium is also excreted to a lesser extent Dilate the arterioles by direct relaxationDilate the arterioles by direct relaxation

46. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Thiazide and Thiazide-Like Diuretics: Drug Effects Lowered peripheral vascular resistanceLowered peripheral vascular resistance Depletion of sodium and waterDepletion of sodium and water

47. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Thiazide and Thiazide-Like Diuretics: Therapeutic Uses Hypertension (one of the most prescribed group of agents for this)Hypertension (one of the most prescribed group of agents for this) Edematous statesEdematous states Idiopathic hypercalciuriaIdiopathic hypercalciuria Diabetes insipidusDiabetes insipidus Adjunct agents in treatment of CHF, hepatic cirrhosisAdjunct agents in treatment of CHF, hepatic cirrhosis

48. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Thiazide and Thiazide-Like Diuretics: Side Effects Body SystemEffect CNSDizziness, headache, blurred vision, paresthesias, decreased libido GIAnorexia, nausea, vomiting, diarrhea

49. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Thiazide and Thiazide-Like Diuretics: Side Effects Body SystemEffect GUImpotence IntegumentaryUrticaria, photosensitivity MetabolicHypokalemia, glycosuria, hyperglycemia