1. Diuretics and Agents that affect water excretion Philip Marcus, MD MPH

2. Diuretics: Increase output of urine - “diuresis” Increase renal Na + excretion - “natriuresis”

3. Clinical use of diuretics: Hypertension Primary modality of treatment Forms base of treatment regimen Mobilization of edema fluid Heart failure Liver disease (Cirrhosis) Renal disease Prevention of renal failure (maintains urine flow)

4. Mechanism of Action Agents best understood in relation to sites of action in the nephron. Each site of nephron highly specialized in function. Almost all diuretics exert their effects at luminal surface of renal tubular cells. Ion transport inhibitors.

5. Mechanism of Action Diuretics compromise normal operation of the kidney to promote excretion of water. Diuretic use can result in: Hypovolemia Acid-base imbalance Loss of electrolytes

6. Attempt to Minimize Adverse Effects By: Short-acting diuretics Time doses to allow drug-free periods between periods of diuresis. Will allow kidney to readjust ECF to compensate for undesired alterations.

7. Diuretic-like Agents: Methylxanthines (caffeine, theophylline), cardiac glycosides (digoxin) and sympathomimetic amines (dopamine) act at the level of the glomerulus to increase volume of blood filtered via increase in cardiac output.

8. Renal Function: Cleansing of extracellular fluid (ECF), maintenance of ECF volume and composition. Maintenance of acid-base balance. Excretion of metabolic wastes and foreign substances (drugs, toxins, etc.).

9. Effects of the Kidney Upon ECF are Net Result of: Filtration Reabsorption Active Secretion

10. The Nephron

11. Filtration: Glomerular level 1st step in urine formation All small molecules filtered… Electrolytes, glucose, amino acids, Na+, K+, Cl-, HCO3- -- most prevalent Large filtration capacity Nonselective…cannot regulate composition of urine

12. Sites of Sodium Absorption

14. Reabsorption: > 99% of filtrate Conserves valuable portions while allowing wastes to be excreted Reabsorption of solutes—active transport H 2 0 follows passively PRIMARY ACTION OF DIURETICS! Na +, K + predominant solutes in filtrate

15. Active Secretion: Transports compounds from plasma into lumen of nephron. Located in PCT. Organic Acids (S2) – uric acid, antibiotics. Organic Bases (S1 and S2) – creatinine, choline, and procainamide.

16. The Nephron

17. Proximal Convoluted Tubule: High resorptive capacity. 65% of filtered Na+, Cl- reabsorbed. Also HCO3 -, K +, glucose, amino acids. H 2 O follows passively. Solutes and H 2 O reabsorbed to = extent… Urine is isotonic (300 mOsm/L).

19. Loop of Henle: Descending Limb: Thin segment. Freely permeable to H 2 0. As tubular urine moves down loop thru hypertonic medulla, H 2 O is drawn from loop into interstitial space. Will decrease volume of urine and increase concentration.

20. Loop of Henle: Ascending Limb: Thick segment. NOT permeable to H 2 O 30% of filtered Na+ & Cl- reabsorbed (actively). H 2 O remains in loop as Na+ and Cl- reabsorbed - tonicity returns to original. Regard as diluting segment. Utilizes Na+/K+/2Cl- cotransport system which is selectively blocked by diuretics. The action of the transporter lead to excess K+ accumulation within the cell. Results in back diffusion of K+ into tubular lumen  lumen + electrical potential. Driving force for reabsorption of Mg+ and Ca+ via paracellular pathway.

21. Distal Convoluted Tubule: 10% of filtered NaCl reabsorbed. H 2 0 follows passively. Na + and Cl - neutral cotransport. Ca+ actively reabsorbed via apical Ca + channel and basolateral Na + /Ca ++ exchanger regulated by PTH.

22. Collecting Tubule: 2-5% of NaCl reabsorption. Responsible for determining final concentration of Na+ in urine. Na+/K+exchange… ALDOSTERONE increases activity of apical membrane channels and basolateral Na+/K+ ATPase. Major site of K+ excretion. Impermeable to H2O in absence of ADH…dilute urine produced. Only site in nephron where membrane H 2 O permeability can be regulated. ADH increases permeability to H 2 O

23. Action of Diuretics: Blockade of Na+ (and Cl-) reabsorption Create osmotic pressure within nephron that prevents passive reabsorption of H2O CAUSE H 2 O & SOLUTES TO BE RETAINED WITHIN THE NEPHRON Thereby PROMOTING THEIR EXCRETION The increase in urine flow that a diuretic produces is directly related to the amount of Na+ and Cl- reabsorption that the drug blocks

24. Sites of Sodium Absorption

25. Drugs Whose Site of Action Is Early in the Nephron Will Have the Opportunity to Block the Greatest of Solute Reabsorption…Produce Greatest Diuresis. 180 L Filtrate/day…almost all reabsorbed. For each 1% of solute reabsorption blocked, urine output increases by 1.8 L 3% blockade = 5.4 L urine/day = 12 lb. weight loss. Small blockade can have profound effects.

26. Classification Loop (High-ceiling) diuretics Thiazide diuretics Osmotic diuretics Potassium-sparing diuretics Aldosterone antagonists Inhibitors of Na + transport Carbonic anhydrase inhibitors Mercurial diuretics

28. Actions of Diuretic Agents: Inhibition of specific membrane transport proteins at luminal surface of renal tubular epithelial cells. Osmotic effect to prevent water reabsorption in water – permeable segments. Enzyme inhibition. Interfere with hormone receptors in renal epithelial cells.

29. Loop (High-Ceiling) Diuretics GREATEST EFFICACY – Cause large increase in fractional excretion of Na + Furosemide (Lasix®) Bumetanide (Bumex®) Ethacrynic Acid (Edecrin®) Torsemide (Demadex®)

31. Loop (High-Ceiling) Diuretics Act to inhibit coupled Na+/K+/2Cl- transport system in luminal membrane of thick ascending limb of loop of Henle Blocks Cl- and Na+ reabsorption and prevents passive H 2 O reabsorption Normally up to 30% of filtered NaCl reabsorbed in ascending limb Also diminishes normal lumen-positive potential that drives K+ recycling Causes increase in Mg++ and Ca++ excretion Transport system driven by Na+/K+ ATPase dependent pump

33. Pharmacokinetics: Rapidly absorbed. Response correlates with urinary excretion rate. Eliminated by renal secretion and filtration. Action may be slowed by probenecid. Duration of action -- 2 or more hours. IV use for rapid effect. Hepatic metabolism. t 1/2 dependent on renal function.

34. Clinical Indications: Rapid or massive fluid mobilization Pulmonary edema Acts to decrease LVEDP and decrease pulmonary vascular congestion Edematous states CHF Cirrhosis Nephrosis Hypertension Hypercalcemia Acute renal failure Convert oliguric to non-oliguric renal failure Anion overdose Inhibits reabsorption of Br -, F -

35. Adverse Effects: Dehydration Hypotension Electrolyte Imbalance Hyponatremia Hypochloremia HYPOKALEMIA Hypocalcemia Hypomagnesemia Hyperglycemia Hyperuricemia Ototoxicity Cross reactivity in patients with SULFA allergy Ethacrynic acid in phenoxyacetic acid derivative

36. Thiazide Diuretics (Benzothiadiazides): All have unsubstituted sulfonamide group. Similar effects as loop diuretics…less efficacy. *Hydrochlorothiazide (HydroDIURIL®) Chlorothiazide (DIURIL®) Diazoxide—non-diuretic thiazide Chlorthalidone (Hygroton®) Indapamide (Lozol®) Metolazone (Zaroxolyn®, Mykrox®)

38. Thiazide Diuretics: Act to inhibit NaCl reabsorption from luminal side of epithelial cells in DCT (early segment). Bind to Cl- site of electroneutral Na+/Cl- cotransport system. No effect on loop of Henle. Enhance Ca +2 reabsorption in DCT.

40. Clinical Indications: Hypertension Drug of choice for initial therapy of hypertension CHF Hypercalciuria, nephrolithiasis Nephrogenic Diabetes Insipidus reduces polyuria and polydipsia where no response to ADH  Seemingly paradoxical effect

41. Adverse Effects: Most Similar To Those Of Loop Diuretics Hypercalcemia Hyperlipidemia {5-15%  in cholesterol (LDL)}. No Ototoxicity. Hyperglycemia

42. Potassium-Sparing Diuretics: Cause mild to moderate increase in urine production Substantial decrease in K+ excretion. Rarely employed to promote diuresis.

43. Spironolactone (Aldactone®) Blocks action of aldosterone via direct competitive antagonism at level of cytoplasmic mineralocorticoid receptors in distal nephron (DCT + CT). Spironolactone-receptor complex does not attach to DNA. Prevents translocation of receptor complex to nucleus. Aldosterone acts to promote Na+ uptake in exchange for K+ secretion… see Na+ loss and K+ sparing…mild diuretic effect…most Na+ already reabsorbed by more proximal nephron. Slow onset of action Need to exhaust proteins already formed by aldosterone action…1-2 days. Well absorbed from GI tract. t ½ =10 minutes Active metabolite canrenone has t ½ = 16 hours.

44. Cellular Action of Aldosterone

45. Spironolactone (Aldactone®) Useful primarily in states of aldosterone excess associated with diminished effective extracellular volume CHF Cirrhosis Nephrotic syndrome Adverse Effects HYPERKALEMIA Increased risk with renal disease, drugs which decrease renin (  - blocker, NSAID) or ACE inhibitor Hyperchloremic metabolic acidosis Inhibits H + secretion along with K + secretion Gynecomastia, impotence

47. Triamterene (Dyrenium®): Influences Na+-K+ exchange in distal nephron. Direct inhibitory effect. No effect on aldosterone. Acts within few hours. Limited diuretic efficacy. Metabolized in liver. Short t 1/2. Well absorbed.

48. Clinical Indications: Hypertension Mild edema Usually combined with another diuretic: +hydrochlorothiazide = Dyazide® Also, AMILORIDE (Midamor®)-blocks luminal Na+ channels by which aldosterone produces main effect. Poorly absorbed, slower onset of action, peak 6 hours. + hydrochlorothiazide = Moduretic®

49. Carbonic Anhydrase Inhibitors: Carbonic anhydrase present in luminal and basolateral membranes, epithelial cell cytoplasm, and RBC’s. Luminal membrane of PCT predominant site. Catalyzes dehydration of H 2 CO 3 …critical step in HCO 3 reabsorption. CO2 + OH-  HCO3- Inhibition of Carbonic Anhydrase causes diuresis and reduction in total body HCO3 stores. Depresses HCO3 reabsorption. HCO3 accumulates in luminal fluid.

50. Carbonic Anhydrase Inhibitors: Forerunners of modern diuretics. Sulfonamides [-SO 2 NH 2 ] noted to cause hyperchloremic, metabolic acidosis with large volumes of alkaline urine. Thiazides developed to separate natriuretic effects from effects of HCO 3 handling.

51. Carbonic Anhydrase Inhibitors: Acetazolamide (Diamox®) Dichlorphenamide (Daranide®) Methazolamide (Neptazane®) Dorzolamide (Trusopt®) SO 2 NH 2 Group is essential for activity 85% of HCO 3 resorptive activity is inhibited in PCT. 45% of whole kidney HCO 3 reabsorption is inhibited.

53. Clinical Actions: Increases urine volume Alkaline pH of urine Increases HCO 3 -, K +, Na + in urine Decreases Cl - in urine Decreases HCO3 - in blood: metabolic acidosis Hypokalemia HCO3 - depletion; enhanced NaCl reabsorption by remaining nephron segments; loss of effectiveness within days.

54. Carbonic Anhydrase Inhibitors: Carbonic anhydrase also present in ciliary body and choroid plexus. Aqueous humor and CSF formation are HCO3 - dependent. Processes are in opposite direction from that in PCT. Both are able to be inhibited and pH and quantity of fluid formed will be affected.

55. Pharmacokinetics: Well absorbed after oral administration. Increase in urine pH within ½ hour; maximal in 2 hours. Excretion by tubular secretion in S2 segment.

56. Clinical Indications: Glaucoma-Inhibition of CA decreases rate of aqueous humor formation and decreases IOP. Urinary alkalinization-uric acid, cystine relatively insoluble in acid urine. Excretion of weak acids (aspirin) enhanced in alkaline urine. Reduction of total body HCO3- stores. Acute mountain sickness. Absence seizures.

57. Toxicity: Hyperchloremic metabolic acidosis. Hypokalemia. Renal stones - Ca ++ salts relatively insoluble in alkaline urine. HCO 3 - loss in urine results also in phosphaturia and hypercalciuria. CONTRAINDICATED in cirrhosis. Urinary alkalinization results in decreased excretion of NH 4 +.

58. Osmotic Diuretics: Mannitol Freely filtered. Minimal reabsorption. Not metabolized. Pharmacologically inert. Given in amounts large enough to constitute appreciable fraction of plasma osmolarity. Also, Urea and Glycerin

59. Osmotic Diuretics: Creates osmotic force within lumen of nephron  prevents H 2 O reabsorption in those segments freely permeable to H 2 O (PCT and descending loop of Henle). Degree of diuresis related to amount of mannitol in filtrate. Little effect on loss of K +. Does not produce diuretic effects by blocking reabsorption of Na + or Cl -. IV use only. Cannot diffuse across GI epithelium.

60. Osmotic Diuretics: Clinical Indications: Prophylaxis of renal shutdown. - Increases Urine volume. Reduction of intracranial or intraocular pressure. Adverse Effects: Volume expansion. Dehydration, hypernatremia.

61. Agents that Affect Water Excretion: ADH (VASOPRESSIN): Acts at collecting tubule to modulate concentration of final urine. Secretion  during hypotonic volume expansion  large volumes of dilute urine formed. Secretion  during volume contraction & hypertonic conditions  urine concentration by water abstraction. Thick ascending limb of loop of Henle plays central role during concentration and dilution of urine.

62. ADH = Antidiuretic + Vasopressor Effects: Vasopressin-nonapeptide…arginine @ position 8. Primarily parenteral administration—IV, IM, intranasal. t1/2 = 20 minutes Renal and hepatic catabolism Reduction of disulfide bond + peptide cleavage.

63. Receptors: V1 mediate vasoconstriction. V2 (Renal) mediate antidiuresis through  H2O permeability and H2O resorption in CT and CD. V2 (extrarenal) mediate release of Factor VIIIc and von Willebrand Factor as well as  BP and  SVR.

64. ADH Antagonists: Li+ salts, demeclocycline inhibit effects of ADH at collecting tubule via adenylyl cyclase and at some step following cAMP generation by ADH…effects of cAMP antagonized.

65. Preparations: Aqueous Vasopressin (Pitressin®) Short acting IV, IM, or SQ Q 3-6 hours Lysine Vasopressin (Diapid®) Short-acting nasal spray Q 4-6 hours Desmopressin (DDAVP®) 1-desamino-8-D-arginine vasopressin. Long-acting synthetic analogue of vasopressin…minimal V1 activity. Antidiuretic: pressor = 4000 x vasopressin. Most expensive. Preferred for chronic therapy. Nasal spray, nasal tube, IV, SQ, or po Q 8-12 hours.

66. ADH Agonists: USE: Diabetes Insipidus (Pituitary): Vasopressin Nocturnal Enuresis: DDAVP GI Bleeding: Vasopressin infusion Assess renal concentrating ability after long-term lithium therapy: DDAVP Coagulopathy (Hemophilia A, von Willebrand’s): DDAVP TOXICITY: Headaches, nausea, cramps Caution: Nasal congestion