1. DIURETICS

2. Functions of the kidneys Volume Acid-base balance Osmotic pressure Electrolyte concentration Excretion of metabolites and toxic substances Maintain internal environment by regulating composition of extracellular compartment

3. Anatomy of the Nephron

4. Renal process involved in the production of urine: 1) Glomerular filtration 2) Renal tubular secretion 3) Renal tubular reabsorption

5. Glomerular filtration

6. Tubular secretion

7. PCT organic acid secretory transport system

8. PCT organic base secretory transport system

9. Renal tubular sodium reabsorption

10. Renal handling of water and substances Average Values for Several Substances Handled by Filtration and Reabsorption Amount Filtered Amount % Substanceper DayExcreted Reabsorbed Water, L 180 1.8 99.0 Sodium, g 630 3.2 99.5 Glucose, g 180 0 100 Urea, g 56 28 50

11. Renal handling of water and substances Average Values for Several Substances Handled by Filtration and Reabsorption Amount Filtered Amount % Substanceper DayExcreted Reabsorbed Water, L 180 1.8 99.0 Sodium, g 630 3.2 99.5 Glucose, g 180 0 100 Urea, g 56 28 50

12. Total Body Sodium Balance: Input = Output

13. Renal excretion of sodium

14. The goal of diuretic therapy is to increase the net excretion of water by the kidneys by : interfering with the renal tubular reabsorption of sodium and subsequently water antagonizing the hydroosmotic effect of vasopressin (antidiuretic hormone)

16. Transport pathways across tubular cells

17. PROXIMAL TUBULES

18. Proximal Tubular Diuretics Osmotic Diuretics Mannitol Urea Glycerin Isosorbide

19. “Mannitol”

20. Sodium, glucose and bicarbonate reabsorption in the proximal convoluted tubule

21. Therapeutic Uses: 1. Acute renal failure (i.e., maintain urine flow) 2. Reduce cerebrospinal fluid volume and pressure 3. Glaucoma 4. Facilitate urinary excretion of toxic substances Adverse Effects: 1.Extracellular expansion and subsequent adverse effects in patients with congestive heart failure and pulmonary edema Mannitol

22. Proximal Tubular Diuretics Carbonic Anhydrase Inhibitors Acetazolamide

24. K+K+ ATP Na + Basolateral Apical CA HCO 3 - CO 2 + H 2 O H+H+ Proximal Convoluted Tubule CA H+H+ HCO 3 - H 2 CO 3 CO 2 + H 2 O

25. K+K+ ATP Na + Basolateral Apical CA HCO 3 - CO 2 + H 2 O H+H+ Action of Acetazolamide Acetazolamide Urine [H +, NH4 +, Cl - ] Plasma [HCO 3 - ] CA H+H+ HCO 3 - H 2 CO 3 CO 2 + H 2 O Urine [ HCO 3 -] Urine [ Na+, K+], pH, H 2 O

26. Therapeutic Uses: 1.Open angle glaucoma (chronic simple) – decreases formation of aqueous humor 2.Create an alkaline urine to facilitate urinary excretion of acidic drugs 3. Metabolic alkalosis 4.High altitude sickness Adverse Effects: 1.Metabolic acidosis Acetazolamide

27. Loop of Henle

29. Loop Diuretics Furosemide Bumetanide Torsemide Ethacrynic acid

31. Electrolyte transport pathways in the TALH

32. [Na +, K +, Cl -, Ca +, Mg +, H +, NH4 + ], H2O pH Urine: [HCO3 - ]No Δ

33. Therapeutic Uses: 1.Removal of edema (e.g., pulmonary edema) and ascites 2.Hypertension 3.Symptomatic hypercalcemia 4.Dilutional hyponatremia during SIADH (i.e., state of high ADH) Adverse Effects: 1.Volume depletion and circulatory contraction 2.Diuretic-induced hyponatremia 3.Diuretic-induced metabolic alkalosis (aka, contraction alkalosis) 4.Hypokalemia 5.Ototoxicity 6.Activation of RAS 7.Drug interactions: a) Anticoagulants (Warfarin) b) Aminoglycosides c) Cardiac glycosides d) Drugs that utilize the proximal tubule organic acid secretory pathway (e.g. probenecid, penicillin, salicylates, etc.) Loop Diuretics

34. Early Distal Convoluted Tubule

36. Thiazide and Thiazide-like Diuretics Hydrochlorothiazide Chlorothiazide Chlorothalidone Metolazone

38. Sodium and chloride reabsorption in the early distal convoluted tubule

39. Urine: [Na +, K +, Cl -, ~HCO3 - ], pH, H2O pH [Ca +, H +, NH4 + ]

40. Therapeutic Uses: 1. Hypertension 2. Hypocalcemia 3.Removal of edema and ascites 4.Nephrogenic diabetes insipidus Adverse Effects: 1.Volume depletion and circulatory contraction 2.Hypokalemia 3.Activation of RAS 4.Aggravate hyperglycemia 5.Increase plasma cholesterol and triglycerides 6.Increase plasma uric acid 7.Drug interactions: a) Cardiac glycosides b) Drugs that utilize the organic acid secretory pathway (eg. penicillin) Thiazide and Thiazide-like Diuretics

41. Late Distal Convoluted Tubule and Collecting Duct

43. Late Distal Tubule Diuretics (aka, potassium-sparing diuretics) Amiloride Triamterene Epithelial Na Channel (ENaC) Antagonists Spironolactone Aldosterone Receptor Antagonists

45. Sodium - Potassium exchange in the late distal convoluted tubule

46. Urine: [Na +, Cl -, HCO3 - ], pH, H2O [K +, H +, NH4 + ]

47. Spironolactone

48. Therapeutic Uses: 1. Hypertension 2. Hypokalemia 3. Refractory edema and ascites 4. Primary aldosteronism Adverse Effects: 1. Hyperkalemia Potassium-Sparing Diuretics

49. Antidiuretic Hormone (vasopressin) and water transport in the collecting ducts

50. AVP-dependent water permeability in the distal nephron

51. Vasopressin – mediated water reabsorption

52. Vasopressin antagonists (Aquaretics) Conivaptan ~ Demeclocycline and Lithium Collecting Duct Diuretics Therapeutic Uses: 1. Hyponatremia (e.g., as in SIADH)

53. Synthetic Vasopressin agonists Desmopressin (DDAVP) Collecting Duct Antidiuretics Therapeutic Uses: 1. Central diabetes insipidus

54. Nephrogenic diabetes insipidus -Thiazide diuretic Therapeutic treatment: -NSAIDs

55. 1. Methylxanthines (eg. theophylline and caffeine) 2. Dopamine, dobutamine, cardiac glycosides 3. Alcohol (ethanol) 4. Water Other Drugs with Diuretic Activity