Deuritics

1. Deuritics Dr. Ebtehal S. Al abdullah ebtehalksu@yahoo.com

2. Outline • Sites of drug action. • Renal function. • Osmotic diuretics. • Carbonic anhydrase inhibitors. • Thiazide diuretics. • Loop diuretics. • Potassium-sparing diuretics.

3. DIURETICS A diuretic is defined as a chemical that elevates the rate of urine formation.

4. Definitions • Diuretic: substance that promotes the excretion of urine • caffeine, cranberry juice, alcohol • Natriuretic: substance that promotes the renal excretion of Na+

5. Uses of Diuretics • In treatment of • Edematous conditions (cause blood volume to increase) reasulting from many causes: • congestive heart failure • nephrotic syndrome • chronic liver disease • renal faliure • and hypertension

6. Uses of Diuretics • Also useful as sole agent (or adjunctive therapy) in : • hypercalcemia • diabetes insipidus • acute mountain sickness • primary hypoaldosteronism • glucoma

7. Diuretics • Functions of the kidneys: • To maintain homostatic balance of electrolytes and water. • To excrete water soluble end products of metabolism. • So the kidneys accomplishes these functions through the formation of urine by nephrons.

8. Renal Physiology • renal epithelial transport • tubular reabsorption • - proximal tubule • - loop of Henle • - thick ascending limb • - distal convoluted tubule • tubular secretion • collecting tubules

9. Summary: Sites of Action

10. Site of Action Class of Diuretics Mechanism of Action Prox. Convoluted tubules 1.Carbonic anhydrase Ihibitors Inhibit. of renal carbonic anhydrase decreases NaHCO3 reabsorption Thick ascend. limb TAL ( loop Henle) Inhibition of the luminal Na+/K+ /2Cl- 2. Loop or high- ceiling Diuretics Thick ascending limb ( loop Henle) and distal tubules Inhibition of sodium chloride reabsorption 3. Thiazide & Thiazide-like Inhibition of Na and H2O reabsorption (Competit. inhibit. of aldosterone); Blockade of Na+ uptake at the luminal membrane 4. Potassium- Sparing Diuretics Distal tubule and collecting duct decrease Na & H2O reabsorption. Decrease medullary hypertonicity elevated urinary flow rate. Proximal tubule Loop of Henle Collecting tubule 5. Osmotics

11. Nephron sites of action of diuretics

12. Diuretics • Diuretics are acting at different sites in the nephron and are classified as: • Carbonic anhydrase inhibitors acting at the proximal convoluted tubule (site1 diuretics). • Loop diuretics acting at the Henle’s loop (site 2 diuretics). • Thiazides and thiazide-like diuretics acting at distal convoluted tubule (site 3 diuretics). • Potassium-sparing diuretics acting at collecting tubule (site 4 diuretics). • Osmotic diuretics; Act at proximal tubules, loop of henle, collecting tubule.

13. therapeutic uses for different Types of diuretics • Carbonic anhydrase inhibitors (work in proximal tubule) • Cystinuria (increase alkalinity of tubular urine) • Glaucoma (decrease occular pressure) • Acute mountain sickness • Metabolic alkalosis • Osmotic diuretics (proximal tubule, loop of Henle) • Acute or incipient renal failure • Reduce preoperative intraocular or intracranial pressure

14. Loop diuretics (ascending limb of loop) • Hypertension, in patients with impaired renal function • Congestive heart failure (moderate to severe) • Acute pulmonary edema • Chronic or acute renal failure • Nephrotic syndrome • Hyperkalemia • Chemical intoxication (to increase urine flow)

15. Thiazide diuretics (distal convoluted tubule) • Hypertension • Congestive heart failure (mild) • Renal calculi • Nephrogenic diabetes insipidus • Chronic renal failure (as an adjunct to loop diuretic) • Osteoporosis

16. Potassium-sparing diuretics (collecting tubule) • Chronic liver failure • Congestive heart failure, when hypokalemia is a problem • Osmotic agents (proximal tubule, descending loop of Henle, collecting duct) • Reduce pre-surgical or post-trauma intracranial pressure • Prompt removal of renal toxins • One of the few diuretics that do not remove large amounts of Na+ • Can cause hypernatremia

17. Potency and efficacy of Diuretics Diuretic efficacy has increased with the corresponding changes in the site of action of each of three classes of diuretics: Class 1, CA inhibitor: Inhibit the reabsorption of Na+/HCO3-at site 1. Weaker Class 2, Thiazide and thiazide-like diuretics: Inhibit the reabsorption of Na+/Cl- at site 3. Stronger Class 3, High-ceiling diuretics: Block Na+/Cl-/K+/Ca+/Mg2+ reabsorption at site 2.

18. Renal Function Basic mechanisms for transmembrane transport of solutes Active transport Passive transport

19. Basic mechanisms for transmembrane transport of solutes • Active transport 1- Primary active transport: Na+-K+ ATPase (sodium pump) in the basolateral membrane of epithelial cells is the major driving force for the transport of solutes in kidney. 2- Secondary active transport: It utilizes energy available from the transmembrane Na+ gradient established by sodium pump to transport other solutes against their electrochemical gradient.

20. Basic mechanisms for transmembrane transport of solutes Secondary active transport includes symport (co-transport) which transports sodium and other solutes in the same direction, and antiport (counter-transport) which exchanges movement of sodium for the counter movement of other solutes.

21. Basic mechanisms for transmembrane transport of solutes • Passive transport a. Simple diffusion. b. Channel-mediated diffusion. c. Carrier-mediated diffusion.

22. Diuretic Drug Classes 1- Osmotic Diuretics 2- Carbonic Anhydrase inhibitors 3- Thiazide and Thiazide-like diuretics 4- loop diuretics 5-Potassium-sparing diuretics

23. Osmotic diuretics

24. Class 1: Osmotic diuretics They have the following key features: 1. low mol.wt. compounds, freely filtered into renal tubules ( They are passively filtered by glomerular filtration.) 2. They undergo limited reabsorption in the renal tubules 3.  They are metabolically and pharmacologically inert, 4.  They have a high degree of water solubility

25. Osmotic diuretics They act by elevating the osmotic pressure of the glumular filtrate to an extent that the tubular re-absorption of water and solutes (mainly Na) are hindered. They include mannitol and urea. Mannitol is the most important and having very important and unique indications.

26. DiureticsOsmotic Diuretics Mechanism of Action • Work mostly in the proximal tubule • Nonabsorbable, producing an osmotic effect • Pull water into renal tubules from the surrounding tissues • Inhibits tubular resorption of water and solutes • Increases glomerular filtration and renal plasma • Reduces excessive intraocular pressure

27. Mechanism of Action • Increase intraluminal osmotic pressure , causes water to pass from body to tubule • - osmotic diuretics are not reabsorbed increases osmotic pressure specifically in the proximal tubule and loop of Henle • prevents passive reabsorption of H2O • not reabsorbed from nephron • it increase volume of urine and execertion of water and almost of electrolytes

28. 1.Osmotic diuretics 60–80%

29. Osmotic Diuretics • do not interact with receptors or directly block renal transport activity dependent on development of osmotic pressure • Mannitol (prototype) • Urea • Glycerol • Isosorbide

30. Class 1: Osmotic diuretics Mannitol * The prototypic osmotic diuretic, * D-Mannitol is a water-soluble, lipid-insoluble hexahydroxy alcohol. * Mannitol should be given by the intravenous route. * Mannitol enters renal luminal fluid only by glomerular filtration. * Its high luminal fluid concentration creates an osmotic effect that may prevent the reabsorption of up to 28% of the filtered load of water. * Because solutions of mannitol may expand the extracellular fluid volume, they should not be used in patients with severe renal disease or cardiac decompensation.

31. Mannitol indications • Oliguric acute renal failure. • During cardiovascular surgery. • Reduction of intracranial pressure prior to and during neurosurgery. • Reduction of IOP in absolute or secondary glucoma and prior to occular surgery.

32. Theophylline • The prototypic xanthine, is known to promote a weak diuresis by stimulation of cardiac function and by a direct action on the nephron. Although theophylline is infrequently used as a diuretic, a diuresis may be an observed side effect when it is used as a bronchodilator.

33. 2. carbonic anhydrase inhibitors

34. Class 2: Carbonic Anhydrase Inhibitors • Shortly after its introduction for the treatment of bacterial infections, sulfanilamide was observed to produce a milddiuresis characterized by presence of urinary Na+ and a substantial amount of HCO3-. • It induced this effect through inhibition of renal carbonic anhydrase • It was a relatively weak inhibitor of renal CA, and the dose needed to exert adequate diuresis was associated with severe adverse effects.

35. Mechanism of action Similar structure

36. Mechanism of Action • 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 • reduces H+ ion concentration in renal tubules • Result: • increased excretion of bicarbonate, sodium, water, & K+ • Resorption of water is decreased and urine volume is increased

37. Mechanism of Action • - inhibits carbonic anhydrase in renal proximal tubule cells • - carbonic anhydrase catalyzes formation of HCO3- and H+ from H2O and CO2 • - inhibition of carbonic anhydrase decreases [H+] in tubule lumen • less H+ for for Na+/H+ exchange • increased lumen Na+, increased H2O retention

38. 2. Carbonic anhydrase inhibitors Acetazolamide inhibits carbonic anhydrase (CA) mainly in proximal tubules. CA H2CO3– + H+ H2CO3 H2O + CO2

39. Prolonged use lead to lose their ability WHY? • Uses • 1- glaucoma • 2-acute mountain sickness • 3-prevention and treatment of metabolic alkalosis in • treatment of absence seizures. • 4-mostly used in combination with other diuretics in • resistant patients Therapeutic Application &Uses

40. Side Effects • 1- rapid tolerance • 2- increased HCO3- excretion causes metabolic acidosis • 3- drowsiness • 4- fatigue • 5- CNS depression • 6- paresthesia (pins and needles under skin) • 7- nephrolithiasis (renal stones) • 8- K+ wasting

41. CA inhibitor • To improve on the CA-inhibitory property of sulfanilamide, many sulfamoyl-containing compounds (-SO2NH2) were synthesized. • Two groups of CA inhibitors emerged: simple heterocyclic sulfonamides and meta-disulfamoylbenzene derivatives.

42. Two groups of CA inhibitors

43. 2. carbonic anhydrase inhibitors Acetazolamide Prototype; Developed from sulfanilamide, after it was noticed that sulfanilamide caused metabolic acidosis and alkaline urine. MOA: Inhibit carbonic anhydrase in proximal tubule; blocks reabsorption of bicarbonate ion, preventing Na+/H exchange. Therapeutic Uses Urinary alkalinization; Metabolic alkalosis Glaucoma: acetazolamide, dorzalamide Acute mountain sickness

44. 1. Acetazolamide N-(5-Sulfamoyl-1, 3, 4-thiadiazol-2-yl) acetamide

45. 2. Diclofenamide 4, 5-Dichloro-m-benzenedisulphonamide • Diclofenamide is employed to lower intraocular • pressure by reducing the rate of secretion of • aqueous humor. • It is recommended for the treatment of both primary and • secondary glaucoma. 3. Dorzolamide (Trusopt®) It is an anti-glaucoma agent and topically applied in the form of eye drops; market introduction 1995 Dorzolamide hydrochloride is used to lower increased intraocular pressure in open-angle glaucoma and ocular hypertension.

46. SAR