1. DIURETICS Part 1 Prof. Hanan Hagar Pharmacology Department

2. Diuretics Are drugs that increase renal excretion of sodium and water resulting in increase in urine volume. Most diuretics act by interfering with the normal sodium reabsorption by the kidney.

3. Sites for water and electrolytes transport along the nephron

4. Mechanism of action of diuretics  Most diuretics act by inhibiting carriers or transporters in luminal membrane of renal tubular cells required for tubular reabsorption of sodium from filtrate back into blood.

5. Sodium Excretion Regulation Nephron Segment Na + TransporterFiltered Na + re- absorbed Proximal convoluted tubules Na + /H + transporter Carbonic anhydrase 85 % As NaHCO3 Ascending Loop of Henle Na + /K + /2Cl - cotransporter 20-30% Active reabsorption Na, K, Cl Distal convoluted tubules Na + /Cl - transporter 5-10% Active reabsorption Na, Cl Cortical Collecting Tubules Na + channel Aldosterone Antidiuretic hormone 5% Na reabsorption K & H secretion

6. Types of diuretics Nephron Segment Na + Transporter Diuretics Proximal convoluted tubules Na+/H+ transporter Carbonic anhydrase Carbonic anhydrase inhibitors Ascending Loop of Henle Na+/K+/Cl- cotransporter Loop diuretics Distal convoluted tubules Na+/Cl- transporter Thiazide diuretics Cortical Collecting Tubules Na+ channel Aldosterone K-sparing diuretics

7. Site of action of diuretics DiureticstransporterFunctionsegment Carbonic anhydrase inhibitors Na/H transporter, Carbonic anhydrase enzyme Re-absorption of 66% Na, K, Ca, Mg, 100% glucose and amino acids; 85% NaHCO3 Proximal convoluted tubules NoneAcid & base transporter Secretion and re- absorption of organic acids and bases Proximal Straight Tubules Loop diuretics Na/K/2Cl transporter Active reabsorption 25% Na, K, Cl Secondary reabsorption Ca, Mg Thick ascending loop Thiazide diuretics Na and Cl cotransporter Active tubular reabsorption of 5%Na, Cl, Ca Distal convoluted tubules K-sparing diuretics Na channels K & H transporter Na reabsorption K & H secretion Collecting tubules

8. Classification of diuretics Carbonic anhydrase inhibitors Loop diuretics Thiazide diuretics Potassium-sparing diuretics Osmotic diuretics

9. CARBONIC ANHYDRASE Luminal membraneBasolateral membrane LumenBlood

10. A SCENDING LOOP OF H ENLE

11. Distal convoluted tubules (DCT)

12. COLLECTING TUBULES (CT)

14. Diuretics

15. Carbonic Anhydrase Inhibitors Acetazolamide – dorzolamide Mechanism of action: Inhibits carbonic anhydrase (CA) enzyme in PCT thus interferes with NaHCO3 re-absorption and causes diuresis.

16. Carbonic Anhydrase Inhibitors CA is required for reversible reaction,reversible reaction in which CO2 +H2O H2CO3 H+ HCO3-

17. Luminal membrane Basolateral membrane Lumen Blood Proximal tubules

18. Carbonic Anhydrase Inhibitors

20. Pharmacokinetics: given orally once a day. Onset of action is rapid (30 min). Duration of action (12 h). Excreted by active secretion in proximal convoluted tubules forming alkaline urine

21. Pharmacological actions: ↑ urine volume ↑ urinary excretion of sodium, potassium, bicarbonate (alkaline urine). Metabolic acidosis. ↑ urinary phosphate excretion. Weak diuretic properties. (decreases after several days ; self- limiting as the blood bicarbonate falls).

22. Carbonic anhydrase inhibitors

23. Therapeutic uses: Open angle glaucoma (↓ IOP by reducing aqueous humor formation via blocking carbonic anhydrase in ciliary body of eye ). As prophylactic therapy, in acute mountain sickness (to decrease CSF and pH of brain). Note that IOP: intraocular pressure CSF: cerebrospinal fluid

24. Therapeutic uses: Epilepsy (decrease cerebrospinal fluid, CSF). Urinary alkalinization to enhance renal excretion of acidic substances (cysteine in cystinuria). Hyperphosphatemia Metabolic alkalosis

25. Adverse effects: Hypokalemia (potassium loss). Metabolic acidosis. Renal stone formation (calcium phosphate stones). Hypersensitivity reactions

26. Dorzolamide Is a carbonic anhydrase inhibitor Used topically for treatment of increased intraocular pressure in open-angle glaucoma. no diuretic or systemic side effects (Why?).

27. LOOP DIURETICS High Ceiling diuretics The most efficacious diuretics Efficacy: High 25-30% natriuresis Drugs as Furosemide - Bumetanide Torsemide - Ethcrynic acid

28. LOOP DIURETICS Mechanism: inhibit Na + / K + / 2 Cl - co-transporter in the luminal membrane of the thick ascending loop of Henle (TAL). inhibit Ca ++ and Mg ++ re-absorption.

29. Ascending loop of Henle

30. A SCENDING LOOP OF H ENLE

31. Pharmacokinetics Given orally or I. V. Have fast onset of action (suitable for emergency) Have short duration of action. Bumetanide is the most potent Excreted by active tubular secretion of weak acids into urine. Interfere with uric acid secretion.

32. Pharmacological effects: ↑ urinary excretion of Na + and K + ↑ urinary excretion Ca ++ and Mg ++ ↑ urine volume ↑ renal blood flow.

33. Uses: are drug of choice for emergency situations as: Acute pulmonary edema due to heart failure Edema due to nephrotic syndrome Acute hyperkalaemia. Acute hypercalcemia

34. Adverse effects : Acute hypovolemia (volume depletion). Hyponatraemia. Hypokalemia (dietary K supplementation or K-sparing diuretics). Hypomagnesaemia Metabolic alkalosis. Postural hypotension

35. Adverse effects : Hyperuricemia (increase gouty attack). Ototoxicity (risk increased if combined with aminoglycosides) Hyperglycemia Allergic reactions