1. DIURETICS Brogan Spencer and Laura Smitherman

2. What is a diuretic? Substance that promotes the formation (excretion) of urine

3. Name 3 common and important diuretics Loop diuretics Thiazide diuretics Potassium sparing diuretics (action at ENaC or MR) Some less important & less commonly used diuretics: Carbonic anhydrase inhibitors Osmotic diuretics

4. What are the indications for use of diuretics? Oedema Congestive heart failure Hypertension Fluid overload

5. Target site of diuretics

6. Loop diuretics Example: Furosemide Site of action: Ascending limb Loop of Henle MoA: Inhibit the Na+K+2Cl- co-transporter (competitively inhibits Cl- part of co-transporter preventing Cl- from binding) Effect: ↓ NaCl reabsorption in thick ascending loop. ↓osmotic concentration in tubular cells (which means more Na+ in collecting duct) so less H2O absorption, due to ↓ADH. ↑ NaCl to distal collecting duct causes ↑Na+ uptake so ↑ loss of K+ (& H+)

7. Uses of loop diuretics Generally used in acute problems as is the most powerful (15-25% of filtered load Na + ) type of diuretic and is fast acting. Peripheral oedema (chronic heart failure) Acute pulmonary oedema (has additional beneficial vasodilator effect) Can be used in resistant hypertension

8. Side effects of loop diuretics Increased frequency of urination Hypovolaemia & hypotension (excessive Na + and water loss (esp. elderly)) Hypokalaemia Metabolic alkalosis can occur Ototoxicity (high doses)

9. Thiazide diuretics Example: Bendroflumethiazide, indapamide, chlortalidone Site of action: Proximal 1/3 distal convoluted tubule MoA: Inhibit the Na+Cl- co-transporter (competitively binds with Cl- part of co-transporter preventing Cl- from binding) Effect: ↓ NaCl reabsorption in the DCT. ↑ Na+ in tubule lumen means increased H 2 0 in tubule. ↑ NaCl to distal collecting duct causes ↑Na+ uptake so ↑ loss of K+ (& H+)

10. Uses of Thiazides Fairly weak, slow acting diuretic (5% of filtered load Na + ). Last longer. Hypertension Peripheral oedema (chronic heart failure)

11. Side effects of thiazides Increased frequency of urination Hypokalaemia / hyponatraemia / (metabolic alkalosis) ↑ plasma uric acid (gout) Erectile dysfunction Hyperglycaemia

12. Potassium Sparing Diuretics -ENac Example: Amiloride Site of action: Late DCT or CCD. MoA: Inhibit the ENaC channels transporter (competitively inhibits Na+ binding site). Effect: ↓ Na+ reabsorption in collecting duct. Therefore H 2 O not reabsorbed. K+ is not exchanged for Na+ so retained in body (tubal cells).

13. Uses of ENaC Antagonists Weak diuretic so used in combination with thiazides/ loop diuretics Side effects of loop diuretics Hyperkalaemia

14. Potassium Sparing Diuretics – Aldosterone antagonists Example: Spironalactone, Eplerenone Site of action: Collecting Duct MoA: Inhibits mineralocorticoid receptor inside the principal cells (competitively binds to Aldosterone binding site). Stops ENaC synthesis and Na+/K+ ATPase channel activation. Effect: ↓ Na+ reabsorption in collecting duct. Therefore H 2 O not reabsorbed. K+ is not secreted into lumen and so is retained in body (principal cells).

15. Uses of Aldosterone Antagonists Chronic heart failure Peripheral oedema & ascites caused by cirrhosis Resistant hypertension Primary hyperaldosteronism (Conn’s syndrome) Can be used in combination to prevent K + loss from use of loop / thiazide diuretics Weak diuretic but often used with thiazides/ loop diuretics to counteract the loss of K+

16. Side effects of Aldosterone antagonists Hyperkalaemia (care if prescribing with other agents that inhibit RAAS) Gynaecomastia (aldosterone antagonists)

17. The drugs and side effects you need to know! ClassExampleSide effects LoopFurosemideIncreased frequency of urination Hypovolaemia & hypotension (excessive Na+ and water loss (esp. elderly)) Hypokalaemia Metabolic alkalosis can occur Ototoxicity (high doses) ThiazideBendroflumethiazideIncreased frequency of urination Hypokalaemia / hyponatraemia / (metabolic alkalosis) ↑ plasma uric acid (gout) Erectile dysfunction Hyperglycaemia Potassium Sparing (ENaC antagonist) Amiloride Hyperkalaemia Hyponatraemia Potassium Sparing (Aldosterone antagonist) Spironalactone Hyperkalaemia Hyponatraemia Gynecomastia

18. RAAS http://www.handwrittentutorials.com/videos.php?id=42

19. Diuretics sites of action