1. Vilasinee Hirunpanich B.Pharm(Hon), M.Sc In Pharm (Pharmacology)

2. Outline of diuretic drugs  Basic knowledge in anatomy and physiology  Classification of diuretics

5. Classification of Diuretics  Loop Diuretics  Thiazides Diuretics  K + -sparing diuretics  Osmotic Diuretics  Carbonic anhydrase inhibitors

7. 1. Loop diuretics (high ceiling diuretics)  block Na + -K + -2Cl - cotransport in the thick ascending limb of the loop of Henle  high efficacy: 25% of filtrated solute is reabsorbed

8. Structure of loop diuretics

9. Mechanism of action of Loop of Henle

10. pharmacokinetic  Rapidly absorbed  Eliminate by renal secretion  Torsemide (1h) is more rapidly than furosemide (Lasix  ) (2-3 h)  Duration 2-3 h (furosemide), 3-4 h(torsemide)

11. Adverse effects 1. Fluid and electrolytes imbalance  Hyponatremia, Hypokalemia and hypomagnesia 2. H + lossmetabolic alkalosis 3. Ototoxicity  ethacrynic most often

12. Adverse effects (cont) 4. Hyperuricemia 5. Hyperglycemia 6. Hypersensitivity to sulfonamide  skin rash 7. Others: dehydration

13.  Ototoxic drugs; aminoglycoside  digitalis glycoside  NSAIDs  probenecid  Litium  anticoagulant Drug interaction

14. Clinical indications 1. Hypertension and CHF 2. Acute pulmonary edema 3. Other edematous conditions 3. Mild hyperkalemia (simultaneous NaCl and water) 4. I -, Br - intoxication

15. 2.Thiazide Diuretics

16. Thiazide diuretics  Sulfonamide and benzothiadiazide (thiazide) derivatives –Hydrochlorothiazide (HCTZ), indapamide, chlorthalidone, metolazone

17. Mechanism of action of thiazide diuretics

18. Mechanism of actions  Increase Na +, Cl -, K +, Mg 2+ in urine ….water retention  Some drug has vasodilator effect such as indapamide (Natrilix  )

19. Pharmacokinetic  Chlorothiazide is less lipid soluble and must given in large dose  Indapamide is excreted primarily by the billiary system

20. Adverse effects 1.Fluid and electrolytes imbalance Hypokalemia Hyponatremia Hypercalcemia 2. hyperglycemia due to impaired pancreatic release of insulin 3.hyperlipidemia 4. allergic reaction 5. Other: weakness, fatigability

21. Drug interaction Decrease the effect of  anticoagulant  uricosuric agent  sulfonylurea  insulin Increase the effect of  digitalis glycoside  lithium Decrease the effect of thiazide  NSAIDs  bile acid sequestering  probencid

22. Clinical indications  Hypertension, CHF  hepatic cirrhosis  nephrolithiasis due to idiopathic hypercalcinuria  nephrogenic diabetes insipidus  Br - intoxicity

23. 3. K + -sparing diuretics

24. K + sparing diuretics 1. Aldosterone antagonists 2. Inhibitor of renal epithelium Na + channel

25. Aldosterone antagonist  Structure similar to aldosterone hormone Ex.  spironolactone (synthesis steriod),  eplerenone (spironolactone analog)

26. spironolactone  specific antagonist prevent protein synthesis that required for Na + and K + transport  increase Na + excretion and preserve of K +  Potentcy is low and depend on aldosterone level

27. pharmacokinetic Spironolactone  Onset and duration of action are determined by the kinetic of aldosterone response in target tissue.  Slow onset (48 hr)  Canrenone is the active metabolized which has very long t 12. than parent drug.

28. Adverse effects  hyperkalemia …..life threatening  Endocrine effects -gynecomastia -hirsutism -deepening voice - decrease libido

29.  Pts using salicylate because inhibiting canrenone  K + administration  coadministration with thiazide or loop diuretic for edema (additive effect)  hyperaldosteronism contraindication Clinical use

30. 2. Inhibitor of renal epithelium Na + channel  Triamterene  amiloride

31.  late distal tubules and collecting ducts  block Na+ channel in the luminal membrane  increase NaCl excretion and decrease K+ excretion Mechanism of action of K+- sparing diuretic

32. Adverse effect  anemia: triamterene, folic antagonist  kidney stone (triamterene is poorly soluble)  ARF (acute renal failure) (combination of triamterene and indomethacin has been reported )  life-threatening: hyperkalemia

33. contraindication  Renal failure  other K + sparing diuretic  ACEI  K + supplement  NSIADs

34.  Co administration with other diuretic (additive effect)  prevent depletion of intracellular K + store Clinical Use

36. Osmotic diuretics  Properties 1. Freely filtered at the glomerulus 2. No reabsorption at the renal tubule 3. No pharmacological effects  Glycerine, Isosorbide, Mannitol, Urea  site of action: Proximal tubule and descending limb of Henle ’ s loop

37. Structure of osmotic diuretics

38. Mechanism of action  Limit water reabsorption  act as increase urine volume.  increase renal blood flow

39. Pharmacokinetic  Poorly absorbed so they must be given parenterally  Mannitol is excreted by glomerular filtration within 30-60 min

40. Adverse effects 1. Extracellular volume expansion  Rapidly distributed in the extracellular compartment and extract water from the intracellular compartment 2. Dehydration 3. Nausea, vomiting, headache

41. Clinical Indications 1. To increase urine volume 2. Reduction of intracranial and intraocular pressure extract water from the eye and brain Glycerine: control intraocular pressure, pre/post operative ocular surgery Mannitol, urea: reduce cerebral edema before/after neuro-surgery

42. 5. Carbonic anhydrase inhibitors  Inhibit carbonic anhydrase enzyme at proximal tubule  SO 2 NH 2 (sulfonamide) group is essential for activity.  Acetazolamide (Diamox  ), dichlorophenamide, ethoxalamide, methazolamide

43. Structure of carbonic anhydrase inhibitors

44. Mechanism of action of carbonic anhydrase inhibitors

45. 1. increase the excretion of HCO 3 - (Urine alkalinization, pH 8)  Increase Na +, K +, secretion 2. Metabolic acidosis 3. eye; decrease formation of aqueous humor 4. Paresthesia, Drowsiness, Somnolence

46. Pharmacokinetic  Well absorbed after oral administration  The effect of increased of HCO 3 - is apparent within 30 min.  Maximal effect within 2 h  Persist for 12 h after single dose  Excrete by tubular secretion

47. Adverse effects 1. Hypersensitivity  sulfonamide derivative (fever, rashes, bone marrow suppression) 2. Renal stone  Ca 2+ salt are relatively insoluble at alkaline pH. 3. Metabolic acidosis and urine alkalinization 4. Renal potassium wasting 5. Others: drowsiness, paresthesia

48. Clinical indications 1. Glaucoma (decrease intraocular pressure)  Dorzolamide, brinzolamide (topically use) 2. Urinary alkalinization  increase the secretion of uric acid, weak acid drugs(aspirin) 3. Metabolic acidosis 4. Acute mountain sickness (24 h before ascent)

49.  Loop diuretic& thiazide (different position)  K + sparing diuretic& loop diuretic or thiazide (decrease ADR)  Moduretic  (amiloride + HCTZ)  Dyazide  (triamterene+HCTZ) Diuretic combination