Diuretics

https://www.facebook.com/profile.php?id=100007500842607

1. DIURETICS By Sanjay kumar yadav B.Pharm Fifth semester

2. Diuretics are the drugs or agents which promotes diuresis i.e. increased urine production and increased rate of urine flow The site of action is kidney, specifically different parts of a nephron Diuretic action is achieved by increasing excretion of Na + ions (natriuretic) which increases excretion of water However some diuretics (osmotic diuretics) have no natriuretic but only aquaretic action Na + ions are excreted accompanied with other ions, particularly Cl - ions, also Ca ++ , Mg ++ , K + etc.

3. THERAPEUTIC USES As antihypertensive agent (decreases blood volume) In treatment of edema (by mobilizing extracellular fluids as NaCl is the major determinant of extracellular volume) To maintain urine volume

4. Structure of nephron

5. PHYSIOLOGY OF URINE FORMATION

6. CLASSIFICATION OF DIURETICS Type Example Site of action Mechanism of action Carbonic anhydrase inhibitors Acetazolamide Methazolamide Proximal convoluted tubule Inhibition of carbonic anhydrase enzyme Loop diuretics Furosemide Torasemide Loop of Henle Blocks Na + /K + / Cl - symporter Thiazide and thiazide like diuretics Hydrochlorthiazide Metolazone Distal convoluted tubule Blocks Na + / Cl - symporter Osmotic diuretics Mannitol Isosorbide Proximal convoluted tubule; Loop of Henle Potassium sparring diuretics Collecting tubule Blocks renal epithelial Na + channel Na+ channel blockers Triamterene Blocks the action of aldosterone Aldosterone antagonist Spironolactone

7. SITE OF ACTION OF VARIOUS DIURETICS

8. SITE OF ACTION OF VARIOUS DIURETICS

9. CARBONIC ANHYDRASE INHIBITORS Weak type of diuretics Act by inhibiting carbonic anhydrase enzyme Examples: Acetazolamide, Methazolamide , Dorzolamide

10. ACTION OF CARBONIC ANHYDRASE Catalyzes the following reaction Located in proximal convoluted tubule; both in the cytoplasm of tubular cells and on luminal membrane Plays a key role in NaHCO 3 reabsorption

11. Fig. Action of Carbonic Anhydrase Enzyme

12. Basolateral Na + pump maintain a lesser concentration of Na + inside the tubular cells which activated Na + /H + exchanger present on luminal membrane H + , transported into lumen in exchange of Na + , bind with HCO 3 - to form H 2 CO 3 which in presence of luminal CA breaks down into H 2 O and CO 2 CO 2 diffuses into tubular cells where it binds with H 2 O and then breaks into HCO 3 - via cytoplasmic CA enzyme This creates electrochemical gradient of HCO 3 - across basolateral membrane which is used by Na + /HCO 3 - symporter present on basolateral membrane resulting in reabsorption of NaHCO 3 followed by water reabsorption isotonically

13. MOA OF CARBONIC ANHYDRASE INHIBITORS (ACETAZOLAMIDE) Inhibition of both luminal and cytoplasmic carbonic anhydrase enzyme results in blockage of NaHCO 3 reabsorption in PCT And thereby increase excretion of water Besides Na + and HCO 3 - , CA inhibitors also increase excretion of Cl - and K + ; but have no effect on Ca ++ and Mg ++ reabsorption It shows self limiting diuretic action

14. EXTRARENAL ACTIONS OF CA INHIBITORS Ciliary processes of eye: CA mediates formation of HCO 3 - in aqueous humor CA inhibitors decrease rate of formation of aqueous humor and decrease IOP CNS Lowering of pH resulting in sedation and elevation of seizure threshold

15. THERAPEUTIC USES Because of self limiting action, production of acidosis and hypokalemia, it is not used as diuretic Edema (in combination with other distal diuretics) Used in glaucoma To alkalinize urine (during UTI and to promote excretion of acidic drugs) Altitude sickness (for symptomatic relief as well as prophylaxis; due to reduced CSF formation as well lowering of brain and CSF pH) Epilepsy To treat metabolic alkalosis

16. ADRs Metabolic acidosis Hypokalemia Drowsiness Tinnitus Parasthesias Abdominal discomfort Bone marrow depression Renal lesions, allergic reactions Renal stones

17. Contraindications Liver cirrhosis May precipitate hepatic coma by interfering with urinary elimination of NH3 due to alkaline urine COPD Increased risk of acidosis

18. DOSE Adult dose for Glaucoma Open angle glaucoma: tab or inj. 250 mg 1 to 4 times a day Closed angle glaucoma: 250 to 500 mg PO/IV followed by 125-250 mg PO q 4 hrs For altitude sickness: 125 to 250 mg orally q 6-12 hrs For seizure prophylaxis : 8 to 30 mg/Kg/day in 1 to 4 divided doses

19. Drug – Drug Interactions Acetazolamide + Aspirin Inhibit each others renal tubular secretion resulting increased plasma levels; also CAIs displace salicylates from plasma to CNS resulting to neurotoxicity Acetazolamide + Carbamazepine Increased levels of carbamazepine, due to inhibition of CYP3A4 by acetazolamide Acetazolamide + ephedrine Increase tubular reabsorption of ephedrine

20. LOOP DIURETICS Also called high ceiling diuretics High efficacy diuretics Site of action is thick ascending limb of loop of Henle , specifically Na + /K + /2Cl - symporter Ex: Furosemide , Torasemide , Bumetanide

21. MOA OF FUROSEMIDE (LOOP DIURETICS)

22. MOA OF FUROSEMIDE (LOOP DIURETICS )

23. Na + /K + /2Cl - symporter present on luminal membrane of TAL is responsible for reabsorption of NaCl and KCl By inhibiting this symporter , furosemide inhibits the reabsorption of Na + , K + and Cl - thereby resulting in diuretic action TAL is responsible for reabsorption of 35% of Na + ; hence inhibition at this site helps in achieving highly efficacious diuretic action Besides, it also inhibits reabsorption of Ca ++ and Mg ++

24. THERAPEUTIC USES Edema (Drug of choice for edema in nephrotic syndrome) Acute pulmonary edema Cerebral edema Hypertension Hypercalcaemia

25. ADR Hypokalemia Hyperuricaemia Hypomagnesaemia, hypocalcemia Hypotension Nausea, vomiting, diarrhoea Ototoxicity Hypersensitivity reactions Alkalosis

26. CONTRA INDICATIONS Severe hyponatremia Severe dehydration Anuria Hypersensitivity to sulfonamides

27. DOSE For edema 20 to 80 mg PO OD For hypertension 20-80 mg PO q 12hr Acute pulmonary edema 0.5-1 mg/Kg IV over 1-2 minutes

28. DRUG-DRUG INTERACTION Furosemide + Aminoglycoside antibiotics ( amikacin , gentamycin, streptomycin) Synergistic pharmacological effects results in ototoxicity and nephrotoxicity Furosemide + NSAIDS Diminished action of furosemide Furosemide + Probenecid Inhibit tubular secretion of furosemide decreasing their action Diminish uricosuric action of probenecid

29. Furosemide + Lithium Increased plasma levels of Lithium due to enhanced reabsorption Furosemide + cardiac glycosides Enhances digitalis toxicity

30. THIAZIDE AND THIAZIDE LIKE DIURETICS These are diuretics of medium efficacy Site of action is distal convoluted tubule; specifically Na + / Cl - symporter E.g.: Hydrochlorthiazide , Benzthiazide , Metalozone , etc.

31. MOA OF HYDROCHLORTHIAZIDE

32. Na + / Cl - symporter , present on luminal membrane of DCT, is responsible for Na + reabsorption at this site (about 5%) Thiazides compete for Cl - binding site of this symporter and by blocking this, it inhibits Na + reabsorption Simultaneously, it also inhibit reabsorption of Cl - , K + and Mg ++ It increases the reabsorption of Ca ++

33. THERAPEUTIC USES To treat edema associated with heart (congestive heart failure), liver (cirrhosis), and renal ( nephrotic syndrome, chronic renal failure, and acute glomerulonephritis) disease As antihypertensive agents (mainly used diuretics) Osteoporosis

34. ADR Hypotension Hypokalemia Metabolic alkalosis Hypernatremia Hypochloremia Hypomagnesaemia Hypercalcemia Hyperuricaemia

35. CONTRA INDICATIONS Sulfonamides hypersensitivity

36. DOSE For hypertension 12.5-50 mg PO OD For edema 25-100 mg PO OD or BD For osteoporosis 25 mg PO OD

37. DRUG-DRUG INTERACTION Thiazides + NSAIDS/Bile acid sequestrants Reduced activity of thiazides due to reduced absorption Thiazides + antiarrythmic drugs (Quinidine) Increased risk of polymorphic ventricular tachycardia due to hypokalaemia induced by thiazides Thiazides + Probenecid Inhibit tubular secretion of furosemide decreasing their action Diminish uricosuric action of probenecid

38. POTASSIUM SPARRING DIURETICS These are the diuretics that have are able to conserve K + while inducing mild natriuresis Includes: Aldosterone antagonists E.g.: Spironolactone, Eplerenone Renal epithelial Na+ channel inhibitors E.g.: Triamterene, Amiloride

39. SPIRONOLACTONE Steroid, chemically related to mineralocorticoid aldosterone Acts as antagonist of aldosterone

40. ACTION OF ALDOSTERONE

41. ACTION OF SPIRONOLACTONE

42. MOA OF SPIRONOLACTONE Aldosterone penetrates the late DT and CD cells Bind to intracellular mineralocorticoid receptor (MR) Induces formation of aldosterone induced proteins (AIP) AIPS promote Na + reabsorption by a number of mechanism and K + secretion

43. Spironolactone binds to MR and inhibits formation of AIPs As a result it increases Na + and decreases K + excretion

44. THERAPEUTIC USES In combination with other diuretics to counteract K + loss Edema Hypertension Congestive heart failure Primary Hyperaldosteronism

45. ADR Hyperkalemia Metabolic acidosis in cirrhotic patients Diarrhoea , gastritis Gynaecomastia Erectile dysfunction Menstrual irregularities Drowsiness, mental confusion

46. CONTRA INDICATIONS In case of severe hyperkalemia Peptic ulcer (may aggravate)

47. DOSE For edema 25-200 mg/day orally Hypertension 50-100 mg/day orally Congestive heart failure 25 mg orally OD Primary Hyperaldosteronism 400 mg/day orally

48. DRUG-DRUG INTERACTION Spironolactone + Salicylates Inhibit tubular secretion of spironolactone thus reducing its action Spironolactone + Cardiac glycosides Increase plasma levels of cardiac glycosides by altering its elimination

49. MANNITOL It is a osmotic diuretic Its major site of action is loop of henle Chemically it is sugar alcohol It is a nonelectrolyte of low molecular weight Pharmacologically inert

50. MOA OF MANNITOL Mannitol is freely filtered at glomerulus, undergo limited reabsorption Being a hypertonic solute, it increase intraluminal osmotic pressure This OP extract from the tubular cells and also prevents water reabsorption Thereby increasing the urine volume Though primary action is to increase urinary volume, mannitol also results in enhanced excretion of all ions

51. THERAPEUTIC USES To treat increased intracranial or intraocular pressure Drug of choice for cerebral edema In acute renal failure

52. ADR Pulmonary edema Headache Nausea Vomiting Dehydration

53. CONTRA INDICATIONS Active intracranial bleeding Pulmonary edema CHF Anuria

54. DOSE For Cerebral edema 1.5-2 g/kg IV infused over 30-60 minutes For increased IOP 1.5-2 g/kg IV infused over 30-60 minutes

55. DRUG-DRUG INTERACTION Mannitol + aminoglycosides Increased risk of nephrotoxicity

56. REFERENCES TRIPATHI, K.D., (2014). Essentials of Medical Pharmacology . 7 th Edition. New Delhi, India: Jaypee Brothers Medical Publishers Pvt. Ltd . BRUNTON, L.L., PARKER, K.L., BLUMENTHAL, D.K., BUXTON, I.L.O, (2006). Goodman and Gilman’s Manual of Pharmacology and Therapeutics. 11 th Edition. USA: The McGraw-Hill Companies, Inc.

57. THANK YOU