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DIURETICS

DIURETICS. Prof. R. K. Dixit Pharmacology K.G.M.U. Lucknow dixitkumarrakesh@gmail.com. Objectives of today’s Lecture. After completion of this lecture you will be able to know Diuretics Definition Classification Names of members in classes Mechanism of action Major indications

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DIURETICS

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  1. DIURETICS Prof. R. K. Dixit Pharmacology K.G.M.U. Lucknow dixitkumarrakesh@gmail.com

  2. Objectives of today’s Lecture After completion of this lecture you will be able to know • Diuretics • Definition • Classification • Names of members in classes • Mechanism of action • Major indications • Major side effects and Precautions • Major drug interactions • MCQs related to Diuretics

  3. Facts of Renal Physiology • Kidney- • Weight- 0.5% of Body, • Receive 25% of cardiac output (50 times) • Kidney functions • Balance of electrolytes, Plasma volume, Acid Base • Activation of Vitamin D • Synthesis of Erythropoietin, Urokinase • Excretion of Urea, Uric acid, Creatinine etc. • Transport types • Passive • Simple, channel mediated and facilitated diffusion, solvent drag • Active • Primary and Secondary (Symports and Secondary Counter transport)

  4. Facts related to Renal Physiology • Pressure difference at Bowman’s Capsule- 20mm Hg • Filter= Plasma-Proteins • Volume of • Filter- 180 liters • Urine- 1.5 liters (1%) • Kidneys • Renal Blood Flow- 1200ml/min • Renal Plasma Flow- 650 ml/min • GFR- 120 ml/min • Reabsorb – Sodium, Chloride and Bicarbonates > 99% while Potassium about 85%

  5. Terminology • Natriuresis- increased sodium excretion • Kaliuresis-Increased Potassium excretion • Diuretics- Drugs which cause a net loss of Na+ and water in urine.(Exception- Osmotic diuretics (Mannitol) don't cause natriuresis but produce diuresis

  6. Nephron Parts and Characters

  7. Proximal Tubule • Leaky- Freely permeable to water, solutes • Active absorption of • Sodium Chloride, • Sodium Bicarbonate • Glucose • Amino Acids • Organic Solutes • Followed by passive absorption of water

  8. Loop Of Henle • Descending limb- • Permeable to water • Thick ascending limb – • Impermeable to water but • Permeable to sodium by Na+K+2Cl- Co transport • About 25% of filtered sodium is absorbed here

  9. Macula Densa and Juxtaglomerular Apparatus • Contact between Ascending limb with afferent arterioles – by specialized columnar epithelial cells Macula Densa • Macula Densa sense NaCl conc. in filtrate • Give signal to J.G. Cells present in afferent arterioles • J.G. Cells of afferent arterioles secrete Renin

  10. RAAS in response to low BP, or Low Na Renin- • Angiotensinogen - Angiotensin I ACE- • Angiotensin II- • Sympathetic, Aldosterone Vasoconstriction, Sodium and water retention,

  11. Early Distal Tubule • Active transport of sodium by NaCl symport • Calcium excretion is regulated (Parathomone and Calcitriol, increase absorption of calcium)

  12. Collecting Tubule and Collecting Duct • Aldosterone- On membrane receptor and cause sodium absorption by Na+/H+/ K+ Exchange • ADH- Collecting tubular epithelium permeable to water (Water enters through aquaporin-2)

  13. Nephron parts and their functions

  14. The relative magnitudes of Na+ reabsorption at sites • PT - 65% • Asc LH - 25% • DT - 9% • CD - 1%.

  15. Control of Renal Function • Sympathetic- Increase Na reabsorption, Renin • RAAS- Renin in response to Low sodium, Low BP • ADH – Water reabsorption at collecting duct • Atrial Natriuretic Peptide/Factor- Released when atrial pressure is high and causes solute and water diuresis and reduces blood volume and BP. Inhibits synthesis of Renin, Aldosterone, ADH and overcomes the long term persistent effect of aldosterone (Opposite of RAAS) • Prostaglandins- maintain renal circulation

  16. Breath for a minute Pharmacology copy by student

  17. Diuretics • Carbonic Anhydrase Inhibitors (Site I) • Brinzolamide, Acetazolamide, Dorzolamide • Osmotic Diuretic (Site II) • Glycerine, Urea, Mannitol, Isosorbide • Loop Diuretics (Site III)- TALH • Frusemide/ Furosemide, Bumetanide, Torasemide, Ethacrynic acid • Thiazide Diuretics (Site IV) • Hydrochlorothiazide, Clopamide, Benzthiazide, Chlorthalidone, Metolazone, Xipamide, Indapamide • Potassium Sparing Diuretics (Site V) • Aldosterone Antagonist • Spironolactone, Canrenone, Eplerone • Direct Acting (Inhibition of renal epithelial Nq+ channel • Triamterene, Amiloride (more potent)

  18. Carbonic An-hydrase Inhibitors Thiazide diuretics Osmotic Diuretics Potassium Sparing Diuretics Loop Diuretics (High Ceiling)

  19. Carbonic Anhydrase Inhibitors Carbonic Anhydrase Inhibitors

  20. Loop Diuretics

  21. Thiazides

  22. Spironolactone Amiloride

  23. A - • GM- • Brings FruTE- • Cuts MIXs with Big Hands- • AndStartsTaking-

  24. A - Acetazolamide • GM- Glycerine, Mannitol • Brings FruTE- Bumetanide, Furosemide, Torasemide, Ethacrynic acid • Cuts MIXs with Big Hands- Clopamide, Chlorthalidone, Metolazone, Indapamide, Xipamide, Benzthiazide, Hydrochlorthiazide, • AndStartsTaking-Amiloride, Spironolactone, Triamterene Carbonic Anhydrase Inhibitors (Site I) Osmotic Diuretics (Site I, II and…) Loop Diuretics (Site III) Thiazide Diuretics (Site IV) Potassium Sparing Diuretics (Site V)

  25. Breathing Please…………….. Pharmacology teacher grfom where you passed

  26. Special mention • Don’t use diuretics overenthusiastically. (dehydration, hypotension) • Brisk diuresis in cirrhosis may precipitate hepatic coma. (hypokalemia, alkalosis and increased NH3 levels) • Diuretics not used in Toxaemia of Pregnancy. (Blood volume is low despite edema. Diuretics will compromise placental circulation)

  27. Most of Loop and Thiazide diuretics are sulphonamide derivatives. (Think of allergic manifestations) • Hypokalemia by diureitcs precipates digitalis, quinidine side effects • Hypokalemia by diuretics decrease sulfonylurea action (reduced insulin release due to reduced action of ATP dependent potassium channel)

  28. High ceiling not given with Amino-glycosides • ACE inhibitors with Thiazides reduce the chances of hypokalaemia (FDC) • Probenicid inhibits tubular secretion of Frusemide and Thiazides and reduce action • Potency of producing hypokalaemia CAsI>Thiazides>Loop • NSAIDS reduce diuretic action due to PG inhibition and affecting glomerular blood flow

  29. CAsE is present in PT, gastric mucosa, exocrine pancreas, ciliary body, arachnoid plexus & RBC • Acetazolamide action is self limiting • Spironolactone breaks the Thiazide resistance • Aspirin blocks Spironolactone action by inhibiting tubular secretion of canrenone

  30. Spironolactone can produce dangerous hyperkalaemia when used along with ACEI and ARBs • Spironolactone has antiandrogenic side effects • Eplirenone is new potassium sparing diuretics with less antiandrogenic effects • Osmotic diuretics indicated in impending ARF. (Don’t use if ARF has set in)

  31. Acetazolamide, CAIs, Alkaline urine, S/E Acidosis Clopamide, Metolazone, Indapamide, Xipamide, Benzthiazide, Hydrochlorthiazide, Hypercalcaemia • A • GM • Brings FruTE • Cuts MIXs with Big Hands • AndStartsTaking Amiloride, Spironolactone, Triamterene Bumetanide, Frusemide, Torasemide, Ethacrynic acid- Loop, Most potent, Hypocalcimia Glycerine, Mannitol, Osmotic, Hyponatremia, Not when ARF already sets in

  32. MCQs on Diuretics • Reabsorption of which of the following is affected maximum by action of vasopressin? • Water • Chloride • Potassium • Hydrogen A

  33. Bumetanide belongs to which of the following class of diuretics? • Carbonic anhydrase inhibitor • Aldosterone antagonist • Thiazide diuretics • Loop diuretics D

  34. All of the following compounds produce diuretic action by acting on thick ascending part of loop of henle EXCEPT • Ethacrynic acid • Torasemide • Furosemide • Clopamide D

  35. Which of the following is thiazide like diuretics? • Spironolactone • Triameterene • Metolazone • Acetazolamide C

  36. Which of the following is carbonic anhydrase inhibitor? • Acetazolamide • Spironolactone • Benzthiazide • Clopamide A

  37. Which of the following is NOT an aldosterone antagonist? • Spironolactone • Canrenone • Eplerenone • Triameterene D

  38. Among all of the following which is most potent? • Frusemide • Bumetanide • Torasemide • Ethracrynic acid B

  39. Spirnolactone may be beneficial in all of the following clinical conditions EXCEPT • Nephrotic edema • Hypertension • Congestive heart failure • Hyperkalaemia D

  40. Among following which is most ototoxic? • Metolazone • Clopamide • Ethacrynic acid • Chlorthalidone C

  41. Which of the following is not an adverse effect of Furosemide? • Hyperuricaemia • Hyperglycaemia • Hyperlipidemia • Hypermagnesaemia D

  42. Which of the following drugs can precipitate hypercalcaemia? • Spironolactone • Hydrochlorthiazide • Furosemide • Mannitol B

  43. Thiazides induced hyperuricaemia may be prevented by administration of which of the following? • Allopurinol • Probenecid • Mannitol • Furosemide A

  44. Which of the following condition is contraindication for Mannitol administration? • Acute congestive glaucoma • Head injury • Impending acute renal failure • Acute Pulmonary Edema D

  45. Among following which compound has maximum potency? • Chlorthiazide • Chlorthalidone • Hydroflumethozide • Clopamide B

  46. Which of the following is most appropriate mechanism of action of Triametrene • Inhibition of Miniralocorticoid receptors • Inhibition of Na+K+2Cl- channels • Inhibition of Na+Cl– channels of DCT • Inhibition of renal epithelial Na+ channels D

  47. Which of the following drug is used in acute mountain sickness • Acetazolamide • Spironolactone • Domperidone • Ethacrynic acid A

  48. Site of action of spironolactone is • Proximal Convoluted Tubule • Descending limb of Loop of Henle • Collecting Duct • Ascedning limb of loop of henle C

  49. Which of the following is converted by Angiotensin Converting Enzyme • Angiotensinogen to Angiotensin I • Angiotensin I to Angiotensin II • Angiotensin II to Angiotensin III • Inactivation of Angiotensin III B

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