1. DIURETICS Prof. R. K. Dixit Pharmacology K.G.M.U. Lucknow

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- Thick ascending 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
SEGMENT
FUNCTION
Glomerulus
Formation of glomerular filtrate
Proximal convoluted tubule (PCT)
Reabsorption of 65% of filtered Na+/K+/ Ca2+, and Mg2+; 85% of NaHCO3, (activity of Carbonic an-hydrase enzyme) and nearly, 100% of glucose and amino acids.
Iso-osmotic reabsorption of water., Secretion and reabsorption of organic acids and bases, including uric acid and most diuretics
Thin descending limb of Henle’s loop
Passive reabsorption of water
Thick ascending limb of Henle’s loop (TAL)
Active reabsorption of 25% of filtered Na+/K+/2Cl−; , secondary re-absorption of Ca2+ and Mg2+
Distal convoluted tubule (DCT)
Active reabsorption of 4–8% of filtered Na+ Cl−; Ca2+ reabsorption under parathyroid hormone control
Cortical collecting tubule (CCT)
Na+ reabsorption (2–5%) coupled to K+ and H+ secretion (under Aldosterone)
Medullary collecting duct
Water reabsorption under Vasopressin control

14. The relative magnitudes of Na+ reabsorption at sites
Asc LH - 25%
DT %
CD %.

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. Pharmacology copy by student
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

20. Loop Diuretics

21. Thiazides

22. Spironolactone
Amiloride

23. A -
GM-
Brings FruTE-
Cuts MIXs with Big Hands-
And Starts Taking-

24. GM- Glycerine, Mannitol
A - Acetazolamide
GM- Glycerine, Mannitol
Brings FruTE- Bumetanide, Furosemide, Torasemide, Ethacrynic acid
Cuts MIXs with Big Hands- Clopamide, Chlorthalidone, Metolazone, Indapamide, Xipamide, Benzthiazide, Hydrochlorthiazide,
And Starts Taking-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. Diuretic Site of Action Adverse Effects Special points
Carbonic anhydrase inhibitors
PTC
(inhibition of CAE)
Metabolic Acidosis
Weak, Used in Glaucoma, Petit mal epilepsy, Acute mountain sickness, to alkaline the urine
Osmotic Diuretics
PTC, LOH, DCT
(Osmotic retention of water, Dilates Afferent arterioles, Increased hydrostatic pressure in glomerulus
Shifting of fluid from intracellular to extracellular, Hyponatremia, Pulmonary edema
Potent
Used in Glaucoma, Poisoning, Increased ICT, impending ARF
Loop Diuretics
Thick Ascending Limb of Henle
(NaK2Cl inhibition)
Weak CAI action
Hyponatremia
Hypomagnesaemia
Hypocalcaemia
Hyperuricemia
Hyperglycemia
Hyperlipidemia
Ototoxic (ECA)
Most potent, Most Potent is Bumetanide, Effective even in low GFR, All except Ethacrynic acid are sulphonamide related,
Venodilatation, Decrease Left Ventricle Pressure, Used in Acute LVF, Pulmonary Edema, Nephrotic syndrome, ARF, NSAIDS blunt effect, Cerebral edema, short term tt of Hypertension, to reduce volume overload during transfusion,
Thiazide Diuretics
DCT
(NaCl)
Hypokalemic metabolic alkalosis (Gitelman’s Syndrome)
Hypercalcemia
Moderate, Chlorthalidone is Longest acting, Paradoxical effect in Diabetes Insipidus
First line in Hypertension,
Potassium Sparing Diuretics CD
HyperKalemia
Antiandrogenic effect
Weak, As supplement to other to counter the hypokalemia, Canrenone is active metabolite, used in Conn’s syndrome (Primary Hyperaldosteronism) cirrhotic edema, polycystic ovary

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

27. 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)

28. Most of Loop and Thiazide diuretics are sulphonamide derivatives
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)

29. 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

30. 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

31. 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)

32. MECHANISM OF ACTION of Amiloride
The luminal membrane of late DT and CD cells expresses a distinct 'amiloride sensitive' or 'renal epithelial' Na+ channel
Through these channels Na+ enters the cell down its electrochemical gradient which is generated by Na+ K+ ATPase operating at the basolateral membrane.
This Na+ entry partially depolarizes the luminal membrane creating a transepithelial potential difference which promotes secretion of K+ into the lumen through K+ channels
Amiloride and triamterene block the luminal Na+ channels- indirectly inhibit K+ excretion, while the net excess loss of Na+ is minor.
The intercalated cells in CD possess an ATP driven H+ pump which secretes H+ ions into the lumen. This pump is facilitated by lumen negative potential. Amiloride, by reducing the lumen negative potential, decreases H+ ion secretion as well; predisposes to acidosis.

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

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

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

36. 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

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

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

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

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

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

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

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

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

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

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

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

48. 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

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

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

51. B 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

52. B Renin is secreted from Macula Densa cells Juxta Glomerular Cells
Specialized cells of Ascending limb of henle
Specialized cells of efferent arterioles B

53. C Which of the follwing is NOT an indication of Acetazolamide
Petit mal epilepsy
Periodic Paralysis
To acidfy urine
To alkalinise urine C

54. B In loop of henle what percentage of sodium is reabsorbed 65% 25% 9%1% B

55. A Which of the following diuretics is not a sulphonamide derivative
Ethacrynic acid
Furosemide
Bumetanide
Torasemide A

56. Which of the follwing diuretic is active even when GFR is less than 20ml/min
Chlorthiazide
Chlorthalidone
Metolazone
Clopamide C

57. Which of the following drug does not produce hypokalaemic metabolic alkalosis
Furosemide
Hydrochlorthiazide
Acetazolamide
Indapamide C

58. D Which of the following is NOT indicated in Diabetes Insipidus?
Desmopressin
Hydrochlorthiazide
Chlorpropamide
Mannitol D

59. Thanks