Diuretics II

This presentation was used for theory class of MBBS Sem III

1. Diuretics-II Dr. Pravin Prasad M.B.B.S., MD Clinical Pharmacology Lecturer, Lumbini Medical College & TH 10 April 2019 (27 Chaitra 2075), Wednesday

2. Answer the following… Classify diuretics Why loop diuretics are also known as high ceiling diuretics? Mechanism of action of thiazide diuretics? Which class diuretic is preferred in essential hypertension? Any two important drug interaction of diuretics.

3. By the end of this class, MBBS Sem III students will be able to: Explain the mechanism of action of weak diuretics Discuss the salient pharmacological aspects of weak diuretics Differentiate between the two types of potassium sparing diuretics

4. Diuretics: Classification High ceiling Medium efficacy Weak / adjunctive

5. Weak/ Adjunctive Diuretics: Classification Carbonic Anhydrase Inhibitors Acetazolamide Osmotic Diuretics Mannitol Isosorbide, Glycerol Potassium sparing diuretics Renal epithelial Na + channel blockers Amiloride, Triamterene Aldosterone antagonists Spironolactone, Eplerenone

6. Carbonic Anhydrase Inhibitors Acetazolamide , Methazolamide, Dorzolamide Reversible, non-competitive inhibitor of carbonic anhydrase Action limited by the availability of HCO 3 - in luminal fluid Self limited diuretic action Na + absorption in distal segment occurs in exchange with K + Marked kaliuresis

7. CAse Inhibitors: Mechanism of Action PT cells Luminal fluid H + Extracellular fluid NaHCO 3 Na + HCO 3 - H 2 CO 3 H 2 O + CO 2 CAse IV CAse II H 2 CO 3 HCO 3 - CAse Inhibitors

8. CAse inhibitors: Mechanism of Action Inhibits Carbonic anhydrase enzyme at multiple sites Type II in cells of PT Less H + available for exchange with Na + Type IV on the membrane of PT cells Less CO 2 available for diffusion into cells Inhibition of Na + and HCO 3 - reabsorption in PT Na + gets absorbed in exchange with K + in DT, CD HCO 3 - lost in excess in urine

9. CAse inhibitors: Mechanism of Action Inhibits Carbonic anhydrase enzyme at multiple sites Present in intercalated cells of DT and CD Less H + available for secretion by H + -ATPase Principal cells Intercalated cells Luminal fluid Extracellular fluid H + Na + Na + Na + Na + Na + Na +

10. Acetazolamide: Extra-renal effects Decrease formation of aqueous humour Lowering of Intraocular tension Used in open angle glaucoma as well as angle closure glaucoma Raised level of CO 2 in brain and lowering of pH Sedation and elevation of seizure threshold Used in High Altitude Sickness

11. Acetazolamide: Uses Glaucoma Decrease formation of aqueous humour Mountain sickness Alters CO 2 transport in lungs, tissues and brain Decreases CSF formation, lowers pH To alkalinise urine Periodic paralysis Epilepsy

12. Acetazolamide: Adverse effects Acidosis, hypokalaemia To be cautiously used in COPD patients Drowsiness Paraesthesia, fatigue, abdominal discomfort Hypersensitivity reaction Bone marrow depression Interferes with elimination of NH 3 in urine CONTRAINDICATED in liver disease

13. Aldosterone antagonists Spironolactone , Eplerenone Conserve K + indirectly, produces mild natriuresis Potassium sparing diuretics No effect in the absence of aldosterone Useful in states related to high aldosterone activity Spironolactone has hormonal side effects Eplerenone is safer in this regard

14. ECF Luminal Fluid Spironolactone: Mechanism of Action Aldosterone Mineralocorticoid receptor Nucleus AIP ATP Na + K + K + Spironolactone

15. Spironolactone: Mechanism of Action Binds to Mineralocorticoid receptors Blocks aldosterone activity Competitive antagonist Aldosterone Induced Protein / Na + channels not expressed Decreased absorption of Na + and water and secretion of K + K + loss in urine is decreased

16. Spironolactone: Uses Hypertension Adjuvant to thiazide, loop diuretics Counteracts K + loss Attenuates hypertensive nephropathy Oedema Cirrhotic/ nephrotic patients Refractory Congestive Heart Failure Primary hyperaldosteronism

17. Spironolactone: Adverse effects Drowsiness, mental confusion, ataxia, epigastric discomfort, loose motions Interacts with progestin and androgen receptors: Gynaecomastia, erectile dysfunction, loss of libido Breast tenderness, menstrual irregularities Hyperkalaemia in renal impaired patients Acidosis in cirrhotics Peptic ulcer: CONTRAINDICATION

18. Eplerenone Lower affinity for androgen and progestin receptors Inactivated by CYP3A4 enzyme Indications: Moderate to severe CHF Post infarct left ventricular dysfunction Hypertension

19. Renal epithelial Na + Channel inhibitors Triamterene, Amiloride Decreases K + excretion, accompanied with small increase in Na + loss Potassium sparing diuretics Alkaline urine produced Cl - , HCO 3 - Reduces Ca 2+ and Mg 2+ excretion

20. Amiloride: Mechanism of Action ECF Luminal Fluid Principal cells of late DT and CD Rich in K+, Low Na+ Activity of Na+-K+ ATPase at basolateral membrane Na + K + K + Amiloride Na + Na + K + K + K + K + K + K + Na + Na +

21. Amiloride: Mechanism of Action Blocks luminal amiloride sensitive renal epithelial Na + channels Decrease reabsorption of Na + in DT and CD Luminal negative charge not developed Less secretion of K + from principal cells Less secretion of H + from intercalated cells

22. Amiloride: Uses Hypertension As adjuvant Prevents hypokalaemia Increase natriuretic response More likely to develop hyperkalaemia if given along with ACEI/ARBs, NSAIDs, β blockers Cystic fibrosis

23. Adverse effects Amiloride: Nausea, diarrhoea, headache Decreases entry of lithium in CD cells Lithium induced diabetes insipidus Triamterene: Impaired glucose tolerance, photosensitivity Rise in blood urea

24. Osmotic diuretics Mannitol , glycerol, isosorbide Non-electrolyte, low molecular weight Pharmacologically inert Acts by: Raising osmolarity of plasma and tubular fluid Gets freely filtered at glomerulus Limits tubular water and electrolyte reabsorption (cations as well as anions)

25. Mannitol Tubular water and electrolyte reabsorption action of mannitol mediated by: Retaining water isosmotically in PT and Descending limb of LoH Inhibit transport process in TAL Expands extracellular fluid volume Increases renal blood flow Corticomedullary osmotic gradient lost

26. Mannitol Given intravenously Uses: Increased intracranial pressure Increased intraocular pressure Counteract low osmolarity of plasma and ECF due to rapid haemodialysis or peritoneal dialysis (dialysis disequilibrium)

27. Mannitol CONTRAINDICATIONS: Renal insufficiency Acute tubular necrosis Anuria Pulmonary oedema Acute left ventricular failure CHF Cerebral haemorrhage Side Effects Headache Nausea/ vomiting Hypersensitive reactions

28. Post Test Inhibition of CAse by Acetazolamide is: Competitive and reversible Non-competitive and reversible Competitive and irreversible Non-competitive and irreversible

29. Post Test All of the following are a potassium sparing diuretics EXCEPT: Acetazolamide Triamterene Eplerenone Spironolactone

30. Post Test All of the following are indications of acetazolamide EXCEPT: Epilepsy Angle closure glaucoma High altitude pulmonary oedema As diuretic

31. Conclusion Weak diuretics either act early in PT or in late DT and CD Acetazolamide has its self limiting action, produces acidosis and marked kaliuresis Not used as diuretics Spironolactone has activity on progestin and androgen receptors Eplerenone safer in this regard Potassium sparing diuretics acts either by antagonising the activity of aldosterone or by directly inhibiting action of epithelial Na + channels