Diuretics Part 2

Lecture for BDS 2nd year

1. Diuretics-II Dr. Pravin Prasad M.B.B.S., MD Clinical Pharmacology Assistant Professor, Maharajgunj Medical Campus 26 November 2021 (10 Mangsir 2078), Friday

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, BDS 2 nd year 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 in congestive heart failure Blocks the effects of aldosterone, which are: Expansion of e.c.f. volume Increased cardiac preload Fibroblast proliferation and fibrotic change in myocardium Worsening systolic dysfunction and pathological remodelling Hypokalemia and hypomagnesemia Increased risk of ventricular arrhythmias, sudden cardiac death

18. Spironolactone in hypertension Slight decrease in blood pressure when used alone Augment the antihypertensive action of thiazide diuretics Inhibits aldosterone induced pathological changes in the body: Ventricular and vascular hypertrophy Renal fibrosis

19. 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

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

21. 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

22. 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 +

23. 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

24. 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

25. 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