Diuretics Part 1

Lecture for BDS 2nd year

1. Diuretics Dr. Pravin Prasad M.B.B.S., MD Clinical Pharmacology Assistant Professor, Maharajgunj Medical Campus 19 November 2021 (3 Mangsir 2078), Friday

2. By the end of this class, BDS 2 nd Year students will be able to: Classify diuretics Explain the mechanism of action of loop diuretics and thiazide diuretics Compare the adverse effects of loop diuretics and thiazide diuretics List their uses Identify their common drug interactions

3. Preliminaries

4. Relevant Physiology Functional Unit of Kidney Nephron Parts of nephron: Glomerulus Proximal Tubule Loop of Henle Distal Tubule Collecting Duct

5. Relevant Physiology Process of urine formation Ultrafiltration Tubular reabsorption Tubular secretion

6. Relevant Physiology Pharmacologically, nephron is divided into: Site I: Proximal Convoluted Tubule Site II: Thick Ascending Limb of Loop of Henle Site III: Cortical Diluting segment of Loop of Henle Site IV: Distal Convoluted Tubule and Collecting Duct

7. Urinary constituent movements: Site I Sodium Potassium Water Reabsorbed Reabsorbed Along the osmotic gradient Processes: Direct entry Coupled to absorption of anions Exchanged with H + Passive diffusion Process: Paracellular pathways Process: Transcellular aquaporin-1 channels Paracellular pathways

8. Urinary constituent movements: Site II Movement of only salts occur Impermeable to water Luminal fluid Cuboidal cells of TAL (medullary portion) Na + -K + -2Cl - K + Cl - K + Na + Na + Ca 2+ , Mg 2+ Extracellular fluid

9. Urinary constituent movements: Site III Movement of only salts occur Impermeable to water Luminal fluid Extracellular fluid Cl - Na + Na + -Cl - symporter No reabsorption or secretion of K +

10. Urinary constituent movements: Site IV Comprises of Distal tubule Collecting duct Two types of cells Principal cells Intercalated cells

11. Urinary constituent movements: Site IV Principal cells Intercalated cells Luminal fluid Extracellular fluid K + Na + Na + Na + Amiloride sensitive renal epithelial Na + channels Sodium channel Present in renal epithelial cells Sensitive to amiloride Modulated by aldosterone H +

12. Diuretics Causes net loss of Na + and water in urine Natriuretics Reabsorption of Na + PT: 65-70% TAL: 20-25% DT: 8-9% CD: 2-3%

13. Diuretics: Classification High ceiling Medium efficacy Weak / adjunctive Furosemide Bumetanide Ethacrynic acid

14. Diuretics: Classification High ceiling Medium efficacy Weak / adjunctive Benzothiadiazines Hydrochlorothiazide Polythiazide Bendroflumazide Thiazide like Chlorthalidone Metolazone Xipamide Indapamide Clopamide

15. Diuretics: Classification High ceiling Medium efficacy Weak / adjunctive Carbonic Anhydrase Inhibitors Acetazolamide Osmotic Diuretics Mannitol Isosorbide, Glycerol Potassium sparing diuretics Spironolactone , Eplerenone Amiloride, Triamterene

16. High ceiling diuretics Furosemide , Bumetanide, Torasemide ; Ethacrynic acid Dose dependent diuresis occurs Up to 10L/d of urine can be produced Quick onset of action Intravenous: 2-5 mins, Oral 20-40 mins Short duration of action 4-6 hours

17. Furosemide: Mechanism of Action Secreted by Organic anion transporter (OATP) present in PT cells Reaches Thick Ascending Limb of LoH Inhibits Na + -K + -2Cl - cotransporter Decreased absorption of Na + High amount of Na + and water excreted in urine

18. Furosemide: Mechanism of Action Luminal fluid Cuboidal cells of TAL (medullary portion) Na + -K + -2Cl - K + Cl - K + Na + Na + Ca 2+ , Mg 2+ Extracellular fluid

19. Furosemide: Mechanism of Action Minor actions: Inhibits Carbonic anhydrase enzyme in PT Increase HCO 3 - excretion Mild alkalosis in high dose (due to loss of Cl - ) Increased local PG synthesis Altered intrarenal haemodynamic Decreased PT reabsorption

20. Furosemide: Other Actions Prompt increase in systemic venous capacitance PG mediated Decreases left ventricular filling pressure Affords quick relief in Left ventricular failure and Pulmonary oedema

21. Furosemide: Pharmacokinetics Absorption after oral administration takes 2-3 hours Bioavailability 60% Reduced in severe congestive heart failure Plasma t 1/2 1-2 hour Single oral dose acts for 4-6 hrs Prolonged in pulmonary oedema, renal and hepatic insufficiency Excreted unchanged in urine

22. Loop diuretics: Uses Oedema Acute pulmonary oedema Hypertension Co-existing renal insufficiency, CHF, resistant cases, hypertensive emergencies Along with Blood Transfusion Hypercalcemia of malignancy Cerebral oedema

23. Medium efficacy diuretics Thiazide and thiazide like drugs Have flat dose-response curves Acts in cortical diluting segment of LoH or early DT Acts by inhibiting Na + -Cl - symporter Additional carbonic anhydrase inhibitor action Alkaline urine rich in Cl - produced

24. Thiazide: Mechanism of action Secreted by OATP in PT Reaches cortical diluting segment or early DT along luminal fluid Inhibits Na + -Cl - symporter Decreased Na + and Cl - absorption Increased urine passed

25. Thiazide: Mechanism of action Luminal fluid Extracellular fluid Cl - Na + Na + -Cl - symporter No reabsorption or secretion of K +

26. Thiazides: Other actions Additional carbonic anhydrase inhibitory action Increase HCO 3 - and PO 4 3- excretion Reduces GFR By reducing blood volume and by inducing intrarenal haemodynamic changes Not effective in patients with low GFR Extrarenal actions Slow developing fall in BP Elevation of blood sugar

27. Thiazides: Pharmacokinetics Well absorbed orally Action starts within 1 hour, duration 6-48 hrs Hydrochlorothiazide: 6hrs Chlorthalidone: 48 hrs Variable distribution (depends on lipid solubility) Eliminated mainly unchanged in urine Elimination t 1/2 : 3-4 hrs

28. Thiazides: Uses Hypertension One of the First line drugs (Chlorthalidone) Oedema Diabetes Insipidus (DI) Nephrogenic DI Hypercalciuria with recurrent calcium stones in the kidney

29. ADRs: Loop Diuretics vs Thiazides Loop Diuretics Thiazide Hypokalaemia Less common More common Acute Saline Depletion Seen Not So Common Dilutional Hyponatremia After vigorous use of Loop diuretics in CHF Rare

30. ADRs: Loop Diuretics vs Thiazides Loop Diuretics Thiazide GIT and CNS Disturbances Nausea/Vomiting, diarrhoea, headache, giddiness, weakness, paraesthesia, impotence Allergic manifestation Rashes, photosensitivity Rarely blood dyscrasias Sulphonamide hypersensitivity Hearing Loss Only with Loop diuretics

31. ADRs: Loop Diuretics vs Thiazides Loop Diuretics Thiazide Mental Confusion and hepatic coma Due to brisk diuresis in cirrhotic patients Magnesium depletion Seen after prolonged use Renal insufficiency Can be used in renal insufficiency Aggravated due to decreased GFR

32. ADRs: Loop Diuretics vs Thiazides Loop Diuretics Thiazide Hyperuricemia Less common High dose thiazides Hyperglycaemia, hyperlipidaemia Hypocalcaemia Seen on chronic administration Not seen Hypercalcaemia Seen

33. Drug Interactions: Loop diuretics and Thiazides Potentiates all other antihypertensives As it induces Hypokalaemia: Enhances digitalis toxicity Increased risk of Cardiac arrhythmia Reduces sulfonylurea action (oral hypoglycaemics)

34. Drug Interactions: Loop diuretics and Thiazides Additive ototoxicity and nephrotoxicity of aminoglycosides Actions reduced when used with indomethacin and other NSAIDs Probenecid and diuretics reduces each other’s actions Serum Lithium level rises

35. Post Test All of the following are the adverse effects of thiazide diuretics EXCEPT: Hypomagnesemia Hypovolaemia Hypocalcaemia Hypokalaemia

36. Conclusion Diuretics can be broadly grouped into three categories Loop diuretics acts by inhibiting Na + -K + -2Cl - cotransporter, Thiazides act by inhibiting Na + -Cl - symporter Loop diuretics and thiazides share some side effects and have some specific side effects Are commonly employed in HTN, oedema Drug interactions of loop diuretics can enhance therapeutic effect as well as aggravate adverse effects

37. Any queries? Next class: Friday Continue Diuretics Revise the topics from BOOK Thank you.