Diuretics, it's use and mechanism of action

Different types of diuretics

1. Mechanisms of Diuretic Action Presenter : Dr. V.VigneshRam Resident, Department of Nephrology Dr.Dy.Y.Patil Hospital

2. The term Diuretic derived from Greek Diouretikos , means “to promote urine”. Many substances promote urine flow, but diuretics are substances that can reduce the extra cellular volume by increasing the urinary solute and water excretion.

3. Normal NaCl handling Sodium chloride and water reabsorption by the nephron is driven by ATP dependant metabolic energy. Na/ KATPase is expressed at the basolateral cell membrane of epithelial cells along the nephron. Pump maintains layer ion gradients across the plasm membrane, intracellular Na+ LOW/ K+ HIGH. This favours electrochemical gradient favouring Na entry from lumen or interstitium .

4. Classified based on primary site of action on one particular segment of nephron. Proximal tubule : Na/H exchanger 50-60% Thick ascending limb : Na-K-2Cl cotansporter 20-25% Distal convoluted tubule : thiazide sensitive Na-Cl cotransporter 5% Cortical collecting duct : amiloride sensitive 3% Osmotic diuretics action on multiple segments of nephron

5. Osmotic Diuretics Substances that are freely filtered at the glomerulus but poorly reabsorbed. Activity of the drug depends on the osmotic pressure exerted by drug molecules in solution Mannitol is prototypical osmotic diuretic agent Others urea, sorbitol, glycerol Urinary electrolyte excretion : Do not directly act on transport channels Na,K,Ca,Mg,Cl, bicarbonate excretion rates increase

6. Mechanism of action: Increases osmotic pressure in PCT and LoH, retarding passive re absorption of water Increase in renal blood flow and wash out of medullary tonicity Functional consequences of mannitol : Increase in cortical and medullary blood flow Variable effect on GFR Increase in Na, water electrolyte excretion Decrease in medullary concentration gradient Quantitatively greater effect on LoH than PCT

7. Renal hemodynamics : Diffuses from blood stream to interstitial space —> increases osmotic pressure —> draws water from cells to increase extracellular fluid volume thereby increasing the RPF. Decrease in hct and blood viscosity Decrease in renal vascular resistance Stimulation of secretion of vasodilators substances – PGI2 , ANP Pharmacokinetics : Not readily absorbed from intestines. Only IV route. Excretion entirely by glomerular filtration Plasma half life 2.2 hours .

8. Clinical uses : Prophylactic prevention of AKI by improving renal hemodynamics Mannitol along with hydration and soda bicarbonate in the treatment of myoglobinuric acute kidney injury and prevention of post transplant acute kidney injury Periop cardiopulmonary bypass surgery Not beneficial when used prophylactic in risk of contrast nephropathy . Short term reduction in IOP in glaucoma Decrease cerebral edema in haemorrhage patients Treatment of dialysis disequilibrium syndrome (rapid removal of solutes such as urea during dialysis is associated with development of osmotic gradient for water movement into brain cells producing edema and neurological dysfunction)

9. Adverse effects. : Increases cardiac output and PCWP. Patients with reduced cardiac output can develop pulmonary edema . Acute and prolonged administration electrolyte disturbances Dilutional metabolic acidosis + hypertonic hyponatremia (transfer of sodium free water from ICF to ECF. Hyperkalemia Accumulates causing reversible kidney injury caused by vasocontrion and tubular vacuolization . Large cumulative doses ~295g with previously compromised renal function.

10. Proximal Tubule Diuretics (Carbonic Anhydrase Inhibitors) Limited therapeutic role as diuretic agents because weakely nayriuretic when employed chronically. Urinary electrolyte excretion : PCT increase bicarbonate excretion 25-30% Na And Cl excretion is smaller because they are reabsorbed in the distal segments. Ca and phosphate inhibited in PCT. Increase K+ excretion

11. Mechanising of action : CA is important for sodium bicarbonate re absorption and H+ ion secretion 3 major CA. TypeIICA distributed widely. Activity at basolateral and luminal membranes of PCT and luminal membranes of intercalated cells catalyses the dehydration of intraluminal carbonic acid generated from secreted protons.

12. Why natriuretic potency of CA inhibitors is weak? 60%PT Na reabsorption is mediated by both CA dependant and independent pathways. Increased sodium delivery to distal nephron segments largely reabsorbed there. CA inhibitors result in hyperchloremic metabolic acidosis, which further cause CA resistance

13. Renal hemodynamics : Decreases GFR by 30% because of increased solute delivery to macula sends activates tubuloglomerular feedback mechanising which reduces the GFR. Pharmacokinetics : Well ansorbed from GI tract. 90% plasma protein bound Highest concentrations in renal cortex and RBC Renal effects noticing in 30 minutes and are usually maximal at 2hrs Not metabolised but is excreted rapidly by glomerular filteration and proximal tubular secretion Half life 5 hours renal excretion complete in 24 hours

14. Adverse effects : Significant hypokalemia and metabolic acidosis due to urinary excreation of bicarbonate. Nephrocalcinosis , nephrolithiasis due to increase in urinary ph Drowsiness, fatigue, depression, paresthesias . Clinical uses : Short term therapy in combination with other diuretics Major treatment in patient with metabolic alkalosis + edema Chronic respiratory acidosis COPD Chronic open angle glaucoma Acute mountain sickness within 12-72 hrs of ascending high altitudes Familial hypokakemic periodic patalysis

15. LOOP DIURETICS Inhibit sodium and chloride transport along LoH and macula densa . They are organic anions, bind to one of the chloride sites in the transporter Urinary electrolyte excretion Increases excretion of water , Na,K,Cl, PO4, Mg, Ca Highest natriuretic and chloruretic potency (25%) Urinary K concentrations during furosemide induced natriuresis remain low, means that clearance of electrolyte free water is increased when loop diuretics are administered during conditions of water diurisis and hydropenia . Thus used in the treatment of hyponatremia along with NS OR hypertonic saline

16. Mechanisim of action . Acts by blocking Na, K, Cl cotransporters at apical surface of TALH thus inhibiting reabsorption . Most potent of all diuretics . Short half life hence dosing are given . The oral bioavailability of furosemide averages 50%, but varies between 10% and 100%; that of bumetanide and torsemide are higher (~80%). . Loop diuretics have a short elimination half-life, so the dosing interval needs to be short to maintain adequate levels in the lumen . The steep dose-response is the reason that loop diuretics are often referred to as “threshold drugs.”

17. A larger dose provides minimal or no extra benefit, and side effects may increase. The effective diuretic dose is higher in patients with HF, advanced cirrhosis, and renal failure. A randomized trial in acute decompensared HF found no difference in the primary end points A higher dose of diuretic was more effec - tive without clinically important negative effects on renal function.5 Adverse effects : Ototoxicity Hypokalemia hyponagnesemia Metabolic alkalosis Interstitial nephritis Gout

18. Drugs acting on DCT Thiazide and Thiazide like diuretics- Chlorthiazide , hydrochlorthiazide , Metalazone and Indepamide . Inhibits NaCl absorption on distal tubule, it causes 5% of filtered Na- and Cl is reabsorbed Less potent than Loop diuretics C ommonly to treat hypertension For edema , occasionally used alone in patients with mild HF, but more often are used in combination to synergize the effect of loop diuretics by blocking multiple nephron segment sites. T hiazide diuretics must reach the lumen to be effective, higher doses are required in patients with impaired renal function.

19. Adverse effects : Hypokalemic metabolic acidosis Hyponatremia Hyperglycemia Hyperlipidemia Hyperurecemia Hypercalcemia

20. Diuretics acting on Collecting duct Drugs acting on Collecting duct- Amiloride , Triamterene, Aldosterone antagonist Amiloride and Triamterene act by interfering with ENaC channels Potassium- sparing diuretics are considered weak diuretics because they block only about 3% of the filtered sodium load reaching their site of action and thus are most often used with other diuretics to augment diuresis or preserve potassium. Collecting duct diuretics are considered first-line agents in certain conditions. spironolactone is used in patients with liver cirrhosis with ascites, and amiloride in the treatment of Liddle syndrome, a rare autosomal dominant condition characterized by a primary increase in ENaC function

21. They when used alone, lose effectiveness at GFR less than 30 mL/min Still enhance the diuretic effect of loop diuretics when coadminis - tered in sufficient doses to attain effective nephron lumen concentration Combination therapy needs close monitoring as it may lead to hypokalemia and excessive ECF depletion Adverse effects : Hyperkalemia arrhythmias Endocrine effects of spirinolactone – gymecomastia anti androgen effects.

22. Approach to Diuretic Treatment of ExtracellularFluid Volume Expansion In HF, either HFREF or HFPEF, initial treatment involves loop diuretics. May be necessary to increase, or double, subsequent doses if the initial dose does not elicit a diuresis. Approach is based on the threshold nature of the loop diuretic dose response curve. In cirrhotic ascites, patients should be started on a combina - tion of spironolactone and furosemide, at a fixed ratio (100 mg spi - ronolactone to 40 mg furosemide).

23. Spironolactone alone has shown to have Potassium imbalance nephrotic syndrome and CKD, loop diuretics are indicate d , H igher doses than used for HF are typically required, because both CKD and nephrotic syndrome are diuretic-resistant conditions

24. Diuretic Resistance Refers to edema that has become refractory to maximal doses of loop diuretics. May be the result of drug interactions. NSAIDs block prostaglandin-mediated increases in renal blood flow and natriuresis and can precipitate HF exacerbations. Arterial underfilling in cirrhosis and HF increases proximal tubular sodium reabsorption This reduces delivery of sodium to the distal nephron segment sites of diuretic action. This problem can be addressed by combining loop and thiazide diuret - ics, because the latter block the distal nephron sites responsible.

25. loop diuretics stimulate renin secretion at the macula densa , leading to Ang II production and aldosterone secretion, Better to initiate aldosterone antagonist therapy before addition of a thiazide diuretic in patients with low or low-normal serum potassium level.

26. References Schrier’s Diseases of the Kidney -9 th edition Comprehensive Clinical Nephrology – Feehally 6 th edition THANK YOU