DIURETICS Prof. R. K. Dixit Pharmacology K.G.M.U. Lucknow dixitkumarrakesh@gmail.com

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

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)

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%

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

Nephron Parts and Characters

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

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

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

RAAS in response to low BP, or Low Na Renin- Angiotensinogen - Angiotensin I ACE- Angiotensin II- Sympathetic, Aldosterone Vasoconstriction, Sodium and water retention,

Early Distal Tubule Active transport of sodium by NaCl symport Calcium excretion is regulated (Parathomone and Calcitriol, increase absorption of calcium)

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)

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

The relative magnitudes of Na+ reabsorption at sites Asc LH - 25% DT - 9% CD - 1%.

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

Pharmacology copy by student Breath for a minute Pharmacology copy by student

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)

Carbonic An-hydrase Inhibitors Thiazide diuretics Osmotic Diuretics Potassium Sparing Diuretics Loop Diuretics (High Ceiling)

Carbonic Anhydrase Inhibitors

Loop Diuretics

Thiazides

Spironolactone Amiloride

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

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)

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

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

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)

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)

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

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

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)

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.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Thanks