1. Diuretics Diuretics DepartmentOfPharmacology Lecture 1

2. Learning Outcomes Please see - at the end of Lecture 2 Please see - at the end of Lecture 2

3. Increased rate of urine flow Increased rate of urine flow Increased rate of sodium excretion (natriuresis): used to adjust the vol. & to adjust the composition of body fluids in clinical situations e.g. Hypertension Increased rate of sodium excretion (natriuresis): used to adjust the vol. & to adjust the composition of body fluids in clinical situations e.g. Hypertension heart failure heart failure renal failure renal failure nephrotic syndrome nephrotic syndrome cirrhosis cirrhosis

5. Overview of Nephron Function 120 ml of ultrafiltrate is formed/min 120 ml of ultrafiltrate is formed/min but only 1 ml/min of urine is produced, but only 1 ml/min of urine is produced, >99% of ultrafiltrate is reabsorbed at a staggering energy cost >99% of ultrafiltrate is reabsorbed at a staggering energy cost

6. The kidney is designed to filter large quantities of plasma, reabsorb those substances that body must conserve and leave behind/secrete substances that must be eliminated Proximal tubule ; 65% of Na+ is reabsorbed along with water- urine is isotonic Descending limb (thin ); highly permeable to water, less for NaCl and urea Ascending limb (thick): Permeable to NaCl and impermeable to water and urea Loop of Henle ; here 25% of Na+ is reabsorbed

7. DCT : transports NaCl and is impermeable to water produces dilute urine DCT and thick ascending limb : are called as diluting segment of nephron - hypotonic fluid is produced Collecting tubule Aldosterone electrolyte adjustments ADH : water is extracted

8. overview Transport of organic acids and bases Transport of organic acids and bases Reabsorption of Cl - (ascending limb, proximal tubule) Reabsorption of Cl - (ascending limb, proximal tubule) Symport of Na+/K+ (thick ascending limb) Symport of Na+/K+ (thick ascending limb) Symport of Na + (DCT) Symport of Na + (DCT) Antiport with HCo3_ (Collecting duct) Antiport with HCo3_ (Collecting duct) Cl- crosses basolateral membrane via symport with K+ (PCT) Cl- crosses basolateral membrane via symport with K+ (PCT) Cl - channels (DCT, CDs) Cl - channels (DCT, CDs)

9. Nephron Nephron The basic urine forming unit of kidney is nephron which consist of a filtering apparatus, Glomerulus, connected to a long tubular portion that reabsorbs & conditions the glomerular ultrafiltrate. Each human kidney has 1 million nephrons The basic urine forming unit of kidney is nephron which consist of a filtering apparatus, Glomerulus, connected to a long tubular portion that reabsorbs & conditions the glomerular ultrafiltrate. Each human kidney has 1 million nephrons

10. Principles of diuretic therapy By definition diuretics are drugs that increase the rate of micturation By definition diuretics are drugs that increase the rate of micturation However clinically useful diuretics also increase the rate of excretion of Na + (natriuresis) and of an accompanying anion, usually Cl -. NaCl in the body is the major determinant of extra cellular fluid volume, and most of the clinical applications of diuretics are directed towards reducing extra cellular fluid volume by decreasing total body NaCl content. However clinically useful diuretics also increase the rate of excretion of Na + (natriuresis) and of an accompanying anion, usually Cl -. NaCl in the body is the major determinant of extra cellular fluid volume, and most of the clinical applications of diuretics are directed towards reducing extra cellular fluid volume by decreasing total body NaCl content.

11.  A sustained imbalance between dietary Na+ intake and.Na+ loss is incompatible with life.  Sustained positive Na+ balance volume overload with pulmonary edema  Sustained negative Na+ balance volume depletion and cardiovascular collapse

12. Compensatory or “breaking” mechanisms (compensatory mechanisms which bring Na+ excretion in line with Na intake) Include activation of sympathetic nervous system, activation of renin – angiotensin - aldosterone axis. Diuretics also modify renal handling of other cations e.g. K+, H+, Ca2+, Mg2+ and anions e.g. Cl-, HCO3-, H2PO4- and uric acid

13. CLASSIFICATION 1. High efficacy diuretics (inhibitors of Na+-K+-2Cl- cotransport ) 1. High efficacy diuretics (inhibitors of Na+-K+-2Cl- cotransport ) a) Sulfamoyl derivatives: Furosemide, a) Sulfamoyl derivatives: Furosemide, Bumetanide, piretanide. Bumetanide, piretanide. b) Phenoxyacetic acid derivative: b) Phenoxyacetic acid derivative: ethacrynic acid ethacrynic acid c) organomercurials: Mersalyl c) organomercurials: Mersalyl

14. 2. Medium efficacy diuretics (inhibitors of Na+ -Cl- symport) a)Thiazides : Chlorothiazide, Hydrochlorothiazide, Polythiazide, cyclopenthiazide, benzthiazide, hydroflumethiazide, clopamide, bendroflumethiazide b) Thiazide like diuretics : chlorthalidone, metolazone, xipamide, indapamide

15. 3. Weak diuretics : a)Carbonic anhydrase inhibitors acetazolamide, ethoxazolamide b)Potassium sparing diuretics -aldosterone antagonist: spironolactone - directly acting: triamterene, amiloride c) Xanthines : theophylline d) Osmotic diuretics : mannitol, isosorbide, glycerol e) Acidifying or alkalinizing salts : ammonium chloride, potassium citrate, potassium acetate.

16. drugCations Na+, K+, H+, Ca2+, mg2+ Anions Cl-, HCO3, H2PO4 Uric acid Ac. Chr. Renal hemodynamic RBF GFR Carbonic anhydrase inhibitors (PT) + ++ - NC +/- (no change) (no change) (variable) (variable) + ++ ++ Inc - - - - - Osmotic diuretics (loop of Henle) Henle) ++ + - + ++ + + + + inc + NC + NC Inhibitors of Na+, K+, 2Cl- symport (AL) ++ ++ + ++ ++ ++ + + + - + - + -

17. drug drugCations Na+, K+, H+, Ca2+, mg2+ Na+, K+, H+, Ca2+, mg2+Anions Cl-, HCO3, H2PO4 Uric Uric acid acid Ac. chr Renal hemodyn amic RBF GFR Inhibitors of renal epi Na+ channels (DT<CD) + - - - - + + + NC inc NC NC Inhibitors of Na+ Cl- symport (DCT) + ++ + V V(+) + + + + - NC V(-) Antagonist mineralocorticoid receptors (DCT<CD) + - - inc - - + inc Inc - NC NC

19. Inhibitors of carbonic anhydrase Acetazolamide Acetazolamide Methazolamide Methazolamide Dichlorphenamide Dichlorphenamide Source: from sulfanilamide Source: from sulfanilamide Mechanism: inhibit the action of carbonic anhydrase in NaHCo3 reabsorption and acid secretion. Mechanism: inhibit the action of carbonic anhydrase in NaHCo3 reabsorption and acid secretion. ADR : Metabolic acidosis ADR : Metabolic acidosis

20. Therapeutic uses of acetazolamide :  Edema-as single agent/in combination  acetazolamide + diuretics (resistant cases) Open angle glaucoma, secondary glaucoma post operatively to decrease ocular Pressure before surgery  Epilepsy  Ac. Mountain sickness- acetazolamide prophylactically  familial periodic paralysis  correcting metabolic alkalosis (diuretic induced)

21. Familial periodic paralyses A group of inherited neurological disorders caused by mutations in genes that regulate sodium and calcium channels in nerve cells. A group of inherited neurological disorders caused by mutations in genes that regulate sodium and calcium channels in nerve cells. They are characterized by episodes in which the affected muscles become slack, weak, and unable to contract. They are characterized by episodes in which the affected muscles become slack, weak, and unable to contract. Between attacks, the affected muscles usually work as normal. Between attacks, the affected muscles usually work as normal.

22. Common types of periodic paralyses The two are: Hypokalemic periodic paralysis is characterized by a fall in potassium levels in the blood. In individuals with this mutation attacks often begin in adolescence and are triggered by strenuous exercise or high carbohydrate meals. Weakness may be mild and limited to certain muscle groups, or more severe and affect the arms and legs. Attacks may last for a few hours or persist for several days. Some patients may develop chronic muscle weakness later in life. The two are: Hypokalemic periodic paralysis is characterized by a fall in potassium levels in the blood. In individuals with this mutation attacks often begin in adolescence and are triggered by strenuous exercise or high carbohydrate meals. Weakness may be mild and limited to certain muscle groups, or more severe and affect the arms and legs. Attacks may last for a few hours or persist for several days. Some patients may develop chronic muscle weakness later in life. Hyperkalemic periodic paralysis is characterized by a rise in potassium levels in the blood. Attacks often begin in infancy or early childhood and are precipitated by rest after exercise or by fasting. Attacks are usually shorter, more frequent, and less severe than the hypokalemic form. Muscle spasms are common. Hyperkalemic periodic paralysis is characterized by a rise in potassium levels in the blood. Attacks often begin in infancy or early childhood and are precipitated by rest after exercise or by fasting. Attacks are usually shorter, more frequent, and less severe than the hypokalemic form. Muscle spasms are common.

23. Treatment of the periodic paralyses Prevent further attacks and relieve acute symptoms. Prevent further attacks and relieve acute symptoms. Avoiding carbohydrate-rich meals and strenuous exercise. Avoiding carbohydrate-rich meals and strenuous exercise. Acetazolamide daily may prevent hypokalemic attacks. Attacks can be managed by drinking a potassium chloride oral solution. Acetazolamide daily may prevent hypokalemic attacks. Attacks can be managed by drinking a potassium chloride oral solution. Eating carbohydrate-rich, low-potassium foods, and avoiding strenuous exercise and fasting, can help prevent hyperkalemic attacks Eating carbohydrate-rich, low-potassium foods, and avoiding strenuous exercise and fasting, can help prevent hyperkalemic attacks

24. Osmotic diuretics Glycerine (oral) ---- t ½ is Glycerine (oral) ---- t ½ is 0.50 to.75hrs 0.50 to.75hrs Isosorbide (oral) ---- “ “ 5 to Isosorbide (oral) ---- “ “ 5 to 9.5 9.5 Mannitol -------------- “ “ 0.25 to1.7 Mannitol -------------- “ “ 0.25 to1.7 Urea -------------------- “ “ no data Urea -------------------- “ “ no data

25. ADR : In Pts with CHF or pulmonary congestion-----frank pulm. edema Hyponatremia ----headache, nausea, vomiting and dehydration Urea----thrombosis Glycerine—hyperglycemia Contra indications : Anuria --- severe renal disease Ac. Cranial bleeding Impaired liver function- risk of increased ammonia levels hyperglycemia

26. Therapeutic uses of osmotic diuretics : 1. Acute renal failure (ARF): rapid decrease in GFR (due to extrinsic- pre renal and post renal causes and Intrinsic- acute tubular necrosis, nephrotoxins, ischemia) Mannitol – causes removal of tubular casts, dilution of nephron toxin decrease in swelling 2. Mild to moderate insufficiency: Hydration- 0.45% NaCl, Mannitol 3.Decrease in GFR secondary to radiocontrast agents 4. jaundiced patients undergoing surgery

27. Mechanism of action-osmotic diuretics Site of action : loop of Henle, Proximal tubule extracts water from intracellular compartments and expand extracellular fluid volume, decrease blood viscosity, decrease renin release, increase renal blood flow, removes NaCl and urea from renal medulla, decrease tone, decrease reabsorption of Na+, mg2+