1. Diuretic Agents

3. Carbonic Anhydrase Inhibitors

4. Carbonic anhydrase is in the PCT, where it catalyzes the dehydration of H 2 CO 3 Carbonic anhydrase is in the PCT, where it catalyzes the dehydration of H 2 CO 3 By blocking carbonic anhydrase, drugs block NaHCO3 reabsorption and cause diuresis By blocking carbonic anhydrase, drugs block NaHCO3 reabsorption and cause diuresis Carbonic anhydrase inhibitors are now rarely used as diuretics Carbonic anhydrase inhibitors are now rarely used as diuretics They have several specific applications They have several specific applications The prototypical drug is acetazolamide The prototypical drug is acetazolamide

5. Carbonic Anhydrase Inhibitors the inhibition of enzyme causes HCO 3 – losses and metabolic acidosis the inhibition of enzyme causes HCO 3 – losses and metabolic acidosis the major clinical applications of acetazolamide involve sites other than the kidney. the major clinical applications of acetazolamide involve sites other than the kidney. The ciliary body of the eye secretes HCO 3 – from the blood into the aqueous humor. The ciliary body of the eye secretes HCO 3 – from the blood into the aqueous humor. formation of CSF by the choroid plexus also involves HCO 3 – secretion. formation of CSF by the choroid plexus also involves HCO 3 – secretion.

6. Clinical Indications Glaucoma (dorzolamide, brinzolamide) Glaucoma (dorzolamide, brinzolamide) Urinary Alkalinization Urinary Alkalinization Uric acid, cystine, and other weak acids are reabsorbed from acidic urine. Uric acid, cystine, and other weak acids are reabsorbed from acidic urine. renal excretion of cystine (in cystinuria) can be enhanced by increasing urinary pH. renal excretion of cystine (in cystinuria) can be enhanced by increasing urinary pH. Metabolic Alkalosis + Edema Metabolic Alkalosis + Edema Acute Mountain Sickness Acute Mountain Sickness

7. Toxicity Metabolic Acidosis Metabolic Acidosis Renal Stones Renal Stones Calcium salts are relatively insoluble at alkaline pH Calcium salts are relatively insoluble at alkaline pH Renal Potassium Wasting Renal Potassium Wasting Drowsiness and paresthesias after large doses Drowsiness and paresthesias after large doses

8. Contraindications alkalinization of the urine decreases urinary excretion of NH 4 + (converts it to rapidly- reabsorbed NH 3 ) alkalinization of the urine decreases urinary excretion of NH 4 + (converts it to rapidly- reabsorbed NH 3 ) in patients with cirrhosis this contributes to hyperammonemia and hepatic encephalopathy. in patients with cirrhosis this contributes to hyperammonemia and hepatic encephalopathy.

9. Loop diuretics

10. Loop Diuretics Loop diuretics selectively inhibit NaCl reabsorption in the TAL Loop diuretics selectively inhibit NaCl reabsorption in the TAL Loop diuretics are the most efficacious diuretics because: Loop diuretics are the most efficacious diuretics because: large NaCl absorptive capacity of TAL large NaCl absorptive capacity of TAL The two prototypical drugs of this group are furosemide and ethacrynic acid. The two prototypical drugs of this group are furosemide and ethacrynic acid. bumetanide and torsemide are also loop diuretics. bumetanide and torsemide are also loop diuretics. The duration of effect for loop diuretics is short. The duration of effect for loop diuretics is short.

11. Loop diuretics inhibit the Na + /K + /2Cl – transporter in the TAL Loop diuretics inhibit the Na + /K + /2Cl – transporter in the TAL They reduce both the reabsorption of NaCl and lumen-positive potential that comes from K + recycling. They reduce both the reabsorption of NaCl and lumen-positive potential that comes from K + recycling. This positive potential normally drives divalent cation reabsorption in the loop This positive potential normally drives divalent cation reabsorption in the loop So loop diuretics cause an increase in Mg 2+ and Ca 2+ excretion. So loop diuretics cause an increase in Mg 2+ and Ca 2+ excretion. Pharmacodynamics

12. Prolonged use can cause significant hypomagnesemia Prolonged use can cause significant hypomagnesemia intestinal absorption of Ca 2+ can be increased and Ca 2+ is actively reabsorbed in the DCT intestinal absorption of Ca 2+ can be increased and Ca 2+ is actively reabsorbed in the DCT So loop diuretics do not generally cause hypocalcemia So loop diuretics do not generally cause hypocalcemia in disorders that cause hypercalcemia, Ca 2+ excretion can be usefully enhanced by loop diuretics combined with saline infusions in disorders that cause hypercalcemia, Ca 2+ excretion can be usefully enhanced by loop diuretics combined with saline infusions Both furosemide and ethacrynic acid have also been shown to reduce pulmonary congestion and LVEDP in heart failure before diuretic effect. Both furosemide and ethacrynic acid have also been shown to reduce pulmonary congestion and LVEDP in heart failure before diuretic effect. Pharmacodynamics

13. Clinical Indications The major application of loop diuretics is in the treatment of edematous states The major application of loop diuretics is in the treatment of edematous states heart failure, ascites, and acute pulmonary edema heart failure, ascites, and acute pulmonary edema They are sometimes used in hypertension if response to thiazides is inadequate, but the short duration of action of loop diuretics is a disadvantage in this condition They are sometimes used in hypertension if response to thiazides is inadequate, but the short duration of action of loop diuretics is a disadvantage in this condition

14. Clinical Indications A less common but important application is in the treatment of severe hypercalcemia A less common but important application is in the treatment of severe hypercalcemia Acute Renal Failure Acute Renal Failure They increase urine flow and enhance K + excretion. They increase urine flow and enhance K + excretion. they can flush out pigment cast in the tubules. they can flush out pigment cast in the tubules.

15. Toxicity Hypokalemic Metabolic Alkalosis Hypokalemic Metabolic Alkalosis They increase salt delivery to the collecting duct. They increase salt delivery to the collecting duct. This leads to increased secretion of K + and H + This leads to increased secretion of K + and H + Ototoxicity Ototoxicity dose-related hearing loss may happen and is usually reversible. dose-related hearing loss may happen and is usually reversible. It is most common in diminished renal function or those who are using other ototoxic drugs. It is most common in diminished renal function or those who are using other ototoxic drugs.

16. Toxicity Hyperuricemia Hyperuricemia They may cause hyperuricemia and precipitate attacks of gout. They may cause hyperuricemia and precipitate attacks of gout. This is caused by hypovolemia-associated enhancement of uric acid reabsorption in the PCT. This is caused by hypovolemia-associated enhancement of uric acid reabsorption in the PCT. Hypomagnesemia Hypomagnesemia Occurs in dietary magnesium deficiency. Occurs in dietary magnesium deficiency. It can be reversed by oral magnesium. It can be reversed by oral magnesium.

17. Toxicity Allergic & Other Reactions Allergic & Other Reactions Most of the loop diuretics are sulfonamides. Most of the loop diuretics are sulfonamides. skin rash, eosinophilia, and interstitial nephritis are occasional adverse effects. skin rash, eosinophilia, and interstitial nephritis are occasional adverse effects. This usually resolves rapidly after drug withdrawal. This usually resolves rapidly after drug withdrawal.

18. Thiazides thiazides inhibit NaCl transport in the DCT. thiazides inhibit NaCl transport in the DCT.

19. Thiazides All thiazides are secreted in the proximal tubule All thiazides are secreted in the proximal tubule They compete with the secretion of uric acid They compete with the secretion of uric acid So thiazides may elevate serum uric acid level. So thiazides may elevate serum uric acid level. Thiazides block the Na + /Cl – transporter (NCC). Thiazides block the Na + /Cl – transporter (NCC). thiazides actually enhance Ca 2+ reabsorption. thiazides actually enhance Ca 2+ reabsorption. thiazides may rarely cause hypercalcemia thiazides may rarely cause hypercalcemia They are useful for kidney stones caused by hypercalciuria. They are useful for kidney stones caused by hypercalciuria.

20. Clinical Indications Clinical Indications Hypertension Hypertension heart failure heart failure nephrolithiasis due to idiopathic hypercalciuria nephrolithiasis due to idiopathic hypercalciuria Thiazides

21. Toxicity Hypokalemia, Metabolic Alkalosis and Hyperuricemia Hypokalemia, Metabolic Alkalosis and Hyperuricemia Hyperglycemia due to impaired release of insulin. Hyperglycemia due to impaired release of insulin. Hyperlipidemia as a 5–15% increase in total serum cholesterol and LDL. Hyperlipidemia as a 5–15% increase in total serum cholesterol and LDL. Allergic Reactions (t he thiazides are sulfonamides). Allergic Reactions (t he thiazides are sulfonamides). Dilutional Hyponatremia is an important adverse effect of thiazides Dilutional Hyponatremia is an important adverse effect of thiazides

22. Potassium-Sparing Diuretics Potassium-Sparing Diuretics Potassium-Sparing Diuretics Spironolactone Spironolactone Eplerenone Eplerenone Amiloride Amiloride Triamterene Triamterene

23. Potassium-Sparing Diuretics

24. They antagonize the effects of aldosterone. They antagonize the effects of aldosterone. Inhibition may occur by: Inhibition may occur by: direct antagonism of receptors (spironolactone, eplerenone) direct antagonism of receptors (spironolactone, eplerenone) inhibition of Na + influx (amiloride, triamterene). inhibition of Na + influx (amiloride, triamterene). Eplerenone is more selective so has less side effects. Eplerenone is more selective so has less side effects. They cause metabolic acidosis. They cause metabolic acidosis.

25. Clinical Indications Compensation of thiazide-induced hypokalemia Compensation of thiazide-induced hypokalemia They are useful in primary and secondary hyperaldosteronism They are useful in primary and secondary hyperaldosteronism eplerenone has been found to reduce myocardial perfusion defects after MI. eplerenone has been found to reduce myocardial perfusion defects after MI. eplerenone reduced mortality rate by 15% (compared with placebo) in heart failure after MI. eplerenone reduced mortality rate by 15% (compared with placebo) in heart failure after MI.

26. Toxicity They can cause life-threatening hyperkalemia. They can cause life-threatening hyperkalemia. This risk is greatly increased by: This risk is greatly increased by: renal disease renal disease the use of drugs that inhibit renin (β blockers) the use of drugs that inhibit renin (β blockers) the use of drugs that inhibit angiotensin II activity (ACEIs, angiotensin receptor blockers (ARBs)). the use of drugs that inhibit angiotensin II activity (ACEIs, angiotensin receptor blockers (ARBs)). Combinations of K + -sparing and thiazides ameliorate thiazide-induced hypokalemia and alkalosis Combinations of K + -sparing and thiazides ameliorate thiazide-induced hypokalemia and alkalosis

27. Toxicity Metabolic Acidosis Metabolic Acidosis Gynecomastia, impotence is reported with spironolactone but not with eplerenone. Gynecomastia, impotence is reported with spironolactone but not with eplerenone. Patients with chronic renal insufficiency are especially vulnerable to hyperkalemia. Patients with chronic renal insufficiency are especially vulnerable to hyperkalemia.

28. Agents That Alter Water Excretion Osmotic Diuretics Osmotic Diuretics Antidiuretic Hormone (ADH) Agonists Antidiuretic Hormone (ADH) Agonists Antidiuretic Hormone (ADH) Antagonists Antidiuretic Hormone (ADH) Antagonists

29. Osmotic Diuretics Any osmotically active agent promotes a water diuresis. Any osmotically active agent promotes a water diuresis. Such agents reduce intracranial and intraocular pressure Such agents reduce intracranial and intraocular pressure The prototypic osmotic diuretic is mannitol. The prototypic osmotic diuretic is mannitol. Oral mannitol causes osmotic diarrhea so for systemic effect, it is given parenterally. Oral mannitol causes osmotic diarrhea so for systemic effect, it is given parenterally.

30. they also oppose the action of ADH. they also oppose the action of ADH. They reduce Na + as well as water reabsorption. They reduce Na + as well as water reabsorption. The natriuresis is of lesser magnitude than the water diuresis, leading to hypernatremia. The natriuresis is of lesser magnitude than the water diuresis, leading to hypernatremia. Osmotic Diuretics

31. Clinical indications It is used to prevent anuria from large pigment loads to the kidney. It is used to prevent anuria from large pigment loads to the kidney. Reduction in ICP in neurologic conditions & IOP before ophthalmologic procedures. Reduction in ICP in neurologic conditions & IOP before ophthalmologic procedures.

32. Toxicity Mannitol is rapidly distributed in the extracellular compartment and extracts water from cells. Mannitol is rapidly distributed in the extracellular compartment and extracts water from cells. Prior to the diuresis, this leads to expansion of the extracellular volume and hyponatremia. Prior to the diuresis, this leads to expansion of the extracellular volume and hyponatremia. This can complicate heart failure and may produce pulmonary edema. This can complicate heart failure and may produce pulmonary edema.

33. ADH Agonists &Antagonists

34. Vasopressin and desmopressin are used in the treatment of central diabetes insipidus. Vasopressin and desmopressin are used in the treatment of central diabetes insipidus. The renal action appears to be mediated primarily via V 2 receptors The renal action appears to be mediated primarily via V 2 receptors They are ineffective in nephrogenic diabetes insipidus They are ineffective in nephrogenic diabetes insipidus Treatment involves salt restriction, water restric- tion, thiazides and loop diuretics Treatment involves salt restriction, water restric- tion, thiazides and loop diuretics

35. ADH Antagonists Syndrome of Inappropriate Antiduiretic Hormone (SIADH) secretion, causes water retention. Syndrome of Inappropriate Antiduiretic Hormone (SIADH) secretion, causes water retention. Conivaptan is an antagonist against both V 1a and V 2 ADH receptors. Conivaptan is an antagonist against both V 1a and V 2 ADH receptors. Tolvaptan is an antagonist with more selectivity for V 2 ADH receptors than V 1a. Tolvaptan is an antagonist with more selectivity for V 2 ADH receptors than V 1a. Lithium & demeclocycline have anti-ADH effects, but have many side effects and are not used. Lithium & demeclocycline have anti-ADH effects, but have many side effects and are not used.

36. Clinical Indications In SIADH when water restriction has failed. In SIADH when water restriction has failed. Toxicity Nephrogenic Diabetes Insipidus