The document discusses the mechanisms and effects of different classes of diuretic drugs, including thiazide and loop diuretics. It explains that thiazides act in the distal tubule to inhibit sodium reabsorption, causing a modest diuresis. Loop diuretics act in the ascending loop of Henle and cause a greater natriuresis than thiazides. Both can cause hypokalemia and other electrolyte abnormalities as side effects. The document outlines the clinical uses of these diuretics to treat conditions like edema, hypertension, and hypocalciuria. It also discusses factors that can contribute to diuretic resistance.

1. From Knauf & Mutschler Klin. Wochenschr. 1991 69:239-250 70% 20% 5% 4.5% 0.5% Volume 1.5 L/day Urine Na 100 mEq/L Na Excretion 155 mEq/day 100% GFR 180 L/day Plasma Na 145 mEq/L Filtered Load 26,100 mEq/day CA Inhibitors Proximal tubule Loop Diuretics Loop of Henle Thiazides Distal tubule Antikaliuretics Collecting duct Thick Ascending Limb

4. N N SO 2 NH 2 SO 2 NH 2 NH 2 NH 2 NH 2 SO 2 NH 2 Cl Cl SO 2 NH 2 SO 2 NH 2 Cl SO 2 NH 2 N C N SO 2 Prontosil Sulfanilamide p-chlorobenzene sulfonamide 1,3 disulfonamide 6 cholrobenzene Cholrothiazide

6. General Structure of Thiazide Diuretics

7. Inhibition of high-affinity 3 H-metolazone binding by ions Data from Beaumont et. Al.: Thiazide diuretic drug receptors in rat kidney: identification with 3H]metolazone. Proc. Natl. Acad. Sci. USA 1988, 85:2311-2314. 112±5 Trisodium citrate 118±12 Dipotassium sulfate 152±22 Disodium sulfate 95±5 K acetate 82±5 Na acetate 12±2 KI 25±1 NaI 24±2 NaBr 36±7 Choline chloride 44±2 KCl 20±0.5 NaCl 4±1 LiCl 143±9 NaF % Control Ion

8. Correlation of the daily clinical doses of thiazide diuretics with their affinity for high-affinity 3 H-metolazone binding sites in rat kidney. Correlation coefficient r=0.7513. From Beaumont et al.: Thiazide diuretic drug receptors in rat kidney: identification with [ 3 H]metolazone. Proc. Natl. Acad. Sci. USA 1988, 85:2311-2314.

11. From Birkenhäger, WH: Diuretics and blood pressure reduction: physiological aspects. J. Hyperten. 1990, 8 (Suppl 2) S3-S7. Schematic drawing of temporal changes in mean arterial pressure (MAP), total peripheral vascular resistance (TPR), cardiac output (CO) and plasma volume (PV) during thiazide treatment of a hypertensive subject

12. From Birkenhäger, WH: Diuretics and blood pressure reduction: physiological aspects. J. Hyperten. 1990, 8 (Suppl 2) S3-S7.

13. From Birkenhäger, WH: Diuretics and blood pressure reduction: physiological aspects. J. Hyperten. 1990, 8 (Suppl 2) S3-S7.

19. From Martinez-Maldonado, M, and Cordova, HR: Cellular and molecular aspects of the renal effects of diuretic agents. Kidney Int. 1990, 38:632-641.

21. From Brater, DC. Pharmacodynamic considerations in the use of diuretics. Ann. Rev. Pharmacol. Toxicol 1983, 23:45-62.

23. From Brater, DC. Pharmacodynamic considerations in the use of diuretics. Ann. Rev. Pharmacol. Toxicol 1983, 23:45-62.

27. From Brater, DC. Pharmacology of Diuretics. Am. J. Med. Sci. 2000, 319:38-50. FE Na (%)

30. Maximum Doses of Loop Diuretics Data from Brater, DC. Pharmacology of Diuretics. Am. J. Med. Sci. 2000, 319:38-50. Oral intravenous Dose of furosemide (mg) Clinical Condition 160 80 Renal Insufficiency 0 < Cl Cr < 50 400 200 Renal Insufficiency Cl Cr < 20 240 120 Nephrotic Syndrome 80 40 Cirrhosis 80-160 40-80 Congestive Heart Failure