Consult the medical resource doctors trust

UpToDate is one of the most respected medical information resources in the world, used by over 360,000 doctors and thousands of patients to find answers to medical questions.

  • Content written by a faculty of over 4,000 physicians from leading medical institutions
  • Unbiased: free of advertising or pharmaceutical funding
  • Evidence-based treatment recommendations
  • Continuously updated to incorporate new medical findings

Mechanism of action of diuretics

INTRODUCTION

Diuretics are among the most commonly used drugs. They act by diminishing sodium chloride reabsorption at different sites in the nephron, thereby increasing urinary sodium chloride and water losses. The ability to induce negative fluid balance has made diuretics useful in the treatment of a variety of conditions, particularly edematous states and hypertension.

A review of the mechanism and time course of action of diuretics will be presented here. Complications of these agents are discussed separately. (See "Time course of diuretic-induced electrolyte complications".)

MECHANISM OF ACTION

The diuretics are generally divided into three major classes, which are distinguished by the site at which they impair sodium reabsorption [1,2]:

  • Loop diuretics act in the thick ascending limb of the loop of Henle
  • Thiazide-type diuretics in the distal tubule and connecting segment (and perhaps the early cortical collecting tubule)
  • Potassium-sparing diuretics in the aldosterone-sensitive principal cells in the cortical collecting tubule

To appreciate how this occurs, it is first necessary to review the general mechanism by which sodium is reabsorbed. Each of the sodium-transporting cells contains Na-K-ATPase pumps in the basolateral membrane [3]. These pumps perform two major functions: they return reabsorbed sodium to the systemic circulation; and they maintain the cell sodium concentration at relatively low levels. The latter effect is particularly important, since it allows filtered sodium to passively enter the cells down a favorable concentration gradient.
To continue reading this article you need to subscribe.

Read the rest of this article and others like it

The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use (click here) ©2010 UpToDate, Inc.
References Top
  1. Rose, BD. Diuretics. Kidney Int 1991; 39:336.
  2. Hropot, M, Fowler, N, Karlmark, B, Giebisch, G. Tubular action of diuretics: Distal effects on electrolyte transport and acidification. Kidney Int 1985; 28:477.
  3. Katz, AI. Distribution and function of classes of ATPases along the nephron. Kidney Int 1986; 29:21.
  4. Wright, FS. Flow-dependent transport processes: Filtration, absorption, secretion. Am J Physiol 1982; 243:F1.
  5. Greger, R, Velazquez, H. The cortical thick ascending limb and early distal convoluted tubule in the urine concentrating mechanism. Kidney Int 1987; 31:590.
  6. Ellison, DH, Velasquez, H, Wright, FS. Adaptation of the distal convoluted tubule of the rat. Structural and functional effects of dietary salt intake and chronic diuretic infusion. J Clin Invest 1989; 83:113.
  7. Stanton, BA, Kaissling, B. Regulation of renal ion transport and cell growth by sodium. Am J Physiol 1989; 257:F1.
  8. Scherzer, P, Wald, H, Popovtzer, MM. Enhanced glomerular filtration and Na-K-ATPase with furosemide administration. Am J Physiol 1987; 252:F910.
  9. Loon, NR, Wilcox, CS, Unwin, RJ. Mechanism of impaired natriuretic response to furosemide during prolonged therapy. Kidney Int 1989; 36:682.
  10. Stanton, BA, Kaissling, B. Adaptation of distal tubule and collecting duct to increased Na delivery. II. Na and K transport. Am J Physiol 1988; 255:F1269.
  11. Hebert, SC, Reeves, WB, Molony, RA, Andreoli, TE. The medullary thick limb: Function and modulation of the single effect multiplier. Kidney Int 1987; 31:580.
  12. O'Grady, SM, Palfrey, HC, Field, M. Characteristics and functions of Na-K-2Cl cotransport in epithelial tissues. Am J Physiol 1987; 253:C177.
  13. Amsler, K, Kinne, R. Photoinactivation of S-P-Cl cotransport in LLC-PK1 / Cl 4 cells by bumetanide. Am J Physiol 1986; 250:C799.
  14. Bronner, F. Renal calcium transport: Mechanisms and regulation — An overview. Am J Physiol 1989; 257:F707.
  15. Friedman, PA. Basal and hormone-activated calcium absorption in mouse renal thick ascending limbs. Am J Physiol 1988; 254:F62.
  16. Bilezikian, JP. Drug therapy: Management of acute hypercalcemia. N Engl J Med 1992; 326:1196.
  17. Hufnagle, KG, Khan, SN, Penn, D, et al. Renal calcifications: a complication of long-term furosemide therapy in preterm infants. Pediatrics 1982; 70:360.
  18. Short, A, Cooke, RW. The incidence of renal calcification in preterm infants. Arch Dis Child 1991; 66:412.
  19. Velazquez, H, Wright, FS. Effect of diuretic drugs on Na, Cl, and K transport in the rat renal distal tubule. Am J Physiol 1986; 250:F1013.
  20. Kunau, RT Jr, Weller, DR, Webb, HL. Clarification of the site of action of chlorothiazide in the rat nephron. J Clin Invest 1975; 56:401.
  21. Plotkin, MD, Kaplan, MR, Verlander, JW, et al. Localization of the thiazide-sensitive Na-Cl cotransporter, rTSC1, in the rat kidney. Kidney Int 1996; 50:174.
  22. Shimizu, T, Yoshitomi, K, Nakamura, M, Imai, M. Site and mechanism of action of trichlormethazide in rabbit distal nephron segments perfused in vitro. J Clin Invest 1988; 82:721.
  23. Terada, Y, Knepper, MA. Thiazide-sensitive NaCl absorption in rat cortical collecting duct. Am J Physiol 1990; 259:F519.
  24. Rouch, AJ, Chen, L, Troutman, SL, Schafer, JA. Na transport in isolated CCD: Effects of bradykinin, ANP, clonidine, and hydrochlorothiazide. Am J Physiol 1991; 260:F86.
  25. Garg, LC, Narang, N. Effects of hydrochlorothiazide on Na-K-ATPase activity along the rat nephron. Kidney Int 1987; 31:918.
  26. Stanton, BA. Cellular actions of thiazide diuretics in the distal tubule. J Am Soc Nephrol 1990; 1:836.
  27. Tran, JM, Farrell, MA, Fanestil, DD. Effect of ions on binding of the thiazide-type diuretic metolazone to the kidney membrane. Am J Physiol 1990; 258:F908.
  28. Hoover, RS, Poch, E, Monroy, A, et al. N-Glycosylation at Two Sites Critically Alters Thiazide Binding and Activity of the Rat Thiazide-sensitive Na(+):Cl(-) Cotransporter. J Am Soc Nephrol 2003; 14:271.
  29. Boer, WH, Koomans, HA, Dorhout Mees, EJ. Acute effects of the thiazides, with and without carbonic anhydrase inhibiting activity, on lithium and free water clearance in man. Clin Sci 1989; 76:539.
  30. Sutton, RA. Disorders of renal calcium excretion. Kidney Int 1983; 23:665.
  31. Costanzo, LS. Localization of diuretic action in microperfused rat distal tubules: Ca and Na transport. Am J Physiol 1985; 248:F527.
  32. Gesek, FA, Friedman, PA. Mechanism of calcium transport stimulation by chlorothiazide in mouse distal collecting tubule cells. J Clin Invest 1992; 90:429.
  33. Nijenhuis, T, Hoenderop, JG, Loffing, J, Van Der, Kemp AW. Thiazide-induced hypocalciuria is accompanied by a decreased expression of Ca2+ transport proteins in kidney. Kidney Int 2003; 64:555.
  34. Frindt, G, Sackin, H, Palmer, LG. Whole-cell currents in rat cortical collecting tubule: Low-Na diet increases amiloride-sensitive conductance. Am J Physiol 1990; 258:F562.
  35. Sansom, S, Muto, S, Giebisch, G. Na-dependent effects of DOCA on cellular transport properties of CCDs from ADX rabbits. Am J Physiol 1987; 253:F753.
  36. Kleyman, TR, Cragoe, EJ Jr. The mechanism of action of amiloride. Semin Nephrol 1988; 8:242.
  37. Horisberger, JD, Giebisch, G. Potassium-sparing diuretics. Ren Physiol 1987; 10:198.
  38. Abdallah, JG, Schrier, RW, Edelstein, C, et al. Loop diuretic infusion increases thiazide-sensitive na(+)/cl(-)-cotransporter abundance: role of aldosterone. J Am Soc Nephrol 2001; 12:1335.
  39. Batlle, DC, von Riotte, AB, Gaviria, M, Grupp, M. Amelioration of polyuria by amiloride in patients receiving long-term lithium therapy. N Engl J Med 1985; 312:408.
  40. Sica, DA, Gehr, TW. Triamterene and the kidney. Nephron 1989; 51:454.
  41. Fairley, KF, Woo, KT, Birch, BF, et al. Triamterene-induced crystalluria and cylinduria: Clinical and experimental studies. Clin Nephrol 1986; 26:169.
  42. Carr, MC, Prien, EL Jr, Babayan, RK. Triamterene nephrolithiasis: Renewed attention is warranted. J Urol 1990; 144:1339.
  43. Farge, D, Turner, MW, Roy, DR, Jothy, S. Dyazide-induced reversible acute renal failure associated with intratubular crystal deposition. Am J Kidney Dis 1986; 8:445.
  44. Weinberg, MS, Quigg, RJ, Salant, DJ, Bernard, DB. Anuric renal failure precipitated by indomethacin and triamterene. Nephron 1985; 40:216.
  45. Woolfson, RG, Mansell, MA. Does triamterene cause renal calculi?. BMJ 1991; 303:1217.
  46. Leaf, A, Schwartz, WB, Relman, AS. Oral administration of a potent carbonic anhydrase inhibitor ("Diamox"). I. Changes in electrolyte and acid-base balance. N Engl J Med 1954; 250:759.
  47. Preisig, PA, Toto, RD, Alpern, RJ. Carbonic anhydrase inhibitors. Ren Physiol 1987; 10:136.
  48. Seely, JF, Dirks, JH. Micropuncture study of hypertonic mannitol diuresis in the proximal and distal tubule of the dog kidney. J Clin Invest 1969; 48:2330.
  49. Mathisen, O, Raeder, M, Kiil, F. Mechanism of osmotic diuresis. Kidney Int 1981; 19:431.
  50. Lieberthal, W, Levinsky, NG. Treatment of acute tubular necrosis. Semin Nephrol 1990; 10:571.
  51. Lieberthal, W, Sheridan, AM, Valeri, CR. Protective effect of atrial natriuretic factor and mannitol following renal ischemia. Am J Physiol 1990; 258:F1266.
  52. Gipstein, RM, Boyle, JD. Hypernatremia complicating prolonged mannitol diuresis. N Engl J Med 1965; 272:1116.
  53. Aviram, A, Pfau, A, Czackes, JW, Ullman, TD. Hyperosmolality with hyponatremia caused by inappropriate administration of mannitol. Am J Med 1967; 42:648.
  54. Wilcox, CS, Guzman, NJ, Mitch, WE, et al. Sodium, potassium, and BP homeostasis in man during furosemide: Effects of prazosin and captopril. Kidney Int 1987; 31:135.
  55. Wilcox, CS, Mitch, WE, Kelly, RA, et al. Response of the kidney to furosemide. I. Effects of salt intake and renal compensation. J Lab Clin Med, 1983; 102:450.
  56. Ram, CV, Garrett, BN, Kaplan, NM. Moderate sodium restriction and various diuretics in the treatment of hypertension. Effects on potassium wastage and blood pressure control. Arch Intern Med 1981; 141:1015.
  57. Liu, F-Y, Cogan, MG. Angiotensin II: A potent regulator of acidification in the rat early proximal convoluted tubule. J Clin Invest 1987; 80:272.
  58. Stanton, BA. Regulation of Na+ and K+ transport by mineralocorticoids. Semin Nephrol 1987; 7:82.
  59. Osborn, JL, Holdaas, H, Thames, MD, DiBona, GF. Renal adrenoreceptor mediation of antinatriuretic and renin secretion responses to low frequency renal nerve stimulation in the dog. Circ Res 1983; 53:298.
  60. Guyton, AC. Blood pressure control — Special role of the kidneys and body fluids. Science 1991; 252:1813.
  61. Bock, HA, Stein, JH. Diuretics and the control of extracellular fluid volume: Role of counterregulation. Semin Nephrol 1988; 8:264.
  62. Dirks, JH, Cirksena, WJ. Micropuncture study of the effect of various diuretics on sodium reabsorption by the proximal tubules of the dog. J Clin Invest 1966; 45:1875.
  63. Nomura, A, Yasuda, H, Minami, M, et al. Effect of furosemide in congestive heart failure. Clin Pharmacol Ther 1981; 30:177.
  64. Maronde, RF, Milgrom, M, Vlachakis, ND, Chan, L. Response of thiazide-induced hypokalemia to amiloride. JAMA 1983; 249:237.
  65. Ikram, H, Chan, W, Espiner, EA, Nicholls, MG. Hemodynamic and hormone responses to acute and chronic frusemide therapy in congestive heart failure. Clin Sci 1980; 59:443.
  66. Morgan, DB, Davidson, C. Hypokalemia and diuretics: An analysis of publications. Br Med J 1980; 280:905.
  67. Ridgeway, NA, Ginn, DR, Alley, K. Outpatient conversion of treatment to potassium-sparing diuretics. Am J Med 1986; 80:785.
white circle LOG IN
white circle DEMO