Skip to main content
SpringerLink
Log in

Pharmacodynamic and kinetic considerations on diuretics as a basis for differential therapy

  • Reviews
  • Published:
Klinische Wochenschrift Aims and scope Submit manuscript

Summary

Diuretics are classified according to their site of action in the nephron: loop diuretics, thiazides, and antikaliuretics. During peak diuresis the pattern of electrolyte excretion is constant and characteristic for a class of diuretics. The ratio of diuretic-induced excretion of K+ to Na+ is 0.12 for loop diuretics, 0.20 for thiazides, and −0.21 for antikaliuretics. The ratio of Ca2+ to Na+ is 0.02 for loop diuretics and 0.003 for thiazides. Mg2+ excretion follows K+ excretion in a ratio of 0.15. The natriuretic effect of a diuretic directly depends on the renal clearance of the drug and is proportionate to the number of intact nephrons. Not only loop diuretics but also thiazides and antikaliuretics were demonstrated to be effective natriuretic drugs down to end-stage renal disease. In renal failure FENa is doubled with every halfening of GFR. Loop diuretics increase FENa to a maximum of 24%, thiazides to 10–15%, and FENa is doubled by antikaliuretics. Comedication of loop diuretics with thiazides in renal failure may therefore be more effective than increasing monotherapy. In liver disease, nonrenal drug clearance is reduced the more the patient's direct bilirubin rises thus causing an increase in AUC and urinary excretion of parent drug and metabolites. Despite increased Ae, the cirrhotic patient may become resistant to diuretics as may patients with congestive heart failure or nephrotic syndrome. This is considered to be due to reduced Na+ load available at the diuretic's site of action following avid proximal Na+ reabsorption. In reduced EABV a short-term comedication of loop diuretics with carboanhydratase inhibitors is considered a more effective diuretic strategy than vigorously increasing monotherapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

GFR:

glomerular filtration rate (ml/min)

Ae :

amount of drug excreted into the urine (% of given dose)

AUC:

area under the plasma level time curve (μg·h/ml)

Clpl :

total plasma clearance=Dosei.v./AUC (ml/min)

Clr :

renal clearance=Ae/AUC (ml/min)

Clnr :

nonrenal clearance=Clpl-Clr (ml/min)

FENa :

fractional sodium excretion (%)=Na excreted x 100/Na filtered=urine sodium × urine volume per minute x 100/plasma sodium x GFR

CHF:

congestive heart failure

EABV:

effective arterial blood volume

RAA:

Renin angiotensin aldosterone system

NE:

Norepinephrin

NSAIDs:

Nonsteroidal anti-inflammatory drugs

References

  1. Brater DC (1981) Resistance to diuretics: emphasis on a pharmacological perspective. Drugs 22:477–494

    Google Scholar 

  2. Brater DC, Anderson SA, Brown-Cartwright D (1986) Response to furosemide in chronic renal insufficiency: Rational for limited dose. Clin Pharmacol Ther 40:134–139

    Google Scholar 

  3. Brater DC, Chennavasin P, Seiwell R (1980) Furosemide in patients with heart failure: Shift in dose-response curves. Clin Pharmacol Ther 28 (2):182–186

    Google Scholar 

  4. Bricker NS (1982) Sodium homeostasis in chronic renal disease. Kidney Internat 21:886–897

    Google Scholar 

  5. Bricker NS, Fine LG, Kaplan MA, Epstein M, Bourgoignie JJ, Licht A (1978) “Magnification phenomenon” in chronic renal disease. N Engl J Med 299:1287–1293

    Google Scholar 

  6. Buscher HP, Fricker G, Gerok W, Kramer W, Kurz G, Müller M, Schneider S (1986) Membrane transport of amphilic compounds by hepatocytes In: Greten H, Windler E, Beisiegel U (eds) Receptor-mediated uptake in the liver. Springer, Berlin Heidelberg, pp 189–199

    Google Scholar 

  7. Epstein M (1988) Renal sodium handling in liver disease. In: Epstein M (ed) The kidney in liver disease (3rd edition). Williams & Wilkins, Baltimore Hongkong London Sydney, pp 3–30

    Google Scholar 

  8. Epstein M (1988) Diuretic therapy in liver disease. In: Epstein M (ed) The Kidney in liver disease (3rd edition) Williams & Wilkins, Baltimore Hongkong London Sydney, pp 537–550

    Google Scholar 

  9. Epstein M, Lepp BA, Hoffman DS, Levinson R (1977) Potentiation of furosemide by metolazone in refractory edema. Curr Therap Res 21:656–667

    Google Scholar 

  10. Gerber JG (1981) Antihypertensive agents and diuretics. In: Anderson RJ, Schrier RW (eds) Clinical use of drugs in patients with kidney and liver disease. Saunders London, pp 211–229

    Google Scholar 

  11. Gerok W (1986) Biotransformation von Diuretika bei Leberkrankheiten. In: Knauf H, Mutschler E (eds) Diuretika, Prinzipien der klinischen Anwendung. Urban & Schwarzenberg, München Wien Baltimore, pp 73–92

    Google Scholar 

  12. Grantham JJ, Chonko AM (1986) Renal handling of organic anions and cations; metabolism and excretion of uric acid. In: Brenner BM, Rector FC (eds) The kidney (3rd ed). WB Saunders, Philadelphia, pp 663–674

    Google Scholar 

  13. Greger R (1986) Diuretische Wirkmechanismen. In: Knauf H, Mutschler E (eds) Diuretika, Prinzipien der klinischen Anwendung. Urban & Schwarzenberg, München Wien Baltimore, pp 3–17

    Google Scholar 

  14. Greger R, Wangemann P (1987) Loop Diuretics. Renal Physiol 10:174–183

    Google Scholar 

  15. Hasenfuß G, Holubarsch C, Herzog C, Knauf H, Spahn H, Mutschler E, Just H (1987) Influence of cardiac function on the diuretic and hemodynamic effects of the loop diuretic piretanide. Clin Cardiol 10:83–88

    Google Scholar 

  16. Heath WC, Freis ED (1963) Triamterene with hydrochlorothiazide in the treatment of hypertension. JAMA 186:119–122

    Google Scholar 

  17. Hropot M, Fowler N, Kalmark B, Giebisch G (1985) Tubular actions of diuretics: Distal effects on electrolyte transport and acidification. Kidney Int 28:477–489

    Google Scholar 

  18. Inoue M, Okajima K, Itch K, Ando Y, Watanabe N, Yasaka T, Nagase S, Morino Y (1987) Mechanisms of furosemide resistance in analbuminemic rats and hypoalbuminemic patients. Kidney Int 32:198–203

    Google Scholar 

  19. Keller E, Hoppe-Seyler G, Mumm R, Schollmeyer P (1981) Influence of hepatic cirrhosis and end-stage renal disease on pharmacokinetics and pharmacodynamics of furosemide. Eur J Clin Pharmacol 20:27–33

    Google Scholar 

  20. Keller E, Hoppe-Seyler G, Schollmeyer P (1982) Disposition and diuretic effect of furosemide in the nephrotic syndrome. Clin Pharmacol Ther 32:442–449

    Google Scholar 

  21. Knauf H (1988) Hereditäre Tubulopathien. In: Sarre H, Gessler U, Seybold D (eds) Nierenkrankheiten. Georg Thieme, Stuttgart New York, pp 556–574

    Google Scholar 

  22. Knauf H, Gerok W, Mutschler E, Schölmerich J, Spahn H, Wietholtz H (1990) Disposition of xipamide in liver cirrhosis. Clin Pharm Ther 48(6):628–632

    Google Scholar 

  23. Knauf H, Just HJ (1984) Neuere Entwicklungen auf dem Gebiet der diuretischen Therapie der Herzinsuffizienz. Therapiewoche 34:2449–2460

    Google Scholar 

  24. Knauf H, Kölle EU, Mutschler E (1990) Gemfibrozil absorption and elimination in kidney and liver disease. Klin Wochenschr 68:692–698

    Google Scholar 

  25. Knauf H, Liebig R, Schollmeyer P, Rosenthal J, Kölle EU, Mutschler E (1984) Pharmacodynamics and kinetics of etozolin/ozolinone in hypertensive patients with normal and impaired kidney function. Eur J Clin Pharmacol 26:687–693

    Google Scholar 

  26. Knauf H, Mutschler E (1984) Pharmacodynamics and pharmacokinetics of xipamide in patients with normal and impaired kidney function. Eur J Clin Pharmacol 26:513–520

    Google Scholar 

  27. Knauf H, Mutschler E (1984) Pharmakodynamik und -kinetik von Triamteren. In: Mutschler E, Knauf H (eds) 30 Jahre Triamteren. Wissenschafts-Verlag, Köln, pp 31–39

    Google Scholar 

  28. Knauf H, Mutschler E (1986) Wirkprofile von Diuretika. In: Knauf H, Mutschler E (eds) Diuretika, Prinzipien der klinischen Anwendung. Urban & Schwarzenberg, München Wien Baltimore, pp 93–108

    Google Scholar 

  29. Knauf H, Mutschler E (1989) The Na load in the nephron segment determines the ceiling quality of a diuretic. In: Puschett JB, Greenberg A (eds) Diuretics III, Chemistry, Pharmacology, and Clinical Applications. Elsevier, Amsterdam New York London, pp 359–362

    Google Scholar 

  30. Knauf H, Mutschler E (1990) Saluretic effects of the loop diuretic torasemide in chronic renal failure. Interdependence of electrolyte excretion. Eur J Clin Pharmacol 39:337–343

    Google Scholar 

  31. Knauf H, Mutschler E (1991) Constant K+/Na+ excretion ratio by piretanide during peak diuresis, but insignificant K+ loss during 24 hours. Eur J Clin Pharmacol (subm. f. publ.)

  32. Knauf H, Mutschler E (1991) Thiazides in advanced renal failure. (in prep)

  33. Knauf H, Schollmeyer P, Gerok W (1986) Diuretika bei Nierenerkrankungen sowie Leberzirrhose mit Aszites. In: Knauf H, Mutschler E (eds) Diuretika, Prinzipien der klinischen Anwendung. Urban & Schwarzenberg, München Wien Baltimore, pp 141–160

    Google Scholar 

  34. Knauf H, Reuter K, Mutschler E (1985) Limitation on the use of amiloride in early renal failure. Eur J Clin Pharmacol 28:61–66

    Google Scholar 

  35. Knauf H, Wenk E, Schölmerich J, Goerg KJ, Gerok W, Leser HG, Mutschler E (1990) Prediction of diuretic mobilization of cirrhotic ascites by pretreatment fractional sodium excretion. Klin Wochenschr 68:545–551

    Google Scholar 

  36. Koczorek KR, Jahrmärker H, Hofmann H, Vogt W, Schmiedek P, Simon B, Balde E (1969) Effects of combined application of antikaliuretic agents and diuretics. In: Thurau K, Jahrmärker H (eds) Renal transport and diuretics. Springer, Berlin Heidelberg New York, pp 269–300

    Google Scholar 

  37. Multicenter Diuretic Study Group (1981) Multiclinic comparison of amiloride, hydrochlorothiazide, and hydrochlorothiazide plus amiloride in essential hypertension. Arch Intern Med 141:482–486

    Google Scholar 

  38. Mutschler E, Gilfrich HJ, Knauf H, Möhrke W, Völger KD (1983) Pharmakokinetik von Triamteren bei Probanden und Patienten mit Leber- und Nierenfunktionsstörungen. Klin Wochenschr 61:683–691

    Google Scholar 

  39. Oster JR, Epstein M, Smoller S (1983) Combined therapy with thiazide-type and loop diuretic agents for resistant sodium retention. Ann Intern Med 99:405–406

    Google Scholar 

  40. Pinzani M, Daskalopoulos G, Laffi G, Gentilini P, Zipser RD (1987) Altered furosemide pharmacokinetics in chronic alcoholic liver disease with ascites contributes to diuretic resistance. Gastroenterology 92:294–298

    Google Scholar 

  41. Rollins DE, Klaassen CE (1979) Biliary excretion of drugs in man. Clin Pharmacokinet 4:368–379

    Google Scholar 

  42. Rupp W, Heidland A, Hajdú P, Neuhaus G (1971) Pharmakokinetik von Furosemid bei normaler und eingeschränkter Nierenfunktion. In: Kluthe R (ed) Medikamentöse Therapie bei Nierenerkrankungen. Georg Thieme, Stuttgart, pp 207–213

    Google Scholar 

  43. Scheler F (1969) Anwendung von Saluretika bei Niereninsuffizienz. In: Krück F, Leppla W (eds) Klinische Pharmakologie der Diuretika. Urban & Schwarzenberg, München Berlin Wien, pp 83–92

    Google Scholar 

  44. Schlatter E, Salomonsson M, Persson AEG, Greger R (1989) Macula densa cells reabsorb NaCl via Furosemide sensitive Na+-K+ -2Cl−-Cotransport. In: Puschett JB, Greenberg A (eds) Diuretics III, Chemistry, Pharmacology, and Clinical Applications. Elsevier, Amsterdam New York London, pp 756–758

    Google Scholar 

  45. Schrier RW (1988) Pathogenesis of sodium and water retention in high and low output cardiac failure, cirrhosis, nephrotic syndrome, and pregnancy. N Engl J Med 319:1065–1072

    Google Scholar 

  46. Schrier RW, Arroyo V, Bernardi M, Epstein M, Henriksen JH, Rodés J (1988) Peripheral arterial vasodilation hypothesis: a proposal for the initiation of renal sodium and water retention in cirrhosis. Hepatology 8 (5):1151–1157

    Google Scholar 

  47. Sigurd B, Olesen KH, Wennevold A (1975) The supra-additive natriuretic effect of addition of bendroflumethiazide and bumetanide in congestive heart failure. Am Heart J 89:163–170

    Google Scholar 

  48. Skorecki KL, Brenner BM (1982) Body fluid homeostasis in congestive hart failure and cirrhosis with ascites. Am J Med 72:323–338

    Google Scholar 

  49. Slatopolsky E, Elken I, Weerts C, Bricker NS (1968) Studies on the characteristics of the control system governing sodium exeretion in uremic man. J Clin Invest 47:521–530

    Google Scholar 

  50. Spahn H, Reuter K, Mutschler E, Gerok W, Knauf H (1987) Amiloride pharmacokinetics in renal and hepatic disease. Eur J Clin Pharmacol 33:493–498

    Google Scholar 

  51. Tannenbaum PJ, Crosley AP (1966) A comparison of the effects of hydrochlorothiazide and hydrochlorothiazide in combination with triamterene on electrolyte balance. Clin Pharmacol Ther 7(6):777–782

    Google Scholar 

  52. Tartagni F, Tomassini F, Cervi V, Bargossi AM, Cappelletti O, Magnani B (1986) Metabolic effects of long-term piretanide use. Curr Ther Res 39:1004–1010

    Google Scholar 

  53. Ullrich KJ, Rumrich G (1988) Contraluminal transport systems in the proximal renal tubule involved in secretion of organic anions. Am J Physiol 254:F453-F462

    Google Scholar 

  54. van Dyke RW (1989) Mechanisms of digestion and absorption of food. In: Sleisenger MH, Fordtran JS (eds) Gastrointestinal Disease. Saunders, Philadelphia, pp 1062–1088

    Google Scholar 

  55. Voelker JR, Cartright-Brown D, Anderson S, Leinfelder J, Sica DA, Kokko JP, Brater DC (1987) Comparison of loop diuretics in patients with renal insufficiency. Kidney Int 31(1):222

    Google Scholar 

  56. Wilcox CS, Mitch WE, Kelly RA et al. (1983) Response of the kidney to furosemide: 1. Effects of salt intake and renal compensation. J Lab Clin Med 201:450–458

    Google Scholar 

  57. Wollam GL, Tarazi RC, Bravo EL, Dusten HP (1982) Diuretic potency of combined hydrochlorothiazide and furosemide therapy in patients with azotemia. Am J Med 72:929–938

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Medizinische Klinik I, St. Bernward-Krankenhaus, Hildesheim

    H. Knauf

  2. Pharmakologisches Institut der Universität Frankfurt, Frankfurt/Main

    E. Mutschler

Authors
  1. H. Knauf
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E. Mutschler
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

Gratefully dedicated to Prof. Dr. K.J. Ullrich

Rights and permissions

Reprints and permissions

About this article

Cite this article

Knauf, H., Mutschler, E. Pharmacodynamic and kinetic considerations on diuretics as a basis for differential therapy. Klin Wochenschr 69, 239–250 (1991). https://doi.org/10.1007/BF01666849

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01666849

Key words

Search

Navigation