Skip to main content
SpringerLink
Log in

Renal excretory responses to single and repeated administration of diuretics in healthy subjects: Clinical connotations

  • Published:
Cardiovascular Drugs and Therapy Aims and scope Submit manuscript

Summary

Administration of an initial oral dose of hydrochlorothiazide 25 mg to healthy subjects is followed by increased 24-hour urinary outputs of sodium, chloride, and potassium. On the fourth day of once-daily dosing with hydrochlorothiazide 25 mg, 24-hour natriuresis and chloriuresis are no longer augmented, but the elevation in 24-hour kaliuresis that follows the first dose remains unchanged. Twenty-four-hour urinary calcium output is consistently reduced during repeated once-daily administration of hydrochlorothiazide 25 mg.

The first oral dose of the loop diuretic torasemide augments the average natriuresis and kaliuresis in the 6 hours immediately after dosing in healthy subjects, in a dose-dependent fashion, within the 2.5 to 10-mg range. These increased urinary outputs are followed by rebounds below postplacebo values between 6 and 24 hours after dosing. As a result of this biphasic response, torasemide 2.5 mg qualifies as a nondiuretic formulation (it does not elevate 24-hour natriuresis), whereas torasemide 5 and 10 mg qualify as diuretic formulations. After the seventh dose of torasemide 5 or 10 mg during a regimen of once-daily therapy, 24-hour urinary sodium and chloride outputs no longer differ from their postplacebo counterparts. Twenty-four-hour kaliuresis tends to increase in a dose-dependent fashion after the first dose of torasemide (torasemide 2.5 and 5 mg do not augment it significantly), but this tendency is no longer present after the seventh once-daily dose, when torasemide (2.5, 5, or 10 mg) does not elevate the mean 24-hour kaliuresis. Twenty-four-hour calciuresis tends to increase in a dose-dependent manner (torasemide 2.5 mg does not elevate it significantly) after the first dose of torasemide; this calciuretic effect does not change in intensity after 7 days of once-daily treatment.

The time course of natriuresis over the 24 hours following the administration of any given formulation of a loop or of an early distal tubular diuretic to healthy subjects is alike after the first and after thenth once-daily dose; therefore, it constitutes a definite characteristic of any given oral formulation. In the case of torasemide, lower doses have more protracted effects on natriuresis, to the extent that the time course of natriuresis over the 24 hours after administration of torasemide 2.5 mg to healthy subjects resembles the time course after administration of hydrochlorothiazide 25 mg, rather than the time course after administration of the overtly diuretic formulation torasemide 10 mg.

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

References

  1. Reyes AJ. Diuretics in heart failure. In: Puschett JB, Greenberg A, eds.Diuretics II: Chemistry, pharmacology, and clinical applications. New York: Elsevier, 1987:332–344.

    Google Scholar 

  2. Reyes AJ. Interactions between magnesium and drugs in congestive heart failure.Magnesium-Bull 1987;9:93–109.

    Google Scholar 

  3. Reyes AJ. Therapy with diuretics in congestive heart failure.Prog Pharmacol 1988;6(3):167–192.

    Google Scholar 

  4. Reyes AJ. Effects of diuretics on outputs and flows of urine and urinary solutes in healthy subjects.Drugs 1991;41(Suppl 3):33–59.

    Google Scholar 

  5. Greger R. Inhibition of active NaCl reabsorption in the thick ascending limb of the loop of Henle by torasemide.Arzneim-Forsch/Drug Res 1988;38(I):151–152.

    Google Scholar 

  6. Ghys A, Denef J, Delarge J, et al. Renal effects of the high ceiling diuretic torasemide in rats and dogs.Arzneim-Forsch/Drug Res 1985;35(II):1527–1531.

    Google Scholar 

  7. Reyes AJ, Leary WP, van der Byl K. Renal excretory responses to single and repeated administration of loop and of early distal tubular diuretics at various doses in healthy man.Prog Pharmacol Clin Pharmacol 1992;9:219–262.

    Google Scholar 

  8. Reyes AJ, Leary WP. Clinicopharmacological definition of the potency of diuretics and reclassification of diuretics by their clinicopharmacological potency.Prog Pharmacol Clin Pharmacol 1992;9:131–146.

    Google Scholar 

  9. Reyes AJ, Leary WP, van der Byl K, et al. Renal excretory pharmacodynamics of diuretics in man: Comparison between furosemide, hydrochlorothiazide and torasemide.Prog Pharmacol 1988;6(3):83–151.

    Google Scholar 

  10. Reyes AJ, Leary WP, van der Byl K. Excretion of urinary fluid and solutes after single doses of furosemide and hydrochlorothiazide and of four single doses of the diuretic torasemide in healthy subjects.Prog Pharmacol Clin Pharmacol 1990;8(1):47–71.

    Google Scholar 

  11. Leary WP, Reyes AJ, van der Byl K, et al. Effects of captopril, hydrochlorothiazide and their combination on timed urinary excretions of water and solutes.J Cardiovasc Pharmacol 1985;7(Suppl 1):S56-S62.

    Google Scholar 

  12. Leary WP, Reyes AJ, Wynne RD, et al. Renal excretory actions of furosemide, of hydrochlorothiazide and of the vasodilator flosequinan in healthy subjects.J Int Med Res 1990;18:120–141.

    PubMed  Google Scholar 

  13. Reyes AJ, Leary WP, van der Byl K. The UY Mathematical Model of urinary fluid and solute continuous flows. In: Puschett JB, Greenberg A, eds.Diuretics III: Chemistry, pharmacology, and clinical applications. New York: Elsevier, 1990:72–74.

    Google Scholar 

  14. Reyes AJ, Leary WP, van der Byl K. Instantaneous renal clearance derived by the UY Mathematical Model. In: Puschett JB, Greenberg A, eds.Diuretics III: Chemistry, pharmacology, and clinical applications. New York: Elsevier, 1990:69–71.

    Google Scholar 

  15. Weidmann P, Beretta-Piccoli C, Meier A, et al. Antihypertensive mechanism of diuretic treatment with chlorthalidone. Complementary roles of sympathetic axis and sodium.Kidney Int 1983;23:320–326.

    PubMed  Google Scholar 

  16. Griffing GT, Sindler BH, Aurecchia SA, et al. The effects of hydrochlorothiazide on the renin-aldosterone system.Metabolism 1983;32:197–201.

    PubMed  Google Scholar 

  17. Wilcox CS. Diuretics and potassium. In: Seldin DW, Giebisch G, eds.The regulation of potassium balance. New York: Raven Press, 1989:325–345.

    Google Scholar 

  18. Lijnen P, Hespel P, Fagard R, et al. Plasma atrial natriuretic peptide and the renin-aldosterone system during long-term administration of the diuretic xipamide in man.Eur J Clin Pharmacol 1989;36:111–117.

    PubMed  Google Scholar 

  19. Sowers JR. The impact of diuretics on potassium and glucose.J Cardiovasc Pharmacol 1984;6:S477-S482.

    PubMed  Google Scholar 

  20. Tannen RL. Diuretic-induced hypokalaemia.Kidney Int 1985;28:988–1000.

    PubMed  Google Scholar 

  21. McMahon FG. The role of potassium in hypertension.Prog Pharmacol 1985;6(1):45–50.

    Google Scholar 

  22. Velázquez H, Wright FS. Control by drugs of renal potassium handling.Annu Rev Pharmacol 1986;26:293–309.

    Google Scholar 

  23. Velázquez H. Thiazide diuretics.Renal Physiol 1987;10:184–197.

    PubMed  Google Scholar 

  24. Young DB. Quantitative analysis of aldosterone's role in potassium regulation.Am J Physiol 1988;255:F811-F822.

    PubMed  Google Scholar 

  25. Agus ZS, Goldfarb S. Renal regulation of calcium balance. In: Seldin DW, Giebisch G, eds.The kidney: Physiology and pathophysiology. New York: Raven Press, 1985:1323–1335.

    Google Scholar 

  26. Costanzo L. Effects of diuretics on the distal convoluted tubular transport of calcium. In: Puschett JB, Greenberg A, eds.Diuretics: Chemistry, pharmacology, and clinical applications. New York: Elsevier, 1984:169–173.

    Google Scholar 

  27. Stier CT, Itskovitz HD. Renal calcium metabolism and diuretics.Annu Rev Pharmacol Toxicol 1986;26:101–116.

    PubMed  Google Scholar 

  28. Reyes AJ, Leary WP. Natriuretic potency of various diuretics. In: Andreucci V, Dal Canton A, eds.Diuretics: Basic, pharmacological, and clinical aspects. Boston: Martinus Nijhoff, 1987:506–508.

    Google Scholar 

  29. Leary WP, Reyes AJ. Renal excretory actions of diuretics in man: Correction of various current errors and redefinition of basic concepts.Prog Pharmacol 1988;6(3):153–166.

    Google Scholar 

  30. Hammarlund MM, Odlind B, Paalzow K. Acute tolerance to furosemide diuresis in humans. Pharmacokinetic-pharmacodynamic modeling.J Pharmacol Exp Ther 1985;233:447–453.

    PubMed  Google Scholar 

  31. Sjöström PA, Odlind BG, Beermann BA, et al. On the mechanism of acute tolerance to furosemide diuresis.Scand J Urol Nephrol 1988;22:133–140.

    PubMed  Google Scholar 

  32. Beermann B, Groschinsky-Grind M. Clinical pharmacokinetics of diuretics.Clin Pharmacokin 1980;5:221–245.

    Google Scholar 

  33. Beermann B, Grind M. Clinical pharmacokinetics of some newer diuretics.Clin Pharmacokin 1987;13:254–256.

    Google Scholar 

  34. Welling PG. Pharmacokinetics of the thiazide diuretics.Biopharm Drug Disp 1986;7:501–535.

    Google Scholar 

  35. Klütsch K, Grosswendt J, Haecker W. Single dose comparison of torasemide and furosemide in patients with advanced renal failure.Arzneim-Forsch/Drug Res 1988;38(I):200–204.

    Google Scholar 

  36. Mourad G, Haecker W, Mion C. Dose-dependent salidiuretic efficacy of torasemide in comparison to furosemide and placebo in advanced renal failure.Arzneim-Forsch/Drug Res 1988;38(I):205–208.

    Google Scholar 

  37. Sjöström P, Beermann B, Odlind B. Pharmacokinetic-pharmacodynamic relationship of piretanide in healthy and uremic subjects.Scand J Urol Nephrol 1987;21:55–64.

    PubMed  Google Scholar 

  38. Scheen AJ, Vancrombreucq JC, Delarge J, et al. Diuretic activity of torasemide and furosemide in chronic heart failure. A comparative double-blind cross-over study.Eur J Clin Pharmacol 1986;31(Suppl):35–42.

    PubMed  Google Scholar 

  39. Broekhuysen J, Deger F, Douchamps J, et al. Torasemide, a new potent diuretic. Double-blind comparison with furosemide.Eur J Clin Pharmacol 1986;31(Suppl):29–34.

    PubMed  Google Scholar 

  40. Hamdy RC, Vinson M, Robbins AD, et al. 24 hour urinary electrolyte profile following frusemide, amiloride and a combination of these drugs Frumil™. In: Puschett JB, Greenberg A, eds.Diuretics: Chemistry, pharmacology, and clinical applications. New York: Elsevier, 1984:364–366.

    Google Scholar 

  41. Wilcox CS, Mitch WE, Kelly RA, et al. Response of the kidney to furosemide: Effects of salt intake and renal compensation.J Lab Med 1983;102:450–458.

    Google Scholar 

  42. Barr WH, Smith H, Karnes HT, et al. Comparison of bioavailability, pharmacokinetics and pharmacodynamics of torasemide in young and elderly healthy volunteers.Prog Pharmacol Clin Pharmacol 1990;8(1):15–28.

    Google Scholar 

  43. Loon NR, Wilcox CS, Unwin RJ. Mechanism of impaired natriuretic response to furosemide during prolonged therapy.Kidney Int 1989;36:682–689.

    PubMed  Google Scholar 

  44. Kelly RA, Wilcox CS, Mitch WE, et al. Response of the kidney to furosemide: Effect of captopril on sodium balance.Kidney Int 1983;24:233–239.

    PubMed  Google Scholar 

  45. Wilcox CS, Guzman NJ, Mitch WE, et al. Na+, K+, and BP homeostasis in man during furosemide: Effect of prazosin and captopril.Kidney Int 1987;31:135–141.

    PubMed  Google Scholar 

  46. Di Nicolantonio R, Morgan TO. Captopril attenuates diuretic and natriuretic actions of furosemide but not atrial natriuretic peptide.Clin Exp Hypertens 1987;A9:19–32.

    Google Scholar 

  47. Bönner G, Gentges A, Wambach G, et al. Diminution by captopril of the diuretic, natriuretic and kallikrein stimulating action of furosemide by reduction in its renal secretion.Agents Actions 1987;22:309–319.

    Google Scholar 

  48. Kaissling B, Bachmann S, Kriz W. Structural adaptation of the distal convoluted tubule to prolonged furosemide treatment.Am J Physiol 1985;248:F374-F381.

    PubMed  Google Scholar 

  49. Stanton BA. Role of adrenal hormones in regulating distal nephron structure and ion transport.Fed Proc 1985;44:2717–2722.

    PubMed  Google Scholar 

  50. Sjöström PA, Beermann BA, Odlind BG. Delayed tolerance to furosemide diuresis.Scand J Urol Nephrol 1988;22:317–325.

    PubMed  Google Scholar 

  51. Greger R. Ion transport mechanisms in the thick ascending limb of Henle's loop of mammalian nephron.Physiol Rev 1985;65:760–797.

    PubMed  Google Scholar 

  52. Greger R, Wangemann P. Loop diuretics.Renal Physiol 1988;10:174–183.

    Google Scholar 

  53. Wright FS. Flow-dependent transport processes: Filtration, absorption, secretion.Am J Physiol 1982;243:F1-F11.

    PubMed  Google Scholar 

  54. Giebisch G. Hormonal control of distal nephron function.Klin Wochen 1985;63:877–885.

    Google Scholar 

  55. Wilcox CS, Mitch WE, Kelly RA, et al. Factors affecting potassium balance during furosemide administration.Clin Sci 1984;67:195–203.

    PubMed  Google Scholar 

  56. Lesne M, Clerckx-Braun F, Duhoux P, et al. Pharmacokinetic study of torasemide in humans: An overview of its diuretic effect.Int J Clin Pharmacol Ther Toxicol 1982;20:382–387.

    PubMed  Google Scholar 

  57. Ambroes Y, Ronflette I, Dodion L. Diuretic activity, safety and pharmacokinetics of torasemide during chronic treatment in normal subjects.Eur J Clin Pharmacol 1986;31(Suppl):1–7.

    Google Scholar 

  58. Cuvelier R, Pellegrini P, Lesne M, et al. Site of action of torasemide in man.Eur J Clin Pharmacol 1986;31(Suppl):15–19.

    Google Scholar 

  59. Neugebauer G, Besenfelder E, von Möllendorf E. Pharmacokinetics and metabolism of torasemide in man.Arzneim-Forsch/Drug Res 1988;38(I):164–166.

    Google Scholar 

  60. Barr WH, Smith HL, Karnes HT, et al. Torasemide dose-proportionality of pharmacokinetics and pharmacodynamics.Prog Pharmacol Clin Pharmacol 1990;8(1):29–37.

    Google Scholar 

  61. Elmgreen J, Tougaard L, Leth A, et al. Elevated serum parathyroid hormone concentration during treatment with high ceiling diuretics.Eur J Clin Pharmacol 1980;18:363–364.

    PubMed  Google Scholar 

  62. Fujita T, Chan CM, Bartter FC. Effects of oral furosemide and salt loading on parathyroid function in normal subjects.Nephron 1984;38:109–114.

    PubMed  Google Scholar 

  63. Dupont AG, Schoors D, Six RO, et al. Antihypertensive efficacy of low dose torasemide in essential hypertension: A placebo-controlled study.J Human Hypertens 1988;2:265–268.

    Google Scholar 

  64. Spannbrucker N, Achhammer I, Metz P, et al. Comparative study on the antihypertensive efficacy of torasemide and indapamide in patients with essential hypertension.Arzneim-Forsch/Drug Res 1988;38(I):190–193.

    Google Scholar 

  65. Reyes AJ. Formal comparison of the antihypertensive effects of torasemide and other diuretics by the Montevideo Mathematical Model.Arzneim-Forsch/Drug Res 1988;38(I):194–199.

    Google Scholar 

  66. Baumgart P, Walger P, v. Eiff M, et al. Long-term efficacy and tolerance of torasemide in hypertension.Prog Pharmacol Clin Pharmacol 1990;8(1):169–181.

    Google Scholar 

  67. Reyes AJ, Chiesa PD, Santucci MR, et al. Hydrochlorothiazide versus a non-diuretic dose of torasemide as once-daily antihypertensive monopharmacotherapy in elderly patients. A randomized and double-blind study.Prog Pharmacol Clin Pharmacol 1990;8(1):183–209.

    Google Scholar 

  68. Achhammer I, Eberhard R. Comparison of serum potassium levels during long-term treatment of hypertensive patients with 2.5 mg torasemide/day or 50 mg triamterene/25 mg hydrochlorothiazide/day.Prog Pharmacol Clin Pharmacol 1990;8(1):211–220.

    Google Scholar 

  69. Beermann B, Groschinsky-Grind M. Antihypertensive effect of various doses of hydrochlorothiazide and its relation to the plasma level of the drug.Eur J Clin Pharmacol 1978;13:195–201.

    PubMed  Google Scholar 

  70. Materson BJ, Oster JR, Michael UF, et al. Dose response to chlorthalidone in patients with mild hypertension.Clin Pharmacol Ther 1978;24:192–198.

    PubMed  Google Scholar 

  71. Reyes AJ, Leary WP, Alcocer L. The antihypertensive effect of diuretics: Overview and formal evaluation by the Montevideo Mathematical Model.Prog Pharmacol 1988;6(3):193–243.

    Google Scholar 

  72. Reyes AJ. Mechanisms and extent of the decrease in magnesiuresis induced by antikaliuretic diuretics in man. In: Itokawa Y, Durlach J, eds.Magnesium in health and disease. London Paris: John Libbey, 1989:415–422.

    Google Scholar 

  73. Reyes AJ. Deleterious effects of antihypertensive treatment on magnesium turnover.Prog Pharmacol 1985;6(1):51–87.

    Google Scholar 

  74. Leary WP, Reyes AJ. Angiotensin-I converting enzyme inhibitors and the renal excretion of urate.Cardiovasc Drugs Ther 1987;1:28–39.

    Google Scholar 

  75. Lant AF. Diuretics. Clinical pharmacology and therapeutic use (part II).Drugs 1985;29:162–168.

    Google Scholar 

  76. Rodicio JL, Alcazar JM, Nieto J, et al. Metabolic effects of long-term diuretic treatment. In: Andreucci V, Dal Canton A, eds.Diuretics: Basic, pharmacological, and clinical aspects. Boston: Martinus Nijhoff, 1987:231–236.

    Google Scholar 

  77. Wicker P, Clementy J. Comparison of the effects of muzolimine and a fixed combination of hydrochlorothiazide and amiloride in mildly to moderately hypertensive patients. In: Puschett JB, Greenberg A, eds.Diuretics: Chemistry, pharmacology, and clinical applications. New York: Elsevier, 1984:109–111.

    Google Scholar 

  78. Kirsten R, Molg KH, Tzonev I, et al. Clinical evaluation of muzolimine and indapamide during treatment for essential hypertension.Z Kardiol 1985;74(Suppl 2):66–72.

    PubMed  Google Scholar 

  79. Canonico V, Morgano G, Petretta M, et al. Muzolimine versus captopril in low and mild hypertension. In: Andreucci V, Dal Canton A, eds.Diuretics: Basic, pharmacological, and clinical aspects. Boston: Martinus Nijhoff, 1987:283–285.

    Google Scholar 

  80. Carnovali M, Borguino C, Crespi E, et al. Efficacy and tolerability of muzolimine in the long-term treatment of essential hypertension. In: Andreucci V, Dal Canton A, eds.Diuretics: Basic, pharmacological, and clinical aspects. Boston: Martinus Nijhoff, 1987:317–319.

    Google Scholar 

  81. Ortalda V, Valvo E, Fabris A, et al. Long-term therapy with muzolimine in patients with mild to moderate essential hypertension. In: Andreucci V, Dal Canton A, eds.Diuretics: Basic, pharmacological, and clinical aspects. Boston: Martinus Nijhoff, 1987:323–325.

    Google Scholar 

  82. Cocchieri M, Chiuini E, Fortunati F, et al. Efficacy of two different doses of muzolimine in the treatment of mild hypertension.Z Kardiol 1985;74(Suppl 2):56–59.

    PubMed  Google Scholar 

  83. Achhammer I, Metz P. Low dose loop diuretics in essential hypertension: Experience with torasemide.Drugs 1991;41(Suppl 3):80–91.

    PubMed  Google Scholar 

  84. Parmley WW. Pathophysiology of congestive heart failure.Am J Cardiol 1985;56:7A-11A.

    PubMed  Google Scholar 

  85. Weber KT, Janicki JS, Maskin CS. Pathophysiology of cardiac failure.Am J Cardiol 1985;56:3B-7B.

    PubMed  Google Scholar 

  86. Remme WJ. Congestive heart failure—pathophysiology and medical treatment.J Cardiovasc Pharmacol 1986;8(Suppl 1):S36-S52.

    Google Scholar 

  87. Harris P. Congestive cardiac failure: The syndrome of volume expansion.Cardiovasc Drug Ther 1989;3:941–946.

    Google Scholar 

  88. Ferrari R, Anand I. Neurohumoral changes in untreated heart failure.Cardiovasc Drugs Ther 1989;3:979–986.

    Google Scholar 

  89. Riegger AJG, Kromer EP, Kochsiek K. Human atrial natriuretic peptide: Plasma levels, hemodynamic, hormonal and renal effects in patients with severe congestive heart failure.J Cardiovasc Pharmacol 1986;8:1107–1112.

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  91. Voltz G. Behaviour of electrolyte and acid-base balance during treatment with 4-chloro-5-sulfamoyl-2′,6′-salicyloxylidide (Xipamid INN) with particular regard to potassium balance.Arzneim-Forsch/Drug Res 1975;25(II):256–258.

    Google Scholar 

  92. Ziakas G, Zioutas G, Arvanitidis T, et al. Muzolimine in patients with cardiac edema: A comparison with furosemide in a repeated-dose, single-blind study.Clin Nephrol 1983;19(Suppl 1):S85-S91.

    Google Scholar 

  93. Stauch M, Stiehl L. Controlled, double-blind clinical trial of the efficacy and tolerance of torasemide in comparison with furosemide in patients with congestive heart failure—a multicenter study.Prog Pharmacol Clin Pharmacol 1990;8(1):121–126.

    Google Scholar 

  94. Achhammer I. Long term efficacy and tolerance of torasemide in congestive heart failure.Prog Pharmacol Clin Pharmacol 1990;8(1):127–136.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Cardiovascular Theory, Montevideo, Uruguay

    Ariel J. Reyes

  2. Department of Experimental and Clinical Pharmacology, University of Natal, Durban, South Africa

    William P. Leary

Authors
  1. Ariel J. Reyes
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. William P. Leary
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Reyes, A.J., Leary, W.P. Renal excretory responses to single and repeated administration of diuretics in healthy subjects: Clinical connotations. Cardiovasc Drug Ther 7 (Suppl 1), 29–44 (1993). https://doi.org/10.1007/BF00877956

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00877956

Key Words

Search

Navigation