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Insights on Diuretic Therapy from Clinical and Pharmacologic Perspectives

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Cardiorenal Syndrome in Heart Failure

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Abstract

Diuretic drugs are employed almost universally in the setting of cardiorenal syndrome. Although they can induce useful decongestion, they can lose their effectiveness or induce worrisome worsening of renal function. It is important to understand and leverage the pharmacokinetic and pharmacodynamic properties of diuretic drugs, if therapeutic success is to be achieved. At its simplest, a diuretic must be administered or ingested and absorbed, must circulate in the bloodstream bound to proteins, must enter renal tubules across the proximal tubule through specific secretory pathways, and must bind to its target at the luminal membrane of the thick ascending limb. Additionally, to be effective, the natriuretic effects of the drug on the thick ascending limb must not be overcome by compensatory salt reabsorption along other nephron segments. This chapter reviews the normal handling of loop and other diuretics, both under normal circumstances and in the presence of heart or kidney failure. It also makes recommendations for avoiding or treating causes of resistance to their action.

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References

  1. Hammarlund MM, Paalzow LK, Odlind B. Pharmacokinetics of furosemide in man after intravenous and oral administration. Application of moment analysis. Eur J Clin Pharmacol. 1984;26:197–207.

    Article  CAS  Google Scholar 

  2. Brater DC, Day B, Burdette A, Anderson S. Bumetanide and furosemide in heart failure. Kidney Int. 1984;26:183–9.

    Article  CAS  Google Scholar 

  3. Shankar SS, Brater DC. Loop diuretics: from the Na-K-2Cl transporter to clinical use. Am J Physiol Renal Physiol. 2003;284:F11–21.

    Article  CAS  Google Scholar 

  4. Huang X, Dorhout Mees E, Vos P, Hamza S, Braam B. Everything we always wanted to know about furosemide but were afraid to ask. Am J Physiol Renal Physiol. 2016;310:F958–71.

    Article  CAS  Google Scholar 

  5. Brater DC. Diuretic pharmacokinetics and pharmacodynamics. In: Seldin DW, Giebisch G, editors. Diuretic Agents: Clinical Physiology and Pharmacology. San Diego: Academic Press; 1997. p. 189–208.

    Chapter  Google Scholar 

  6. Brater DC. Pharmacodynamic considerations in the use of diuretics. Ann Rev Pharmacol Toxicol. 1983;23:45–62.

    Article  CAS  Google Scholar 

  7. Murray MD, Haag KM, Black PK, Hall SD, Brater DC. Variable furosemide absorption and poor predictability of response in elderly patients. Pharmacotherapy. 1997;17:98–106.

    CAS  PubMed  Google Scholar 

  8. Vargo DL, Kramer WG, Black PK, Smith WB, Serpas T, Brater DC. Bioavailability, pharmacokinetics, and pharmacodynamics of torsemide and furosemide in patients with congestive heart failure. Clin Pharmacol Ther. 1995;57:601–9.

    Article  CAS  Google Scholar 

  9. McCrindle JL, Li Kam Wa TC, Barron W, Prescott LF. Effect of food on the absorption of frusemide and bumetanide in man. Br J Clin Pharmacol. 1996;42:743–6.

    Article  CAS  Google Scholar 

  10. Kramer WG. Effect of Food on the Pharmacokinetics and Pharmacodynamics of Torsemide. Am J Ther. 1995;2:499–503.

    Article  Google Scholar 

  11. Murray MD, Ferguson JA, Bennett SJ, Adams LD, Forrhofer MM, Minick SM, Tierny WM, Brater DC. Fewer hospitalizations for heart failure by using a completely and predictably absorbed lood diuretic. J Gen Intern Med. 1998;13:18.

    Google Scholar 

  12. Murray MD, Deer MM, Ferguson JA, Dexter PR, Bennett SJ, Perkins SM, Smith FE, Lane KA, Adams LD, Tierney WM, Brater DC. Open-label randomized trial of torsemide compared with furosemide therapy for patients with heart failure. Am J Med. 2001;111:513–20.

    Article  CAS  Google Scholar 

  13. Bikdeli B, Strait KM, Dharmarajan K, Partovian C, Coca SG, Kim N, Li SX, Testani JM, Khan U, Krumholz HM. Dominance of furosemide for loop diuretic therapy in heart failure: time to revisit the alternatives? J Am Coll Cardiol. 2013;61:1549–50.

    Article  Google Scholar 

  14. DiNicolantonio JJ. Should torsemide be the loop diuretic of choice in systolic heart failure? Futur Cardiol. 2012;8:707–28.

    Article  CAS  Google Scholar 

  15. Mentz RJ, Hasselblad V, DeVore AD, Metra M, Voors AA, Armstrong PW, Ezekowitz JA, Tang WH, Schulte PJ, Anstrom KJ, Hernandez AF, Velazquez EJ, O'Connor CM. Torsemide Versus Furosemide in Patients With Acute Heart Failure (from the ASCEND-HF Trial). Am J Cardiol. 2016;117:404–11.

    Article  CAS  Google Scholar 

  16. Vasavada N, Saha C, Agarwal R. A double-blind randomized crossover trial of two loop diuretics in chronic kidney disease. Kidney Int. 2003;64:632–40.

    Article  CAS  Google Scholar 

  17. Vasko MR, Brown-Cartwright D, Knochel JP, Nixon JV, Brater DC. Furosemide absorption altered in decompensated congestive heart failure. Ann Intern Med. 1985;102:314–8.

    Article  CAS  Google Scholar 

  18. Gilotra NA, Princewill O, Marino B, Okwuosa IS, Chasler J, Almansa J, Cummings A, Rhodes P, Chambers J, Cuomo K, Russell SD. Efficacy of Intravenous Furosemide Versus a Novel, pH-Neutral Furosemide Formulation Administered Subcutaneously in Outpatients With Worsening Heart Failure. JACC Heart Failure. 2018;6:65–70.

    Article  Google Scholar 

  19. Sica DA, Muntendam P, Myers RL, Ter Maaten JM, Sale ME, de Boer RA, Pitt B. Subcutaneous furosemide in heart failure: pharmacokinetic characteristics of a newly buffered solution. JACC Basic Transl Sci. 2018;3:25–34.

    Article  Google Scholar 

  20. Inoue M, Okajima K, Itoh K, Ando Y, Watanabe N, Yasaka T, Nagase S, Morino Y. Mechanism of furosemide resistance in analbuminemic rats and hypoalbuminemic patients. Kidney Int. 1987;32:198–203.

    Article  CAS  Google Scholar 

  21. Kitsios GD, Mascari P, Ettunsi R, Gray AW. Co-administration of furosemide with albumin for overcoming diuretic resistance in patients with hypoalbuminemia: a meta-analysis. J Crit Care. 2014;29:253–9.

    Article  CAS  Google Scholar 

  22. Brater DC. Diuretic therapy. N Engl J Med. 1998;339:387–95.

    Article  CAS  Google Scholar 

  23. Brater DC. Disposition and response to bumetanide and furosemide. Am J Cardiol. 1986;57:20A–5A.

    Article  CAS  Google Scholar 

  24. Voelker JR, Cartwright-Brown D, Anderson S, Leinfelder J, Sica DA, Kokko JP, Brater DC. Comparison of loop diuretics in patients with chronic renal insufficiency. Kidney Int. 1987;32:572–8.

    Article  CAS  Google Scholar 

  25. Delpire E, Lu J, England R, Dull C, Thorne T. Deafness and imbalance associated with inactivation of the secretory Na-K-2Cl co-transporter. Nat Genet. 1999;22:192–5.

    Article  CAS  Google Scholar 

  26. Flagella M, Clarke LL, Miller ML, Erway LC, Giannella RA, Andringa A, Gawenis LR, Kramer J, Duffy JJ, Doetschman T, Lorenz JN, Yamoah EN, Cardell EL, Shull GE. Mice lacking the basolateral Na-K-2Cl cotransporter have impaired epithelial chloride secretion and are profoundly deaf. J Biol Chem. 1999;274:26946–55.

    Article  CAS  Google Scholar 

  27. Dormans TP, Van Meyel JJ, Gerlag PG, Tan Y, Russel FG, Smits P. Diuretic efficacy of high dose furosemide in severe heart failure: bolus injection versus continuous infusion. J Am Coll Cardiol. 1996;28:376–82.

    Article  CAS  Google Scholar 

  28. Ho KM, Sheridan DJ. Meta-analysis of frusemide to prevent or treat acute renal failure. BMJ. 2006;333:420.

    Article  CAS  Google Scholar 

  29. Keller F, Hann A. Clinical pharmacodynamics: principles of drug response and alterations in kidney disease. Clin J Am Soc Nephrol. 2018;13:1413–20.

    Article  CAS  Google Scholar 

  30. Nigam SK, Wu W, Bush KT, Hoenig MP, Blantz RC, Bhatnagar V. Handling of drugs, metabolites, and uremic toxins by kidney proximal tubule drug transporters. Clin J Am Soc Nephrol. 2015;10:2039–49.

    Article  CAS  Google Scholar 

  31. Lau HS, Shih LJ, Smith DE. Effect of probenecid on the dose-response relationship of bumetanide at steady state. J Pharmacol Exp Ther. 1983;227:51–4.

    CAS  PubMed  Google Scholar 

  32. Vallon V, Rieg T, Ahn SY, Wu W, Eraly SA, Nigam SK. Overlapping in vitro and in vivo specificities of the organic anion transporters OAT1 and OAT3 for loop and thiazide diuretics. Am J Physiol Renal Physiol. 2008;294:F867–73.

    Article  CAS  Google Scholar 

  33. Heerdink ER, Leufkens HG, Herrings RMC, Ottervanger JP, Stricker BHC, Bakker A. NSAIDs associated with increased risk of congestive heart failure in elderly patients taking diuretics. Arch Intern Med. 1998;158:1108–12.

    Article  CAS  Google Scholar 

  34. Burckhardt G. Drug transport by organic anion transporters (OATs). Pharmacol Ther. 2012;136:106–30.

    Article  CAS  Google Scholar 

  35. Wu W, Bush KT, Nigam SK. Key role for the organic anion transporters, OAT1 and OAT3, in the in vivo handling of uremic toxins and solutes. Sci Rep. 2017;7:4939.

    Article  Google Scholar 

  36. Cemerikic D, Wilcox CS, Giebisch G. Intracellular potential and K+ activity in rat kidney proximal tubular cells in acidosis and K+ depletion. J Membr Biol. 1982;69:159–65.

    Article  CAS  Google Scholar 

  37. Loon NR, Wilcox CS. Mild metabolic alkalosis impairs the natriuretic response to bumetanide in normal human subjects. Clin Sci. 1998;94:287–92.

    Article  CAS  Google Scholar 

  38. Mann B, Hartner A, Jensen BL, Kammerl M, Kramer BK, Kurtz A. Furosemide stimulates macula densa cyclooxygenase-2 expression in rats. Kidney Int. 2001;59:62–8.

    Article  CAS  Google Scholar 

  39. Stokes JB. Effects of prostaglandin E2 on chloride transport across the rabbit thick ascending limb of Henle. J Clin Invest. 1979;64:495–502.

    Article  CAS  Google Scholar 

  40. Hebert RL, Jacobson HR, Breyer MD. Prostaglandin E2 inhibits sodium transport in rabbit cortical collecting duct by increasing intracellular calcium. J Clin Invest. 1991;87:1992–8.

    Article  CAS  Google Scholar 

  41. Fernandez-Llama P, Ecelbarger CA, Ware JA, Andrews P, Lee AJ, Turner R, Nielsen S, Knepper MA. Cyclooxygenase inhibitors increase Na-K-2Cl cotransporter abundance in thick ascending limb of Henle’s loop. Am J Phys. 1999;277:F219–26.

    CAS  Google Scholar 

  42. Oppermann M, Hansen PB, Castrop H, Schnermann J. Vasodilatation of afferent arterioles and paradoxical increase of renal vascular resistance by furosemide in mice. Am J Physiol Renal Physiol. 2007;293:F279–87.

    Article  CAS  Google Scholar 

  43. Lapi F, Azoulay L, Yin H, Nessim SJ, Suissa S. Concurrent use of diuretics, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers with non-steroidal anti-inflammatory drugs and risk of acute kidney injury: nested case-control study. BMJ. 2013;346:e8525.

    Article  Google Scholar 

  44. Ellison DH, Felker GM. Diuretic treatment in heart failure. N Engl J Med. 2017;377:1964–75.

    Article  CAS  Google Scholar 

  45. Salvador DR, Rey NR, Ramos GC, Punzalan FE. Continuous infusion versus bolus injection of loop diuretics in congestive heart failure. Cochrane Database Syst Rev. 2005;CD003178.

    Google Scholar 

  46. Grodin JL, Stevens SR, de Las Fuentes L, Kiernan M, Birati EY, Gupta D, Bart BA, Felker GM, Chen HH, Butler J, Davila-Roman VG, Margulies KB, Hernandez AF, Anstrom KJ, Tang WH. Intensification of medication therapy for cardiorenal syndrome in acute decompensated heart failure. J Card Fail. 2016;22:26–32.

    Article  Google Scholar 

  47. Shah S, Pitt B, Brater DC, Feig PU, Shen W, Khwaja FS, Wilcox CS. Sodium and fluid excretion with torsemide in healthy subjects is limited by the short duration of diuretic action. J Am Heart Assoc. 2017;6:e006135.

    PubMed  PubMed Central  Google Scholar 

  48. Titze J. Estimating salt intake in humans: not so easy! Am J Clin Nutr. 2017;105:1253–4.

    CAS  PubMed  Google Scholar 

  49. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, Fonarow GC, Geraci SA, Horwich T, Januzzi JL, Johnson MR, Kasper EK, Levy WC, Masoudi FA, McBride PE, McMurray JJ, Mitchell JE, Peterson PN, Riegel B, Sam F, Stevenson LW, Tang WH, Tsai EJ, Wilkoff BL. 2013 ACCF/AHA guideline for the management of heart failure: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2013;128:1810–52.

    Article  Google Scholar 

  50. Butler J, Forman DE, Abraham WT, Gottlieb SS, Loh E, Massie BM, O'Connor CM, Rich MW, Stevenson LW, Wang Y, Young JB, Krumholz HM. Relationship between heart failure treatment and development of worsening renal function among hospitalized patients. Am Heart J. 2004;147:331–8.

    Article  Google Scholar 

  51. Brisco MA, Zile MR, Hanberg JS, Wilson FP, Parikh CR, Coca SG, Tang WH, Testani JM. Relevance of changes in serum creatinine during a heart failure trial of decongestive strategies: insights from the DOSE trial. J Card Fail. 2016;22:753–60.

    Article  CAS  Google Scholar 

  52. Ahmad T, Jackson K, Rao VS, Tang WHW, Brisco-Bacik MA, Chen HH, Felker GM, Hernandez AF, O'Connor CM, Sabbisetti VS, Bonventre JV, Wilson FP, Coca SG, Testani JM. Worsening renal function in patients with acute heart failure undergoing aggressive diuresis is not associated with tubular injury. Circulation. 2018;137:2016–28.

    Article  Google Scholar 

  53. Walser M. Phenomenological analysis of renal regulation of sodium and potassium balance. Kidney Int. 1985;27:837–41.

    Article  CAS  Google Scholar 

  54. Wilcox CS, Mitch WE, Kelly RA, Skorecki K, Meyer TW, Friedman PA, Souney PF. Response of the kidney to furosemide: I. Effects of salt intake and renal compensation. J Lab Clin Med. 1983;102:450–8.

    CAS  PubMed  Google Scholar 

  55. Wilcox CS, Guzman NJ, Mitch WE, Kelly RA, Maroni BJ, Souney PF, Rayment CM, Braun L, Colucci R, Loon NR. Na+,K+ and BP homeostasis in man during furosemide: effects of prozosin and captopril. Kidney Int. 1987;31:135–41.

    Article  CAS  Google Scholar 

  56. Kelly RA, Wilcox CS, Mitch WE, Meyer TW, Souney PF, Rayment CM, Friedman PA, Swartz SL. Response of the kidney to furosemide. II. Effect of captopril on sodium balance. Kidney Int. 1983;24:233–9.

    Article  CAS  Google Scholar 

  57. Loon NR, Wilcox CS, Unwin RJ. Mechanism of impaired natriuretic response to furosemide during prolonged therapy. Kidney Int. 1989;36:682–9.

    Article  CAS  Google Scholar 

  58. Rao VS, Planavsky N, Hanberg JS, Ahmad T, Brisco-Bacik MA, Wilson FP, Jacoby D, Chen M, Tang WHW, Cherney DZI, Ellison DH, Testani JM. Compensatory distal reabsorption drives diuretic resistance in human heart failure. J Am Soc Nephrol. 2017;28:3414–24.

    Article  CAS  Google Scholar 

  59. Subramanya AR, Ellison DH. Distal convoluted tubule. Clin J Am Soc Nephrol. 2014;9:2147–63.

    Article  CAS  Google Scholar 

  60. Yang YS, Xie J, Yang SS, Lin SH, Huang CL. Differential roles of WNK4 in regulation of NCC in vivo. Am J Physiol Renal Physiol. 2018;314:F999–F1007.

    Article  CAS  Google Scholar 

  61. Castaneda-Bueno M, Gamba G. Mechanisms of sodium-chloride cotransporter modulation by angiotensin II. Curr Opin Nephrol Hypertens. 2012;21:516–22.

    Article  CAS  Google Scholar 

  62. Abdallah JG, Schrier RW, Edelstein C, Jennings SD, Wyse B, Ellison DH. Loop diuretic infusion increases thiazide-sensitive Na(+)/Cl(−)-cotransporter abundance: role of aldosterone. J Am Soc Nephrol. 2001;12:1335–41.

    CAS  PubMed  Google Scholar 

  63. Saritas T, Puelles VG, Su XT, McCormick JA, Welling PA, Ellison DH. Optical clearing in the kidney reveals potassium-mediated tubule remodeling. Cell Rep. 2018;25:2668–2675 e2663.

    Article  CAS  Google Scholar 

  64. Fliser D, Schröter M, Neubeck M, Ritz E. Coadministration of thiazides increases the efficacy of loop diuretics even in patients with advanced renal failure. Kidney Int. 1994;46:482–8.

    Article  CAS  Google Scholar 

  65. Ellison DH. The physiologic basis of diuretic synergism: its role in treating diuretic resistance. Ann Intern Med. 1991;114:886–94.

    Article  CAS  Google Scholar 

  66. Kountz DS, Goldman A, Mikhail J, Ezer M. Chlorthalidone: the forgotten diuretic. Postgrad Med. 2012;124:60–6.

    Article  Google Scholar 

  67. Grimm PR, Taneja TK, Liu J, Coleman R, Chen YY, Delpire E, Wade JB, Welling PA. SPAK isoforms and OSR1 regulate sodium-chloride co-transporters in a nephron-specific manner. J Biol Chem. 2012;287:37673–90.

    Article  CAS  Google Scholar 

  68. Jentzer JC, DeWald TA, Hernandez AF. Combination of loop diuretics with thiazide-type diuretics in heart failure. J Am Coll Cardiol. 2010;56:1527–34.

    Article  CAS  Google Scholar 

  69. Terker AS, Zhang C, McCormick JA, Lazelle RA, Zhang C, Meermeier NP, Siler DA, Park HJ, Fu Y, Cohen DM, Weinstein AM, Wang WH, Yang CL, Ellison DH. Potassium modulates electrolyte balance and blood pressure through effects on distal cell voltage and chloride. Cell Metab. 2015;21:39–50.

    Article  CAS  Google Scholar 

  70. Eng M, Bansal S. Use of natriuretic-doses of spironolactone for treatment of loop diuretic resistant acute decompensated heart failure. Int J Cardiol. 2014;170:e68–9.

    Article  Google Scholar 

  71. Butler J, Anstrom KJ, Felker GM, Givertz MM, Kalogeropoulos AP, Konstam MA, Mann DL, Margulies KB, McNulty SE, Mentz RJ, Redfield MM, Tang WHW, Whellan DJ, Shah M, Desvigne-Nickens P, Hernandez AF, Braunwald E, National Heart Lung and Blood Institute Heart Failure, Clinical Research Network. Efficacy and safety of spironolactone in acute heart failure: the ATHENA-HF randomized clinical trial. JAMA Cardiol. 2017;2:950–8.

    Article  Google Scholar 

  72. Bart BA, Goldsmith SR, Lee KL, Givertz MM, O’Connor CM, Bull DA, Redfield MM, Deswal A, Rouleau JL, LeWinter MM, Ofili EO, Stevenson LW, Semigran MJ, Felker GM, Chen HH, Hernandez AF, Anstrom KJ, McNulty SE, Velazquez EJ, Ibarra JC, Mascette AM, Braunwald E. Ultrafiltration in decompensated heart failure with cardiorenal syndrome. N Engl J Med. 2012;367:2296–304.

    Article  CAS  Google Scholar 

  73. Somasekharan S, Tanis J, Forbush B. Loop diuretic and ion binding residues revealed by scanning mutagenesis of transmembrane helix 3 (TM3) of the Na-K-Cl Cotransporter (NKCC1). J Biol Chem. 2012;287:17308–17.

    Article  CAS  Google Scholar 

  74. Ellison DH. Clinical pharmacology in diuretic use. Clin J Am Soc Nephrol. 2019:CJN.09630818.

    Google Scholar 

  75. Milionis HJ, Alexandrides GE, Liberopoulos EN, Bairaktari ET, Goudevenos J, Elisaf MS. Hypomagnesemia and concurrent acid-base and electrolyte abnormalities in patients with congestive heart failure. Eur J Heart Fail. 2002;4:167–73.

    Article  CAS  Google Scholar 

  76. Karim A. Spironolactone: disposition, metabolism, pharmacodynamics and bioavailability. Drug Metab Rev. 1978;8:151–88.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Departments of Medicine and Physiology & Pharmacology, Oregon Health & Science University, Portland, OR, USA

    David H. Ellison

  2. Renal Section, VA Portland Health Care System, Portland, OR, USA

    David H. Ellison

  3. Division of Nephrology & Hypertension, Portland, OR, USA

    David H. Ellison

  4. Renal Section, South Texas Veterans Health Care System, San Antonio, TX, USA

    Shweta Bansal

  5. Division of Nephrology, Department of Medicine, University of Texas Health at San Antonio, San Antonio, TX, USA

    Shweta Bansal

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  1. David H. Ellison
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Correspondence to David H. Ellison .

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Editors and Affiliations

  1. Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH, USA

    W. H. Wilson Tang

  2. Department of Internal Medicine, UZ Leuven, Leuven, Belgium

    Frederik H. Verbrugge

  3. Ziekenhuis Oost-Limburg, Genk University Hasselt, Genk, Belgium

    Wilfried Mullens

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Ellison, D.H., Bansal, S. (2020). Insights on Diuretic Therapy from Clinical and Pharmacologic Perspectives. In: Tang, W., Verbrugge, F., Mullens, W. (eds) Cardiorenal Syndrome in Heart Failure. Springer, Cham. https://doi.org/10.1007/978-3-030-21033-5_5

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