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Loop Diuretics in the Treatment of Hypertension

  • Antihypertensive Agents: Mechanisms of Drug Action (M Ernst, Section Editor)
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Abstract

Loop diuretics are not recommended in current hypertension guidelines largely due to the lack of outcome data. Nevertheless, they have been shown to lower blood pressure and to offer potential advantages over thiazide-type diuretics. Torsemide offers advantages of longer duration of action and once daily dosing (vs. furosemide and bumetanide) and more reliable bioavailability (vs. furosemide). Studies show that the previously employed high doses of thiazide-type diuretics lower BP more than furosemide. Loop diuretics appear to have a preferable side effect profile (less hyponatremia, hypokalemia, and possibly less glucose intolerance). Studies comparing efficacy and side effect profiles of loop diuretics with the lower, currently widely prescribed, thiazide doses are needed. Research is needed to fill gaps in knowledge and common misconceptions about loop diuretic use in hypertension and to determine their rightful place in the antihypertensive arsenal.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo Jr JL, et al. Seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure. Hypertension. 2003;42(6):1206–52. doi:10.1161/01.HYP.0000107251.49515.c2.

    Article  CAS  PubMed  Google Scholar 

  2. James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311(5):507–20. doi:10.1001/jama.2013.284427. Current North American guidelines for the treatment of hypertension.

    Article  CAS  PubMed  Google Scholar 

  3. Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Bohm M, et al. 2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J. 2013;34:2159–219. doi:10.1093/eurheartj/eht15110.1093/eurheartj/eht151. Current European guidelines for the treatment of hypertension.

    Article  PubMed  Google Scholar 

  4. Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, Germano G, et al. 2007 guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2007;25(6):1105–87. doi:10.1097/HJH.0b013e3281fc975a.

    Article  CAS  PubMed  Google Scholar 

  5. Tamargo J, Segura J, Ruilope LM. Diuretics in the treatment of hypertension. Part 2: loop diuretics and potassium-sparing agents. Expert Opin Pharmacother. 2014;15(5):605–21. doi:10.1517/14656566.2014.879117.

    Article  CAS  PubMed  Google Scholar 

  6. Ernst ME, Moser M. Use of diuretics in patients with hypertension. N Engl J Med. 2009;361(22):2153–64. doi:10.1056/NEJMra0907219.

    Article  CAS  PubMed  Google Scholar 

  7. Tu W, Pratt JH. A consideration of genetic mechanisms behind the development of hypertension in blacks. Curr Hypertens Rep. 2013;15(2):108–13. doi:10.1007/s11906-013-0332-9.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Chun TY, Bankir L, Eckert GJ, Bichet DG, Saha C, Zaidi SA, et al. Ethnic differences in renal responses to furosemide. Hypertension. 2008;52(2):241–8. doi:10.1161/hypertensionaha.108.109801.

    Article  CAS  PubMed  Google Scholar 

  9. Davidov M, Kakaviatos N, Finnerty Jr FA. Antihypertensive properties of furosemide. Circulation. 1967;36(1):125–35.

    Article  CAS  PubMed  Google Scholar 

  10. Healy JJ, McKenna TJ, Canning BS, Brien TG, Duffy GJ, Muldowney FP. Body composition changes in hypertensive subjects on long-term oral diuretic therapy. Br Med J. 1970;1(5698):716–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Orlov SN, Tremblay J, Hamet P. NKCC1 and hypertension: a novel therapeutic target involved in the regulation of vascular tone and renal function. Curr Opin Nephrol Hypertens. 2010;19(2):163–8. doi:10.1097/MNH.0b013e3283360a46.

    Article  CAS  PubMed  Google Scholar 

  12. Fortuno A, Muniz P, Ravassa S, Rodriguez JA, Fortuno MA, Zalba G, et al. Torasemide inhibits angiotensin II-induced vasoconstriction and intracellular calcium increase in the aorta of spontaneously hypertensive rats. Hypertension. 1999;34(1):138–43.

    Article  CAS  PubMed  Google Scholar 

  13. Hocherl K, Kees F, Kramer BK, Kurtz A. Cyclosporine A attenuates the natriuretic action of loop diuretics by inhibition of renal COX-2 expression. Kidney Int. 2004;65(6):2071–80. doi:10.1111/j.1523-1755.2004.00627.x.

    Article  PubMed  Google Scholar 

  14. Harris RC, Zhang MZ, Cheng HF. Cyclooxygenase-2 and the renal renin-angiotensin system. Acta Physiol Scand. 2004;181(4):543–7. doi:10.1111/j.1365-201X.2004.01329.x.

    Article  CAS  PubMed  Google Scholar 

  15. Matzdorf C, Kurtz A, Hocherl K. COX-2 activity determines the level of renin expression but is dispensable for acute upregulation of renin expression in rat kidneys. Am J Physiol Ren Physiol. 2007;292(6):F1782–90. doi:10.1152/ajprenal.00513.2006.

    Article  CAS  Google Scholar 

  16. Musini VM, Rezapour P, Wright JM, Bassett K, Jauca CD. Blood pressure-lowering efficacy of loop diuretics for primary hypertension. Cochrane Database Syst Rev. 2015;5, CD003825. doi:10.1002/14651858.CD003825.pub4. Interesting review of antihypertensive effects of loop diuretics.

    PubMed  Google Scholar 

  17. Wertheimer L, Finnerty Jr FA, Bercu BA, Hall RH. Furosemide in essential hypertension. A statistical analysis of three double-blind studies. Arch Intern Med. 1971;127(5):934–8.

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  19. Spannbrucker N, Achhammer I, Metz P, Glocke M. Comparative study on the antihypertensive efficacy of torasemide and indapamide in patients with essential hypertension. Arzneimittelforschung. 1988;38(1A):190–3.

    CAS  PubMed  Google Scholar 

  20. Dupont AG, Schoors D, Six RO, Vanhaelst L. Antihypertensive efficacy of low dose torasemide in essential hypertension: a placebo-controlled study. J Hum Hypertens. 1988;2(4):265–8.

    CAS  PubMed  Google Scholar 

  21. Baumgart P. Torasemide in comparison with thiazides in the treatment of hypertension. Cardiovasc Drugs Ther. 1993;7 Suppl 1:63–8.

    Article  PubMed  Google Scholar 

  22. Brater DC. Clinical pharmacology of loop diuretics. Drugs. 1991;41 Suppl 3:14–22.

    Article  PubMed  Google Scholar 

  23. Vasavada N, Saha C, Agarwal R. A double-blind randomized crossover trial of two loop diuretics in chronic kidney disease. Kidney Int. 2003;64(2):632–40. doi:10.1046/j.1523-1755.2003.00124.x.

    Article  CAS  PubMed  Google Scholar 

  24. Knauf H, Mutschler E. Diuretic effectiveness of hydrochlorothiazide and furosemide alone and in combination in chronic renal failure. J Cardiovasc Pharmacol. 1995;26(3):394–400.

    Article  CAS  PubMed  Google Scholar 

  25. Agarwal R, Sinha AD, Pappas MK, Ammous F. Chlorthalidone for poorly controlled hypertension in chronic kidney disease: an interventional pilot study. Am J Nephrol. 2014;39(2):171–82. doi:10.1159/000358603.

    Article  CAS  PubMed  Google Scholar 

  26. Broekhuysen J, Deger F, Douchamps J, Ducarne H, Herchuelz A. Torasemide, a new potent diuretic. Double-blind comparison with furosemide. Eur J Clin Pharmacol. 1986;31(Suppl):29–34.

    Article  PubMed  Google Scholar 

  27. Dunn CJ, Fitton A, Brogden RN. Torasemide. An update of its pharmacological properties and therapeutic efficacy. Drugs. 1995;49:121–42.

    Article  CAS  PubMed  Google Scholar 

  28. Knauf H, Mutschler E. Clinical pharmacokinetics and pharmacodynamics of torasemide. Clin Pharmacokinet. 1998;34(1):1–24. doi:10.2165/00003088-199834010-00001.

    Article  CAS  PubMed  Google Scholar 

  29. Luft FC. Torasemide in the treatment of arterial hypertension. J Cardiovasc Pharmacol. 1993;22 Suppl 3:S32–9.

    Article  PubMed  Google Scholar 

  30. Vlase H. Effectiveness of furosemide in uncontrolled hypertension in the elderly: role of renin profiling. Am J Hypertens. 2003;16(3):187–93. doi:10.1016/s0895-7061(02)03260-0.

    Article  CAS  PubMed  Google Scholar 

  31. Vadasz TA, Chadha DR. Experience with once-daily and twice-daily slow-release frusemide in hypertension. J Int Med Res. 1982;10(4):199–203.

    CAS  PubMed  Google Scholar 

  32. Araoye MA, Chang MY, Khatri IM, Freis ED. Furosemide compared with hydrochlorothiazide. Long-term treatment of hypertension. JAMA. 1978;240(17):1863–6.

    Article  CAS  PubMed  Google Scholar 

  33. Finnerty Jr FA, Maxwell MH, Lunn J, Moser M. Long-term effects of furosemide and hydrochlorothiazide in patients with essential hypertension a two-year comparison of efficacy and safety. Angiology. 1977;28(2):125–33.

    Article  PubMed  Google Scholar 

  34. Valmin K, Hansen T. Treatment of benign essential hypertension: comparison of furosemide and hydrochlorothiazide. Eur J Clin Pharmacol. 1975;8(6):393–401.

    Article  CAS  PubMed  Google Scholar 

  35. Ram CV, Garrett BN, Kaplan NM. Moderate sodium restriction and various diuretics in the treatment of hypertension. Arch Intern Med. 1981;141(8):1015–9.

    Article  CAS  PubMed  Google Scholar 

  36. Anderson J, Godfrey BE, Hill DM, Munro-Faure AD, Sheldon J. A comparison of the effects of hydrochlorothiazide and of frusemide in the treatment of hypertensive patients. Q J Med. 1971;40:541–60.

    CAS  PubMed  Google Scholar 

  37. Taler SJ, Textor SC, Augustine JE. Resistant hypertension: comparing hemodynamic management to specialist care. Hypertension. 2002;39(5):982–8.

    Article  CAS  PubMed  Google Scholar 

  38. Vaughan Jr ED, Laragh JH, Gavras I, Bühler FR, Gavras H, Brunner HR, et al. Volume factor in low and normal renin essential hypertension: treatment with either spironolactone or chlorthalidone. Am J Cardiol. 1973;32(4):523–32. doi:10.1016/S0002-9149(73)80044-X.

    Article  PubMed  Google Scholar 

  39. Mann SJ, Ernst ME. Personalizing the diuretic treatment of hypertension: the need for more clinical and research attention. Curr Hypertens Rep. 2015;17(4):542. doi:10.1007/s11906-015-0542-4. Review of subtleties of diuretic use in hypertension.

    Article  PubMed  Google Scholar 

  40. Egan BM, Basile JN, Rehman SU, Davis PB, Grob 3rd CH, Riehle JF, et al. Plasma Renin test-guided drug treatment algorithm for correcting patients with treated but uncontrolled hypertension: a randomized controlled trial. Am J Hypertens. 2009;22(7):792–801. doi:10.1038/ajh.2009.63.

    Article  CAS  PubMed  Google Scholar 

  41. Wilcox CS, Mitch WE, Kelly RA, Skorecki K, Meyer TW, Friedman PA, et al. 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 

  42. Ellison DH. Diuretic resistance: physiology and therapeutics. Semin Nephrol. 1999;19(6):581–97.

    CAS  PubMed  Google Scholar 

  43. Yakovlevitch M, Black HR. Resistant hypertension in a tertiary care clinic. Arch Intern Med. 1991;151:1786–92.

    Article  CAS  PubMed  Google Scholar 

  44. Shen W, Khwaja F, Feig PU, Shah S, Wilcox C. A novel extended release formulation of torsemide enhances natriuresis without lowering Gfr in normal human subjects. J Am Coll Cardiol. 2014;63(12_S). doi: 10.1016/S0735-1097(14)61401-7

  45. Lambe R, Kennedy O, Kenny M, Darragh A. Study of the tolerance and diuretic properties of torasemide following oral or intravenous administration to healthy volunteers. Eur J Clin Pharmacol. 1986;31(Suppl):9–14.

    Article  CAS  PubMed  Google Scholar 

  46. Reyes AJ, Leary WP. Renal excretory responses to single and repeated administration of diuretics in healthy subjects: clinical connotations. Cardiovasc Drugs Ther. 1993;7 Suppl 1:29–44.

    Article  PubMed  Google Scholar 

  47. Uchida T, Yamanaga K, Nishikawa M, Ohtaki Y, Kido H, Watanabe M. Anti-aldosteronergic effect of torasemide. Eur J Pharmacol. 1991;205(2):145–50.

    Article  CAS  PubMed  Google Scholar 

  48. McAdams DeMarco MA, Maynard JW, Baer AN, Gelber AC, Young JH, Alonso A, et al. Diuretic use, increased serum urate levels, and risk of incident gout in a population-based study of adults with hypertension: the Atherosclerosis Risk in Communities cohort study. Arthritis Rheum. 2012;64(1):121–9. doi:10.1002/art.33315.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Holland OB, Pool PE. Metabolic changes with antihypertensive therapy of the salt-sensitive patient. Am J Cardiol. 1988;61(16):53H–9H.

    Article  CAS  PubMed  Google Scholar 

  50. Jackson WP, Nellen M. Effect of frusemide on carbohydrate metabolism, blood-pressure, and other modalities. A comparison with chlorothiazide. Br Med J. 1966;2(5509):333–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Mann SJ. The silent epidemic of thiazide-induced hyponatremia. J Clin Hypertens (Greenwich). 2008;10(6):477–84.

    Article  CAS  Google Scholar 

  52. Spital A. Diuretic-induced hyponatremia. Am J Nephrol. 1999;19(4):447–52. doi:13496.

    Article  CAS  PubMed  Google Scholar 

  53. Kazory A. Hyponatremia in heart failure: revisiting pathophysiology and therapeutic strategies. Clin Cardiol. 2010;33(6):322–9. doi:10.1002/clc.20791.

    Article  PubMed  Google Scholar 

  54. Porzio P, Halberthal M, Bohn D, Halperin ML. Treatment of acute hyponatremia: ensuring the excretion of a predictable amount of electrolyte-free water. Crit Care Med. 2000;28(6):1905–10.

    Article  CAS  PubMed  Google Scholar 

  55. Sunderam SG, Mankikar GD. Hyponatraemia in the elderly. Age Ageing. 1983;12(1):77–80.

    Article  CAS  PubMed  Google Scholar 

  56. Sonnenblick M, Friedlander Y, Rosin AJ. Diuretic-induced severe hyponatremia. Review and analysis of 129 reported patients. Chest. 1993;103(2):601–6.

    Article  CAS  PubMed  Google Scholar 

  57. Byatt CM, Millard PH, Levin GE. Diuretics and electrolyte disturbances in 1000 consecutive geriatric admissions. J R Soc Med. 1990;83(11):704–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Wright Jr JT, Williamson JD, Whelton PK, Snyder JK, Sink KM, Rocco MV, et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 2015;373(22):2103–16. doi:10.1056/NEJMoa1511939.

    Article  PubMed  Google Scholar 

  59. Garrison SR, Dormuth CR, Morrow RL, Carney GA, Khan KM. Nocturnal leg cramps and prescription use that precedes them: a sequence symmetry analysis. Arch Intern Med. 2012;172(2):120–6. doi:10.1001/archinternmed.2011.1029.

    Article  PubMed  Google Scholar 

  60. Ikeda K, Oshima T, Hidaka H, Takasaka T. Molecular and clinical implications of loop diuretic ototoxicity. Hear Res. 1997;107(1–2):1–8.

    Article  CAS  PubMed  Google Scholar 

  61. Salvador DR, Rey NR, Ramos GC, Punzalan FE. Continuous infusion versus bolus injection of loop diuretics in congestive heart failure. Cochrane Database Syst Rev. 2004;1, CD003178. doi:10.1002/14651858.CD003178.pub2.

    PubMed  Google Scholar 

  62. Gallagher KL, Jones JK. Furosemide-induced ototoxicity. Ann Intern Med. 1979;91(5):744–5.

    Article  CAS  PubMed  Google Scholar 

  63. Brown CB, Ogg CS, Cameron JS. High dose frusemide in acute renal failure: a controlled trial. Clin Nephrol. 1981;15(2):90–6.

    CAS  PubMed  Google Scholar 

  64. Wulf NR, Matuszewski KA. Sulfonamide cross-reactivity: is there evidence to support broad cross-allergenicity? Am J Health Syst Pharm. 2013;70(17):1483–94. doi:10.2146/ajhp120291.

    Article  CAS  PubMed  Google Scholar 

  65. Strom BL, Schinnar R, Apter AJ, Margolis DJ, Lautenbach E, Hennessy S, et al. Absence of cross-reactivity between sulfonamide antibiotics and sulfonamide nonantibiotics. N Engl J Med. 2003;349(17):1628–35. doi:10.1056/NEJMoa022963.

    Article  CAS  PubMed  Google Scholar 

  66. Loon NR, Wilcox CS, Unwin RJ. Mechanism of impaired natriuretic response to furosemide during prolonged therapy. Kidney Int. 1989;36(4):682–9.

    Article  CAS  PubMed  Google Scholar 

  67. Dussol B, Moussi-Frances J, Morange S, Somma-Delpero C, Mundler O, Berland Y. A pilot study comparing furosemide and hydrochlorothiazide in patients with hypertension and stage 4 or 5 chronic kidney disease. J Clin Hypertens (Greenwich). 2012;14(1):32–7. doi:10.1111/j.1751-7176.2011.00564.x. Interesting article challenging the common misconception that thiazide diuretics have no effect in patients with kidney disease.

    Article  Google Scholar 

  68. Wollam GL, Tarazi RC, Bravo EL, Dustan HP. Diuretic potency of combined hydrochlorothiazide and furosemide therapy in patients with azotemia. Am J Med. 1982;72(6):929–38.

    Article  CAS  PubMed  Google Scholar 

  69. Setaro JF, Black HR. Refractory hypertension. N Engl J Med. 1992;327(8):543–7. doi:10.1056/nejm199208203270808.

    Article  CAS  PubMed  Google Scholar 

  70. Ellison DH. The physiologic basis of diuretic synergism: its role in treating diuretic resistance. Ann Intern Med. 1991;114(10):886–94.

    Article  CAS  PubMed  Google Scholar 

  71. Laragh JH, Sealey JE. The plasma renin test reveals the contribution of body sodium-volume content (V) and renin-angiotensin (R) vasoconstriction to long-term blood pressure. Am J Hypertens. 2011;24(11):1164–80. doi:10.1038/ajh.2011.171.

    Article  CAS  PubMed  Google Scholar 

  72. Cody RJ, Laragh JH, Case DB, Atlas SA. Renin system activity as a determinant of response to treatment in hypertension and heart failure. Hypertension. 1983;5(5 Pt 2):III36–42.

    CAS  PubMed  Google Scholar 

  73. Ramsay LE, Silas JH, Freestone S. Diuretic treatment of resistant hypertension. Br Med J. 1980;281(6248):1101–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Verdalles U, de Vinuesa SG, Goicoechea M, Quiroga B, Reque J, Panizo N, et al. Utility of bioimpedance spectroscopy (BIS) in the management of refractory hypertension in patients with chronic kidney disease (CKD). Nephrol Dial Transplant. 2012;27 Suppl 4:iv31–5. doi:10.1093/ndt/gfs420.

    Article  PubMed  Google Scholar 

  75. Molnar J, Somberg JC. The clinical pharmacology of ethacrynic acid. Am J Ther. 2009;16(1):86–92. doi:10.1097/MJT.0b013e318195e460.

    Article  PubMed  Google Scholar 

  76. Porcellati C, Verdecchia P, Schillaci G, Guerrieri M, Boldrini F, Gatteschi C, et al. Torasemide treatment of arterial hypertension. Basi Razionali della Terapia. 1990;20(5):407–10.

    Google Scholar 

  77. Reyes AJ, Chiesa PD, Santucci MR, Batista LB, Olhaberry JV, Mosler AL, 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 

  78. Boelke T, Achhammer I, Meyer-Sabellek WA. Blutdrucksenkung und metabolische Veranderungen bei essentiellen Hypertonikern nach Langzeitgabe unterschiedlicher Diuretika. Hochdruck. 1990;9:40–1.

    Google Scholar 

  79. Boelke T, Achhammer I, Meyer-Sabellek WA, et al. Tagesund Nachrthythmik ambulanter 24-h Blutdruckwerte von alteren essentiellen Hypertonikern bei Therapie mit verschiedenen Antihypertonika. Hochdruck. 1990;10.

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  1. Department of Nephrology and Hypertension, Hypertension Center, NY Presbyterian Hospital–Weill Cornell Medicine, 424 E. 70th Street, New York, NY, 10021, USA

    Line Malha & Samuel J. Mann

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Malha, L., Mann, S.J. Loop Diuretics in the Treatment of Hypertension. Curr Hypertens Rep 18, 27 (2016). https://doi.org/10.1007/s11906-016-0636-7

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