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Use of thiazide diuretics in patients with primary (essential) hypertension

Johannes FE Mann, MD
Karl F Hilgers, MD
Section Editor
George L Bakris, MD
Deputy Editor
John P Forman, MD, MSc


Thiazide and thiazide-like diuretics have been a mainstay of the therapy of primary hypertension. The most popular agent in this class, hydrochlorothiazide, was traditionally used in doses of 50 to 100 mg/day. These doses were associated with metabolic and electrolyte complications. Low-dose therapy has since been demonstrated to be efficacious and to have a much lower incidence of side effects. Chlorthalidone and indapamide, both thiazide-like diuretics, have been shown to provide greater antihypertensive efficacy and, more importantly, to reduce cardiovascular events and mortality compared with hydrochlorothiazide (a thiazide-type diuretic) [1]. No trial has documented a mortality benefit from hydrochlorothiazide.

This topic will review the antihypertensive mechanisms of thiazide and thiazide-like therapy, the common side effects associated with high doses of these diuretics, and the benefits of low-dose therapy. The role of these drugs in the treatment of primary hypertension is discussed elsewhere. (See "Choice of drug therapy in primary (essential) hypertension".)


The mechanisms responsible for the decline in blood pressure (BP) are incompletely understood. The BP response appears to require initial volume loss (averaging about 1.5 kg) since it is not seen in patients who are resistant to the diuretic or who are ingesting a high-salt diet [2]. The BP in responders begins to fall within the first week, but a slow decline can continue for as long as 12 weeks [3]. Longer-acting diuretics are more effective than short-acting loop diuretics in patients with mild to moderate primary hypertension because they maintain the decline in intravascular volume. (See "Thiazides versus loop diuretics in the treatment of hypertension".)

The initial hypotensive response is mediated by a modest reduction in plasma volume and cardiac output [3,4]. However, the fall in BP is blunted by hypovolemia-induced activation of the renin-angiotensin system [2,5]. Thus, nonresponders to a thiazide or thiazide-like diuretic may have a diuresis that is equivalent to that in responders, but little or no reduction in BP due to a rise in systemic vascular resistance (figure 1) [3]. This relationship explains the synergistic response between a diuretic and an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB). These agents block either the generation or the effects of angiotensin II, thereby allowing the full antihypertensive effect of the diuretic to be expressed. (See "Renin-angiotensin system inhibition in the treatment of hypertension".)

Long-term maintenance of the decrease in BP is associated with partial reversal of the initial hemodynamic changes: the plasma volume and cardiac output partially rise toward the baseline level, while the systemic vascular resistance falls [3,4]. Despite near-normalization of the plasma volume, it is likely that the plasma volume remains low in relation to the vasodilation-induced increase in the vascular capacity. Two observations are consistent with this hypothesis: (1) the plasma renin activity is persistently elevated; and (2) discontinuation of the diuretic leads to rapid fluid retention before any reversal of the fall in systemic vascular resistance [6].

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Literature review current through: Nov 2017. | This topic last updated: Mar 08, 2017.
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  1. Kaplan NM. Chlorthalidone versus hydrochlorothiazide: a tale of tortoises and a hare. Hypertension 2011; 58:994.
  2. Freis ED, Reda DJ, Materson BJ. Volume (weight) loss and blood pressure response following thiazide diuretics. Hypertension 1988; 12:244.
  3. van Brummelen P, Man in 't Veld AJ, Schalekamp MA. Hemodynamic changes during long-term thiazide treatment of essential hypertension in responders and nonresponders. Clin Pharmacol Ther 1980; 27:328.
  4. Shah S, Khatri I, Freis ED. Mechanism of antihypertensive effect of thiazide diuretics. Am Heart J 1978; 95:611.
  5. Vaughan ED Jr, Carey RM, Peach MJ, et al. The renin response to diuretic therapyl A limitation of antihypertensive potential. Circ Res 1978; 42:376.
  6. Tarazi RC, Dustan HP, Frohlich ED. Long-term thiazide therapy in essential hypertension. Evidence for persistent alteration in plasma volume and renin activity. Circulation 1970; 41:709.
  7. Blaustein MP. Endogenous ouabain: role in the pathogenesis of hypertension. Kidney Int 1996; 49:1748.
  8. Pickkers P, Hughes AD, Russel FG, et al. Thiazide-induced vasodilation in humans is mediated by potassium channel activation. Hypertension 1998; 32:1071.
  9. Carlsen JE, Køber L, Torp-Pedersen C, Johansen P. Relation between dose of bendrofluazide, antihypertensive effect, and adverse biochemical effects. BMJ 1990; 300:975.
  10. Materson BJ, Cushman WC, Goldstein G, et al. Treatment of hypertension in the elderly: I. Blood pressure and clinical changes. Results of a Department of Veterans Affairs Cooperative Study. Hypertension 1990; 15:348.
  11. Psaty BM, Lumley T, Furberg CD, et al. Health outcomes associated with various antihypertensive therapies used as first-line agents: a network meta-analysis. JAMA 2003; 289:2534.
  12. Harper R, Ennis CN, Sheridan B, et al. Effects of low dose versus conventional dose thiazide diuretic on insulin action in essential hypertension. BMJ 1994; 309:226.
  13. Freis ED, Thomas JR, Fisher SG, et al. Effects of reduction in drugs or dosage after long-term control of systemic hypertension. Am J Cardiol 1989; 63:702.
  14. Savage PJ, Pressel SL, Curb JD, et al. Influence of long-term, low-dose, diuretic-based, antihypertensive therapy on glucose, lipid, uric acid, and potassium levels in older men and women with isolated systolic hypertension: The Systolic Hypertension in the Elderly Program. SHEP Cooperative Research Group. Arch Intern Med 1998; 158:741.
  15. Musini VM, Nazer M, Bassett K, Wright JM. Blood pressure-lowering efficacy of monotherapy with thiazide diuretics for primary hypertension. Cochrane Database Syst Rev 2014; :CD003824.
  16. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002; 288:2981.
  17. Wright JT Jr, Probstfield JL, Cushman WC, et al. ALLHAT findings revisited in the context of subsequent analyses, other trials, and meta-analyses. Arch Intern Med 2009; 169:832.
  18. Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). ALLHAT Collaborative Research Group. JAMA 2000; 283:1967.
  19. Ernst ME, Carter BL, Goerdt CJ, et al. Comparative antihypertensive effects of hydrochlorothiazide and chlorthalidone on ambulatory and office blood pressure. Hypertension 2006; 47:352.
  20. Ernst ME, Moser M. Use of diuretics in patients with hypertension. N Engl J Med 2009; 361:2153.
  21. Beckett NS, Peters R, Fletcher AE, et al. Treatment of hypertension in patients 80 years of age or older. N Engl J Med 2008; 358:1887.
  22. Patel A, ADVANCE Collaborative Group, MacMahon S, et al. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet 2007; 370:829.
  23. Leung AA, Wright A, Pazo V, et al. Risk of thiazide-induced hyponatremia in patients with hypertension. Am J Med 2011; 124:1064.
  24. Siscovick DS, Raghunathan TE, Psaty BM, et al. Diuretic therapy for hypertension and the risk of primary cardiac arrest. N Engl J Med 1994; 330:1852.
  25. Elliott WJ, Meyer PM. Incident diabetes in clinical trials of antihypertensive drugs: a network meta-analysis. Lancet 2007; 369:201.
  26. Hilgers KF, Mann JF. The choice of antihypertensive therapy in patients with the metabolic syndrome--time to change recommendations? Nephrol Dial Transplant 2008; 23:3389.
  27. Brown MJ, Williams B, Morant SV, et al. Effect of amiloride, or amiloride plus hydrochlorothiazide, versus hydrochlorothiazide on glucose tolerance and blood pressure (PATHWAY-3): a parallel-group, double-blind randomised phase 4 trial. Lancet Diabetes Endocrinol 2016; 4:136.
  28. Mancia G, Grassi G, Zanchetti A. New-onset diabetes and antihypertensive drugs. J Hypertens 2006; 24:3.
  29. Wassertheil-Smoller S, Blaufox MD, Oberman A, et al. Effect of antihypertensives on sexual function and quality of life: the TAIM Study. Ann Intern Med 1991; 114:613.