Version May 2024
INTRODUCTION — 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".)
ANTIHYPERTENSIVE MECHANISM — The mechanisms responsible for the decline in blood pressure (BP) are incompletely understood. The BP response appears to require initial volume loss (averaging approximately 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].
Mechanism of vasodilation — The secondary vasodilatory response with thiazide diuretics is modest, is most pronounced with longer-acting drugs such as chlorthalidone and indapamide, and has only a minor role in long-term BP reduction with these agents.
The factors responsible for the secondary vasodilation remain unclear. One hypothesis has proposed a central role for a circulating endogenous digitalis-like natriuretic hormone (distinct from atrial natriuretic peptide) that inhibits the cellular Na-K-ATPase pump [7]. Chlorthalidone and indapamide could diminish the secretion of this hormone, leading sequentially to a rise in Na-K-ATPase activity, a fall in cell sodium concentration (since more sodium is pumped out of the cell), and increased calcium efflux from the cells. The ensuing decline in the cell calcium concentration then leads to vasodilation and a fall in systemic vascular resistance. This theory, however, has yet to be confirmed.
Another possibility is a direct effect upon potassium channels. Modest vasodilation of the forearm in response to hydrochlorothiazide can be abolished with the concurrent administration of tetraethylammonium, a calcium-activated potassium channel blocker [8]. Since this is only observed with high doses of hydrochlorothiazide, it is unclear whether a similar effect occurs in patients undergoing chronic low-dose therapy.
EFFICACY AND SAFETY
Efficacy of low-dose therapy — In patients with primary hypertension and normal kidney function, thiazide-type and thiazide-like diuretics are typically used at low doses (eg, 12.5 to 25 mg/day of chlorthalidone or hydrochlorothiazide, or 1.25 mg/day of indapamide) to minimize metabolic complications while maintaining the antihypertensive response [9-15].
Although higher diuretic doses tend to produce more fluid loss, there may be little or no greater antihypertensive effect because of greater activation of the renin-angiotensin system [5]. More potent thiazide diuretics (ie, chlorthalidone, indapamide), or the use of loop diuretics, may be required in patients with resistant hypertension and/or advanced chronic kidney disease [16]. (See "Treatment of resistant hypertension" and "Thiazides versus loop diuretics in the treatment of hypertension", section on 'Patients with chronic kidney disease'.)
Used at low doses, the fall in blood pressure (BP) is significantly larger with chlorthalidone and indapamide as compared with hydrochlorothiazide; in addition, both chlorthalidone and indapamide have been shown to reduce cardiovascular events in randomized trials, whereas there is no evidence that low-dose hydrochlorothiazide alone reduces cardiovascular events:
●The benefits of low-dose chlorthalidone (12.5 mg/day increased to a maximum of 25 mg/day) were illustrated in the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), in which it was compared with amlodipine, lisinopril, and doxazosin (the doxazosin arm was prematurely terminated because of an increased risk of heart failure) [17-19]. After almost five years of follow-up, each antihypertensive agent successfully lowered BP (with the goal of less than 140/90 mmHg achieved in approximately 75 percent of patients). Compared with amlodipine and lisinopril, chlorthalidone was associated with the same frequency of the primary end point of cardiovascular death or nonfatal myocardial infarction (figure 2) but was associated with a significantly lower rate of heart failure (figure 3) and, compared with lisinopril, stroke (figure 4) [17]. The interpretation of these findings, however, was somewhat hampered by the fact that the chlorthalidone-based regimen lowered systolic BP more than either the calcium channel blocker-based or the angiotensin-converting enzyme (ACE) inhibitor-based regimen [17]. (See "Choice of drug therapy in primary (essential) hypertension".)
Chlorthalidone is 1.5 to 2 times as effective as hydrochlorothiazide at lowering BP at the same dose given its longer duration of action [20,21]. Thus, although some guidelines recommend 12.5 to 25 mg/day of either drug, one cannot assume that the benefits of chlorthalidone in trials such as ALLHAT would have been replicated with similar doses of hydrochlorothiazide. (See "Choice of drug therapy in primary (essential) hypertension".)
●Indapamide was shown to reduce cardiovascular events in two large trials, including the Hypertension in the Very Elderly Trial (HYVET; in which it was used as initial monotherapy) and the Action in Diabetes and Vascular Disease-PreterAx and DiamicroN Controlled Evaluation (ADVANCE; in which it was given as a fixed-dose combination with perindopril) [22,23]. As with chlorthalidone, indapamide is a more potent antihypertensive agent than hydrochlorothiazide. (See "Choice of drug therapy in primary (essential) hypertension".)
As a result, some experts suggest chlorthalidone (12.5 to 25 mg/day) or indapamide (1.25 to 2.5 mg/day) as the low-dose diuretic of choice. This issue is discussed in detail elsewhere. (See "Choice of drug therapy in primary (essential) hypertension".)
Side effects — The potential adverse metabolic effects of thiazide and thiazide-like therapy include:
●Dose-dependent metabolic effects – Thiazide diuretics are associated with hypokalemia, hyponatremia, hyperuricemia, hyperglycemia, hyperlipidemia, hypomagnesemia and, occasionally, hypercalcemia. The incidence and magnitude of these side effects are lower with low-dose therapy (figure 5). (See 'Dose-dependent metabolic effects' below and "Diuretics and calcium balance", section on 'Clinical implications'.)
●Non-dose-dependent effects – Thiazide diuretics are associated with sexual dysfunction and sleep disturbance. (See 'Non-dose-dependent side effects' below.)
Dose-dependent metabolic effects — Hypokalemia, hyponatremia [24], hyperuricemia, elevations in the plasma glucose and cholesterol concentrations, and magnesium depletion can all result from thiazide diuretics [9]. The incidence and magnitude of these side effects are much lower with low-dose therapy (eg, 12.5 to 25 mg/day of hydrochlorothiazide or chlorthalidone or 1.25 mg/day of indapamide), as commonly used in the treatment of primary hypertension (figure 5) [9,14,15]. By contrast, hypertensive patients who are treated with high doses of a diuretic without a potassium-sparing agent have an increased incidence of sudden cardiac death, presumably as a result of these metabolic disturbances [25]. The incidence of these metabolic perturbations is greater with low doses of chlorthalidone than with low doses of hydrochlorothiazide and indapamide [15].
●(See 'Efficacy of low-dose therapy' above.)
●(See "Causes of hypokalemia in adults", section on 'Diuretics'.)
●(See "Diuretic-induced hyponatremia".)
●(See "Diuretic-induced hyperuricemia and gout".)
●(See "Antihypertensive drugs and lipids".)
●(See "Diuretics and calcium balance".)
●(See "Effect of diuretics on magnesium handling by the kidney".)
In ALLHAT, chlorthalidone was associated with a mean reduction in plasma potassium of 0.2 mEq/L, and 8.5 percent of patients required potassium supplements. In addition, chlorthalidone increased the incidence of type 2 diabetes, defined as a fasting blood glucose value of ≥126 mg/dL (7 mmol/L), compared with amlodipine and lisinopril (11.6 versus 9.8 and 8.1 percent, respectively). An increase in risk for new-onset diabetes with thiazide diuretics was also noted in a meta-analysis of trials of antihypertensive agents [26]. The long-term sequelae of new-onset diabetes cannot be appreciated in the usual time frame of trials comparing antihypertensive drugs (which is usually four to five years) [27].
Some of the adverse effects of thiazide diuretics can be alleviated by combining them with certain other drug classes. The risk of hypokalemia, for example, may be minimized by combining thiazides with ACE inhibitors, angiotensin II receptor blockers (ARBs), mineralocorticoid receptor antagonists (eg, spironolactone), or blockers of the epithelial sodium channel (eg, amiloride). These drugs lower BP, which may reduce the required diuretic dose, and prevent renal potassium excretion, which can counteract the hypokalemia associated with diuretics. The same drug classes can also alleviate the impaired glucose tolerance associated with thiazides [28,29]. (See "Renin-angiotensin system inhibition in the treatment of hypertension" and "Causes and evaluation of hyperkalemia in adults", section on 'Reduced urinary potassium excretion'.)
A low-sodium diet, which is recommended for all hypertensive patients, will also reduce the required dose of diuretic and limit the incidence of hypokalemia by reducing sodium delivery to the distal nephron. (See "Salt intake and hypertension" and "Causes of hypokalemia in adults", section on 'Increased urinary losses'.)
Conversely, beta blockers are known to aggravate the perturbations of glucose metabolism associated with thiazides [30].
Other dose-dependent side effects — Hydrochlorothiazide enhances DNA damage induced by ultraviolet radiation and therefore may increase the risk of skin cancer [31].
In a large, Danish, case-control study, the use of hydrochlorothiazide was associated with squamous cell carcinoma of the lip and also with nonmelanoma skin cancers [32,33]. No association was observed with other diuretics or antihypertensive medications. The risk with hydrochlorothiazide was dose dependent and was evident only with large cumulative doses. This implies that prior randomized trials of hydrochlorothiazide, in which patients were typically followed for fewer than five years, would not have detected this relationship.
Thiazide-like diuretics (indapamide, chlorthalidone) are used much less frequently than hydrochlorothiazide [34]; fewer data are therefore available, although one study found an association between indapamide and skin cancer [35].
Non-dose-dependent side effects — Although low-dose therapy seems to minimize the metabolic complications induced by a thiazide or thiazide-like diuretic, it may not necessarily eliminate other side effects. As an example, as many as 25 percent of men treated with 25 mg/day of chlorthalidone develop a decline in sexual function [36]. Sleep disturbances can also occur, particularly if the patient is on a low-sodium diet [36]. How these problems occur is not known.
Monitoring — Diuretics may induce changes in several laboratory parameters, including reduced serum levels of sodium and potassium and raised serum levels of bicarbonate, creatinine (if the patient becomes hypovolemic), uric acid, and glucose.
●(See "Diuretic-induced hyponatremia".)
●(See "Causes of hypokalemia in adults", section on 'Increased urinary losses'.)
●(See "Causes of metabolic alkalosis", section on 'Excessive renal hydrogen loss'.)
●(See "Diuretic-induced hyperuricemia and gout".)
●(See "Pathogenesis of type 2 diabetes mellitus", section on 'Drug-induced hyperglycemia'.)
Strong data regarding how and when to monitor for these abnormalities are lacking. We usually measure these parameters once within the first one to two weeks of initiating treatment and again after 6 to 12 months. We monitor more frequently if the dose is intensified or if the patient becomes symptomatic and the diuretic is thought to be at least in part responsible for the symptoms (for example, if dizziness or cardiac rhythm abnormalities are reported).
In addition, we instruct patients to temporarily halt their diuretics if they develop an intermittent disorder that can contribute to hypovolemia, such as diarrhea, vomiting or decreased food intake, or fever. Once the intermittent illness resolves, the diuretic can be resumed.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hypertension in adults".)
SUMMARY
●The mechanisms responsible for the decline in blood pressure (BP) with thiazide diuretics are incompletely understood. The BP response appears to require initial volume loss since it is not seen in patients who are resistant to the diuretic or who are ingesting a high-salt diet. The BP in responders begins to fall within the first week, but a slow decline can continue for as long as 12 weeks. 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. The fall in BP is blunted by hypovolemia-induced activation of the renin-angiotensin system. 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 (secondary vasodilation). (See 'Antihypertensive mechanism' above.)
●In patients with primary hypertension and normal kidney function, thiazide-type and thiazide-like diuretics are typically used at low doses (eg, 12.5 to 25 mg/day of chlorthalidone or hydrochlorothiazide, or 1.25 mg/day of indapamide) to minimize metabolic complications while maintaining the antihypertensive response. Although higher diuretic doses tend to produce more fluid loss, there may be little or no greater antihypertensive effect because of greater activation of the renin-angiotensin system. (See 'Efficacy of low-dose therapy' above.)
●Used at low doses, the fall in BP is significantly larger with chlorthalidone and indapamide as compared with hydrochlorothiazide; in addition, both chlorthalidone and indapamide have been shown to reduce cardiovascular events in randomized trials, whereas there is no evidence that low-dose hydrochlorothiazide alone reduces cardiovascular events. As a result, some experts suggest chlorthalidone (12.5 to 25 mg/day) or indapamide (1.25 to 2.5 mg/day) as the low-dose diuretic of choice. (See 'Efficacy of low-dose therapy' above and "Choice of drug therapy in primary (essential) hypertension".)
●The potential adverse metabolic and other effects of thiazide therapy include (see 'Side effects' above):
•Dose-dependent metabolic effects – Thiazide diuretics are associated with hypokalemia, hyponatremia, hyperuricemia, hyperglycemia, hyperlipidemia, and hypomagnesemia. The incidence and magnitude of these side effects are lower with low-dose therapy (figure 5). (See 'Dose-dependent metabolic effects' above.)
The risk of hypokalemia, for example, may be minimized by combining thiazides with angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), mineralocorticoid receptor antagonists (eg, spironolactone), or blockers of the epithelial sodium channel (eg, amiloride). A low-sodium diet will reduce the required dose of the diuretic and also limit the incidence of hypokalemia by reducing sodium delivery to the distal nephron. Conversely, beta blockers are known to aggravate the perturbations of glucose metabolism associated with thiazides.
•Other dose-dependent effects – Large cumulative doses of thiazide diuretics may increase the risk of squamous cell carcinoma of the lip and other nonmelanoma skin cancers.
•Non-dose-dependent effects – Thiazide diuretics are associated with sexual dysfunction and sleep disturbance. (See 'Non-dose-dependent side effects' above.)
●We usually measure the serum sodium, potassium, and creatinine once within the first one to two weeks after initiating treatment and again after 6 to 12 months. We monitor more frequently if the dose is intensified or if the patient becomes symptomatic and the diuretic is thought to be at least in part responsible for the symptoms.
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Norman Kaplan, MD, who contributed to earlier versions of this topic review.
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