Diuretics for hypertension: Hydrochlorothiazide or chlorthalidone?

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ABSTRACTThiazide diuretics are the cornerstone of treatment of hypertension in most patients. Hydrochlorothiazide is the most commonly used thiazide diuretic in the United States, but interest in chlorthalidone is increasing. The authors summarize the literature comparing these two agents.


  • Chlorthalidone has a longer duration of action and a longer half-life than hydrochlorothiazide.
  • Chlorthalidone may be more potent than hydrochlorothiazide in lowering blood pressure, but it also may be associated with more metabolic adverse effects, such as hypokalemia.
  • No study has conclusively shown either drug to be better in preventing adverse clinical outcomes.
  • These differences should be considered when making choices about thiazide diuretic therapy for hypertension.



The thiazide diuretic hydrochlorothiazide and the thiazidelike diuretic chlorthalidone are two old drugs that are still useful. Although similar, they differ in important ways still not fully appreciated more than a half century after they were introduced.

Most hypertension guidelines recommend thiazide diuretics as one of the classes of agents that can be used either as initial antihypertensive drug therapy or as part of combination therapy.1–3

In the United States, hydrochlorothiazide is used more often than chlorthalidone, but many clinical trials of antihypertensive therapy have used chlorthalidone.4,5 In recent years, particularly after the publication of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), interest in chlorthalidone has been increasing, and new data are now available comparing these two diuretics.6 While current US guidelines do not recommend one over the other, British guidelines prefer chlorthalidone.7

This review summarizes the data comparing the two drugs’ pharmacology, antihypertensive effect, and impact on clinical outcomes to help guide clinicians in choosing antihypertensive drug therapy.


Many of the differences in effectiveness and adverse effects of hydrochlorothiazide and chlorthalidone are thought to be due to their different pharmacodynamic and pharmacokinetic effects.

Pharmacodynamic effects

Figure 1. Although the chemical structures of hydrochlorothiazide (top) and chlorthalidone (bottom) differ, they both contain a sulfonamide group that inhibits carbonic anhydrase activity. This action may be associated with lower vascular contractility.

Hydrochlorothiazide and chlorthalidone differ significantly in chemical structure (Figure 1), but both contain a sulfonamide group that inhibits carbonic anhydrase activity, which may be associated with lower vascular contractility. Both drugs are concentrated in the kidney and secreted into the tubular lumen8; therefore, their therapeutic diuretic effects are often achieved with relatively low plasma concentrations.

Both drugs inhibit the sodium-chloride cotransporter in the luminal membrane of the distal convoluted tubule of the ascending loop of Henle, leading to a modest natriuresis and diuresis. The exact mechanism by which they lower blood pressure is not known: while the initial response is from diuresis and volume changes, long-term reduction in blood pressure is through uncertain mechanisms. In addition, chlorthalidone may have beneficial effects on endothelial function and oxidative stress.9,10

Both drugs also increase secretion of potassium and hydrogen ions and promote increased reabsorption of calcium through increased expression of a sodium-calcium exchange channel.8 Chlorthalidone may cause more inhibition of carbonic anhydrase than hydrochlorothiazide, which can lead to lower intracellular pH and cell volume. This effect may in part explain a pleiotropic effect of chlorthalidone, ie, inhibition of platelet function, which in turn may contribute to this drug’s beneficial effect on cardiovascular outcomes.9

Pharmacokinetic differences

Hydrochlorothiazide and chlorthalidone have important differences in their pharmacokinetic properties (Table 1).11

Hydrochlorothiazide has its onset of action in about 2 hours, and it reaches its peak in 4 to 6 hours. Though its duration of action is short—up to 12 hours—its pharmacodynamic response can be much longer than predicted by its kinetics, allowing once-daily dosing.8

Chlorthalidone has a longer duration of action than hydrochlorothiazide. This may be because it has a very high volume of distribution, since it is taken up into red blood cells and is bound to carbonic anhydrase.12 This may result in a “drug reservoir” that keeps drug levels higher for a longer time.13 Its long duration of action makes it a favorable choice for patients who have difficulty adhering to medication instructions. In addition, a missed dose is unlikely to have a “rebound” effect like that seen with some other antihypertensive agents. However, both chlorthalidone and hydrochlorothiazide are effective if taken once daily.


Both hydrochlorothiazide and chlorthalidone are effective antihypertensive agents. Table 2 summarizes findings from studies that evaluated their blood pressure-lowering effect at various doses.14–33 However, relatively few studies have directly compared these two agents’ effects on blood pressure.

Ernst et al,34 in a small study (but probably the best one to address this issue), compared chlorthalidone 12.5 mg/day (force-titrated to 25 mg/day) and hydrochlorothiazide 25 mg/day (force-titrated to 50 mg/day) in untreated hypertensive patients. After 8 weeks, ambulatory blood pressure monitoring indicated a greater reduction from baseline in systolic blood pressure with chlorthalidone 25 mg/day than with hydrochlorothiazide 50 mg/day (24-hour mean –12.4 vs –7.4 mm Hg, P = .05). Interestingly, the change in nighttime blood pressure was greater in the chlorthalidone group (–13.5 mm Hg) than in the hydrochlorothiazide group (–6.4 mm Hg; P = .009). These data suggest that at the doses studied, chlorthalidone is more effective than hydrochlorothiazide in lowering systolic blood pressure.

Bakris et al,35 using a different study design, compared the single-pill combination of azilsartan medoxomil and chlorthalidone vs coadministration of azilsartan medoxomil and hydrochlorothiazide in participants with stage 2 primary hypertension (≥ 160/100 mm Hg). Systolic blood pressure, as measured in the clinic, declined more with the chlorthalidone combination (–35.1 mm Hg) than with the hydrochlorothiazide combination (–29.5 mm Hg, mean difference –5.6 mm Hg, P < .001).

Meta-analyses also support the conclusion that chlorthalidone is more potent than hydrochlorothiazide in lowering blood pressure.35,36 Several studies have shown that chlorthalidone at the same dose is 1.5 to 2 times as potent as hydrochlorothiazide.33,36,37 Therefore, for clinical purposes, it is reasonable to consider chlorthalidone 12.5 mg daily as similar to 25 mg of hydrochlorothiazide daily.

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