REVIEW CME EDUCATIONAL OBJECTIVE: Readers will summarize the similarities and differences between hydrochlorothiazide CREDIT and chlorthalidone DANIELLE COONEY, PharmD SHERRY MILFRED-LaFOREST, PharmD MAHBOOB RAHMAN, MD, MS Louis Stokes Cleveland VA Medical Center, Louis Stokes Cleveland VA Medical Center, Louis Stokes Cleveland VA Medical Center; Cleveland, OH Cleveland, OH University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, OH Diuretics for hypertension: Hydrochlorothiazide or chlorthalidone? ABSTRACT he thiazide diuretic hydrochlorothia- T zide and the thiazidelike diuretic chlortha- Thiazide diuretics are the cornerstone of treatment of lidone are two old drugs that are still useful. hypertension in most patients. Hydrochlorothiazide is Although similar, they differ in important ways the most commonly used thiazide diuretic in the United still not fully appreciated more than a half cen- States, but interest in chlorthalidone is increasing. The tury after they were introduced. authors summarize the literature comparing these two Most hypertension guidelines recommend agents. thiazide diuretics as one of the classes of agents that can be used either as initial antihyperten- KEY POINTS sive drug therapy or as part of combination therapy.1–3 Chlorthalidone has a longer duration of action and a In the United States, hydrochlorothiazide longer half-life than hydrochlorothiazide. is used more often than chlorthalidone, but many clinical trials of antihypertensive thera- Chlorthalidone may be more potent than hydrochloro- py have used chlorthalidone.4,5 In recent years, thiazide in lowering blood pressure, but it also may be particularly after the publication of the Anti- associated with more metabolic adverse effects, such as hypertensive and Lipid-Lowering Treatment hypokalemia. to Prevent Heart Attack Trial (ALLHAT), interest in chlorthalidone has been increasing, and new data are now available comparing No study has conclusively shown either drug to be better these two diuretics.6 While current US guide- in preventing adverse clinical outcomes. lines do not recommend one over the other, British guidelines prefer chlorthalidone.7 These differences should be considered when making This review summarizes the data comparing choices about thiazide diuretic therapy for hypertension. the two drugs’ pharmacology, antihypertensive effect, and impact on clinical outcomes to help guide clinicians in choosing antihypertensive drug therapy. ■ PHARMACOLOGY AND MECHANISM OF ACTION Many of the differences in effectiveness and ad- verse effects of hydrochlorothiazide and chlortha- lidone are thought to be due to their different pharmacodynamic and pharmacokinetic effects. Pharmacodynamic effects Hydrochlorothiazide and chlorthalidone differ doi:10.3949/ccjm.82a.14091 significantly in chemical structure (Figure 1), CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 82 • NUMBER 8 AUGUST 2015 527 HYDROCHLOROTHIAZIDE AND CHLORTHALIDONE Hydrochlorothiazide inhibition of carbonic anhydrase than hydro- chlorothiazide, which can lead to lower intra- H cellular pH and cell volume. This effect may in Cl N part explain a pleiotropic effect of chlorthali- done, ie, inhibition of platelet function, which in turn may contribute to this drug’s beneficial 9 H2N NH effect on cardiovascular outcomes. Sulfonamide SSPharmacokinetic differences group Hydrochlorothiazide and chlorthalidone have O OO O important differences in their pharmacokinet- ic properties (Table 1).11 Chlorthalidone Hydrochlorothiazide has its onset of action Cl in about 2 hours, and it reaches its peak in 4 to 6 hours. Though its duration of action is OH short—up to 12 hours—its pharmacodynamic H2N response can be much longer than predicted Sulfonamide S by its kinetics, allowing once-daily dosing.8 group Chlorthalidone has a longer duration of O O HN action than hydrochlorothiazide. This may be because it has a very high volume of distribu- tion, since it is taken up into red blood cells O and is bound to carbonic anhydrase.12 This FIGURE 1. Although the chemical structures may result in a “drug reservoir” that keeps drug of hydrochlorothiazide (top) and chlortha- levels higher for a longer time.13 Its long dura- lidone (bottom) differ, they both contain a tion of action makes it a favorable choice for sulfonamide group that inhibits carbonic anhydrase activity. This action may be asso- patients who have difficulty adhering to medi- A pleiotropic ciated with lower vascular contractility. cation instructions. In addition, a missed dose is unlikely to have a “rebound” effect like that effect of but both contain a sulfonamide group that in- seen with some other antihypertensive agents. chlorthalidone: hibits carbonic anhydrase activity, which may However, both chlorthalidone and hydrochlo- inhibition be associated with lower vascular contractility. rothiazide are effective if taken once daily. Both drugs are concentrated in the kidney and of platelet secreted into the tubular lumen8; therefore, their ■ BLOOD PRESSURE-LOWERING function therapeutic diuretic effects are often achieved Both hydrochlorothiazide and chlorthalidone with relatively low plasma concentrations. are effective antihypertensive agents. Table 2 Both drugs inhibit the sodium-chloride co- summarizes findings from studies that evaluat- transporter in the luminal membrane of the ed their blood pressure-lowering effect at vari- distal convoluted tubule of the ascending loop ous doses.14–33 However, relatively few studies of Henle, leading to a modest natriuresis and have directly compared these two agents’ ef- diuresis. The exact mechanism by which they fects on blood pressure. lower blood pressure is not known: while the Ernst et al,34 in a small study (but probably initial response is from diuresis and volume the best one to address this issue), compared changes, long-term reduction in blood pressure chlorthalidone 12.5 mg/day (force-titrated to is through uncertain mechanisms. In addition, 25 mg/day) and hydrochlorothiazide 25 mg/day chlorthalidone may have beneficial effects on (force-titrated to 50 mg/day) in untreated hy- endothelial function and oxidative stress.9,10 pertensive patients. After 8 weeks, ambulatory Both drugs also increase secretion of potas- blood pressure monitoring indicated a greater sium and hydrogen ions and promote increased reduction from baseline in systolic blood pres- reabsorption of calcium through increased sure with chlorthalidone 25 mg/day than with expression of a sodium-calcium exchange hydrochlorothiazide 50 mg/day (24-hour mean channel.8 Chlorthalidone may cause more –12.4 vs –7.4 mm Hg, P = .05). Interestingly, 528 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 82 • NUMBER 8 AUGUST 2015 COONEY AND COLLEAGUES the change in nighttime blood pressure was greater in the chlorthalidone group (–13.5 mm TABLE 1 Hg) than in the hydrochlorothiazide group Pharmacokinetics and pharmacodynamics (–6.4 mm Hg; P = .009). These data suggest of hydrochlorothiazide and chlorthalidone that at the doses studied, chlorthalidone is more effective than hydrochlorothiazide in Hydrochlorothiazide Chlorthalidone lowering systolic blood pressure. Onset 2 hours 2.6 hours Bakris et al,35 using a different study de- sign, compared the single-pill combination of Peak effect 4–6 hours 1.5–6 hours azilsartan medoxomil and chlorthalidone vs Absorption Well absorbed a 65% coadministration of azilsartan medoxomil and hydrochlorothiazide in participants with stage Duration 6–12 hours 48–72 hours 2 primary hypertension (≥ 160/100 mm Hg). Protein binding 40%–68% 75% Systolic blood pressure, as measured in the clinic, declined more with the chlorthalidone Metabolism Not metabolized Hepatic combination (–35.1 mm Hg) than with the b hydrochlorothiazide combination (–29.5 mm Elimination half-life 10–12 hours 40–89 hours Hg, mean difference –5.6 mm Hg, P < .001). Excretion pathway Urine (as unchanged Urine c Meta-analyses also support the conclu- drug) sion that chlorthalidone is more potent than a When taken with food, time to maximum concentration increases from 1.6 hours to hydrochlorothiazide in lowering blood pres- 2.9 hours. Absorption is reduced in patients with chronic heart failure. sure.35,36 Several studies have shown that b Large variation due to biphasic elimination; may be much longer with renal impair- chlorthalidone at the same dose is 1.5 to 2 ment. times as potent as hydrochlorothiazide.33,36,37 c Data not available on the percentage of dose as unchanged drug and metabolites, concentration of the drug in body fluids, degree of uptake by a particular organ or in Therefore, for clinical purposes, it is reason- the fetus, or passage across the blood-brain barrier. able to consider chlorthalidone 12.5 mg daily Information from US National Library of Medicine. Dailymed. dailymed.nlm.nih.gov. as similar to 25 mg of hydrochlorothiazide Accessed May 31, 2015. daily. ■ ADVERSE EFFECTS unless the dose is increased, extrarenal losses of potassium increase, or dietary potassium is Electrolyte disturbances are a common ad- reduced. verse effect of thiazide diuretics. Other electrolyte changes. Thiazide and Hypokalemia. All thiazide diuretics cause thiazide-like diuretics can cause other meta- potassium wasting. The frequency of hypoka- bolic and endocrine abnormalities such as lemia depends on the dose, frequency of ad- ministration, diet, and other pharmacologic hypochloremic alkalosis, hyponatremia, and hypercalcemia.40,41 They can also cause photo- agents used. 42 Two large clinical trials, the