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Home / How Long Will Hctz Continue to Work

How Long Will Hctz Continue to Work

Thiazide diuretics have been the cornerstone in hypertension management for nearly 5 decades. Although diuretic use declined for 20 years,1 it has begun to increase.2 The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7) suggests thiazide diuretics for most patients with hypertension.3 The JNC guidelines, however, do not distinguish between the thiazide diuretics and actually list several acceptable options.

Most major clinical trials used either hydrochlorothiazide (HCTZ) or chlorthalidone.4–16 Trials sponsored by the National Heart, Lung, and Blood Institute used chlorthalidone, primarily because of the belief that it might have advantages related to its longer duration of action. In addition, intriguing findings from the Multiple Risk Factor Intervention Trial (MRFIT) suggested that chlorthalidone might confer mortality benefits over HCTZ, but these findings have never been investigated in a prospective study.10 Most experts generally consider HCTZ and chlorthalidone interchangeable, with little discussion about whether these drugs are truly equivalent.

Chlorthalidone (Hygroton) was commonly used in the 1970s, but its use has sharply declined in the past 20 years.2 The average physician has rarely prescribed chlorthalidone (it is often not listed on formularies), and most younger pharmacists have never dispensed the drug. It is not known why the drug has fallen out of favor. One theory is that clinicians observed more hypokalemia with chlorthalidone than with HCTZ.

The debate between possible differences between chlorthalidone and HCTZ has been reinvigorated by the seemingly disparate findings from the Antihypertensive and Lipid-Lowering to Prevent Heart Attack Trial (ALLHAT) and the Second Australian National Blood Pressure Study (ANBP2).11,12 ALLHAT found fewer events for all cardiovascular disease, stroke, and heart failure with chlorthalidone than with an angiotensin-converting enzyme (ACE) inhibitor and lower risk of heart failure with chlorthalidone than with amlodipine. In contrast, the ANBP2 used HCTZ as the diuretic but found an ACE inhibitor to be superior at reducing combined morbidity and mortality in men but not in women.

Possible explanations for these findings include differences in populations studied, sample sizes, numbers of outcomes, or the validity of outcome measures.17 It is not the purpose of this article to review these differences. However, these studies have fueled one of the most interesting therapeutic debates: namely, which, if any, diuretic is preferred for the treatment of hypertension. The purpose of this article is to (1) evaluate the scientific evidence to support whether chlorthalidone and HCTZ can be considered equivalent agents for hypertension, (2) propose equivalent doses of the 2 agents, and (3) suggest possible mechanisms for differences between these agents.

Literature Search

A literature search of Index Medicus from 1966 to 2003 was conducted by using the terms "hydrochlorothiazide" or "chlorthalidone." References were reviewed for additional citations, especially those before 1966. Each article was reviewed to determine whether either HCTZ or chlorthalidone had been used as a single agent or as initial therapy in clinical trials. Preference was given to studies that used single diuretic entities and studies that involved either fixed doses or randomized, crossover studies.

Clinical Trials

Trials that used several diuretics and/or β-blockers in combination with diuretics as initial therapy or that did not separate results by type of diuretic or drug were difficult to interpret and are not discussed here. A few studies that included combinations with potassium-sparing diuretics were considered secondary sources of data, because several studies demonstrated that neither amiloride nor triamterene added to the antihypertensive effects of HCTZ or chlorthalidone.18–23

It is impossible to directly compare trials because of heterogeneous populations. However, on review of these articles, it is interesting to note that several trials reporting neutral or negative results in the diuretic groups often included HCTZ,4–6,11 whereas those with more favorable outcomes included chlorthalidone.10,12–16 Several trials of HCTZ, however, had favorable outcomes.6,7,9

Some experts have begun to speculate whether there are true differences between HCTZ and chlorthalidone. One of the most intriguing findings was reported by MRFIT.10 Patients were randomized to either special intervention (SI) or usual care (UC). Initial therapy in the SI group was either HCTZ or chlorthalidone, and the choice was made locally by the clinic staff. The initial evaluation followed up 8012 men for 6.9 years, and there was a trend in favor of the SI group compared with the UC group, but the differences were not statistically significant. A follow-up analysis 3.8 years later (10.5 years' total follow-up) found more favorable outcomes in the SI group compared with UC group, which is in contrast to the earlier observation.10 Six years into the trial, it was observed that in the 9 clinics that predominately used HCTZ, mortality was 44% higher in the SI group compared with the UC group.10 The opposite was true in the 6 clinics that predominately used chlorthalidone. The MRFIT Data Safety Monitoring Board changed the protocol near the end of the trial to exclusively use chlorthalidone. In the initial clinics that used HCTZ that had a 44% higher mortality in the SI group, the trend was reversed after the protocol was changed to chlorthalidone, and they then had a 28% lower risk (P=0.04 for comparison of coronary heart disease mortality at the 2 time periods). The investigators proposed several explanations, including a possible time delay in risk reduction that required longer follow-up to observe the effect or alternatively, that the change in the protocol to switch to chlorthalidone produced the more favorable effect observed toward the end of the trial. It is important to note that these findings were from a retrospective analysis of a design that was not randomized or blinded and must be interpreted with extreme caution. The findings do, however, raise interesting questions.

If chlorthalidone has more favorable effects on cardiovascular outcomes than does HCTZ, what are the possible mechanisms? The following discussion highlights some of the features of these 2 agents that might explain possible outcome differences.

Chemistry

HCTZ belongs to the benzothiadiazine class, referred to simply as thiazide diuretics. Benzothiadiazines were developed in an effort to find more potent carbonic anhydrase inhibitors.24 The prototype thiazide diuretic was chlorothiazide, but this drug is not commonly used today because of problems with bioavailability.

HCTZ has the chemical name 2H-1,2,4-benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-, 1,1-dioxide (Figure 1). HCTZ has one additional hydrogen substituted on a nitrogen on the sulfonamide ring compared with chlorothiazide. All thiazides have a similar dual-ring structure.

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Figure 1. Structures of chlorothiazide, HCTZ, and chlorthalidone.

Though commonly considered a thiazide, chlorthalidone is not a benzothiadiazine and is more appropriately called a thiazide-like diuretic. Though chemically related to the sulfonamides, Figure 1 demonstrates that chlorthalidone is chemically unique. The chemical name for chlorthalidone is benzenesulfonamide, 2-chloro-5-(2,3-dihydro-1-hydroxy-3-oxo-1H-isoindol-1-yl).

Pharmacokinetics and Pharmacodynamics

Pharmacokinetic differences are often responsible for differences in clinical effects within a given drug class. It is known that pharmacokinetic parameters differ at steady state, especially in the elderly, in patients with renal insufficiency, or with drug-drug interactions.25–29 Another important principle with antihypertensive agents is that their pharmacodynamic response is generally much longer than their half-life would predict.27–29 For these reasons, most antihypertensive drugs can be given once or twice daily despite half-lives that would predict the need for more frequent dosing.

Hydrochlorothiazide

Sources continue to list the half-life of HCTZ as short as 2.5 hours.30,31 Studies, however, have found that the half-life and duration of HCTZ are much longer. After single oral doses, HCTZ achieved peak concentrations in ≈2 hours and had a half-life of ≈6.5 to 9 hours (Table 1).32,33 Only one study found a half-life of 2.4 hours.34 The half-life of HCTZ is 8 to 15 hours with long-term dosing.33,35–37

TABLE 1. Pharmacokinetic and Pharmacodynamic Comparisons of HCTZ and Chlorthalidone

Drug Onset, h Peak, h Half-Life, h Duration, h
HCTZ 2 4–6 6–9 (Single dose) 12 (Single dose)
8–15 (Long-term dosing) 16–24 (Long-term dosing)
Chlorthalidone 2–3 2–6 40 (Single dose) 24–48 (Single dose)
45–60 (Long-term dosing) 48–72 (Long-term dosing)

The half-life of HCTZ would suggest that the drug should be given twice daily. Several studies, however, support once-daily dosing of HCTZ, demonstrating that the pharmacodynamic response is much longer than predicted by the half-life.38–41 One double-blind, randomized, crossover study in 24 patients administered HCTZ 100 mg once daily or 50 mg twice daily.41 Blood pressures (BPs) were measured 12 hours after twice-daily dosing and 24 hours after daily, single dosing. Mean sitting BP was 131/85 mm Hg with once-daily and 130/84 mm Hg with twice-daily therapy (P=0.22). These studies suggest that HCTZ can be given as a single, daily dose, which has been recommended in several of the last JNC guidelines.3

Chlorthalidone

Chlorthalidone serum concentrations peak ≈2 to 6 hours after oral administration (Table 1).42,43 One randomized, crossover study in healthy volunteers found that peak serum concentrations after single doses of 50, 100, or 200 mg were 3.2, 5.6, and 7.9 μg/mL, respectively.42 The half-life of chlorthalidone in this single-dose study was ≈42 hours (range, 29 to 55 hours). Interindividual variability in the half-life of chlorthalidone is large, with typical mean half-lives of 45 to 60 hours after long-term dosing.42–46 Chlorthalidone serum concentrations after 100 mg are only twice those of a 25-mg dose, indicating a flat dose–serum concentration curve (Table 2).42,45

TABLE 2. Mean Chlorthalidone Serum Concentrations and BP Response (n=37)

Dose, mg/d Mean Serum Concentration, μg/mL Mean Fall in Upright SBP, mm Hg Mean Fall in Upright DBP, mm Hg
Serum concentrations and BP responses were extrapolated from original figures by visual inspection.61
25 6 18 8
50 9.3 23 11
100 11.2 24 10
200 13.3 28 10.5

Chlorthalidone rapidly enters (half-life, 15 minutes) and concentrates in erythrocytes.47 Studies have found 7 to 10 times greater concentrations of chlorthalidone in erythrocytes than in plasma.42,48 One possible explanation for the long half-life is that chlorthalidone concentrates in erythrocytes and is slowly released from this compartment.

The natriuretic effect of chlorthalidone was maximal at 18 hours and lasted >48 hours in one early study of the drug.49 One double-blind study found that thrice-weekly dosing of chlorthalidone did not completely control systolic BP (SBP), suggesting that every-other-day dosing might not be maximally effective.50

Dose Response

Hydrochlorothiazide

Doses of HCTZ often exceeded 100 mg daily, and the use of 200 to 450 mg daily was not unusual.51,52 Later studies revealed that 25 mg daily was nearly as effective as higher doses with less hypokalemia.22,53–55 Doses of HCTZ as low as 12.5 mg daily have significant antihypertensive effects in some patients but are not as effective as higher doses.56–58 In one study, 111 patients with hypertension were randomly assigned to placebo or 3, 6, 12.5, or 25 mg HCTZ for 6 weeks.58 SBP was reduced by 2.1, 3.8, 6.4, 6.5, and 12.0 mm Hg by these respective doses (Figure 2). Another study found reductions in SBP of 29, 21, 32, and 24 mm Hg in 51 elderly patients randomly assigned to 25 mg daily, 25 mg twice daily, 50 mg daily, and 50 mg twice daily, respectively.55

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Figure 2. Effects of HCTZ and chlorthalidone on SBP as a function of daily dose (mg). Values for HCTZ of 3, 6, 12.5, and 25 mg were from one study,58 whereas results for 50 and 100 mg were derived from 3 other studies.67,68,70 Data for chlorthalidone were from a single study.61

Five important principles are evident with HCTZ dosing: (1) some patients will respond to doses of 12.5 mg daily, (2) doses >25 mg daily often lower BP only slightly more than does 25 mg (ie, a relatively flat dose response), (3) hypokalemia is dose related, and the risk increases with dose,53,57,58 (4) there is a great deal of variability in response with some patients, requiring doses of 25 to 50 mg before substantial antihypertensive effects are observed,22,52,53 and the reduction in BP is greater when baseline BP is highest.

Chlorthalidone

Early studies with chlorthalidone used doses of 200 to 600 mg daily.49,59,60 In a study published in 1962, mean arterial pressure was reduced from 148 mm Hg at baseline to 128 mm Hg with chlorthalidone 50 mg daily and to 122 mm Hg with 100 mg daily.59 Tweeddale et al61 conducted a randomized, double-blind trial and found that chlorthalidone serum concentrations and BP dose response were flat (Table 2 and Figure 2). Although there was an 8-fold increase in dose (25 to 200 mg), serum concentration increased only ≈2-fold. BP dropped 18/8 mm Hg with 25 mg daily but only 28/11 mm Hg with 200 mg daily.

Materson et al62 randomly assigned 100 patients with hypertension to 12.5, 25, 50, or 75 mg daily or placebo for 12 weeks in a parallel design. Baseline BP differed between groups but was generally 144 to 148/97 to 98 mm Hg. After treatment, BP was 146/95, 140/91, 138/93, 135/91, and 135/91 mm Hg with placebo and with 12.5, 25, 50, and 75 mg, respectively. A standing diastolic BP (DBP) <90 mm Hg and/or a decrease of 10 mm Hg or more was achieved in 0% of patients on placebo, in 45% with 12.5 mg, in 35% with 25 mg, in 41% with 50 mg, and in 42% with 75 mg daily. Thus, 12.5 mg did lower BP in many patients, though not statistically differently from placebo. The higher doses achieved BP that was significantly lower than with placebo. Hypokalemia was clearly dose related: 5% with placebo and 30%, 40%, 58%, and 68% with 12.5, 25, 50, and 75 mg daily, respectively. The authors concluded that 25 mg daily was nearly as effective as higher doses and was associated with less hypokalemia.

Several other studies have confirmed that lower doses of chlorthalidone, especially 12.5 mg and 25 mg daily, offer the best efficacy-to–side effect ratio with respect to hypokalemia.50,63–66

Dose Equivalence

The studies cited earlier give some insight into dose equivalence between HCTZ and chlorthalidone, but none of these studies directly compared the 2 agents. Various compendia suggest that the 2 agents are equipotent (50 mg HCTZ is equivalent to 50 mg chlorthalidone).30,37 Interestingly, an article published in 1960, when chlorthalidone first became available, suggested that the dose equivalence of meralluride (a mercurial diuretic), HCTZ, and chlorthalidone had potency estimates of 1.0, 1.4, and 1.8, although the data for these estimates were not provided.60 If this estimate is accurate, then 50 mg HCTZ would be equivalent to ≈39 mg chlorthalidone.

The earliest study of dose equivalence was a randomized, double-blind study of placebo, HCTZ 100 mg daily, and chlorthalidone 50 mg daily, each given for 6 weeks separated by a 2-week washout (Table 3).67 Pretreatment BPs were ≈180/110 mm Hg. Chlorthalidone 50 mg reduced BP by 25/10 mm Hg, and HCTZ 100 mg reduced BP by 18/8 mm Hg. Although there was no statistically significant difference between the 2 drugs, the sample size was small and the power to detect a difference was low. Interestingly, potassium increased slightly with chlorthalidone (0.02 mEq/L) and decreased significantly with HCTZ (0.22 mEq/L, P=0.009). The fact that chlorthalidone appeared to be more than twice as potent as HCTZ might make it difficult to extrapolate to lower doses, because the flat dose-response curves for these 2 drugs likely differ in shape and slope.

TABLE 3. Comparative Trials of HCTZ and Chlorthalidone

Author, y (Sample Size) Diuretic Doses BP Reduction, mm Hg
Bowlus et al, 196467 (n=19) HCTZ 100 mg daily 18/8
Chlorthalidone 50 mg daily 25/10
Clark et al, 197970 (n=126) HCTZ 25 mg+triamterene 50 mg daily 15/8
HCTZ 50 mg+triamterene 100 mg daily 18/12
Chlorthalidone 50 mg daily 25/16
Finnerty, 197668 (n=55) HCTZ 50 mg twice daily (100 mg daily) 22/16
Chlorthalidone 50 mg daily 18/15

Finnerty68 conducted a double-blind, randomized evaluation of HCTZ 50 mg twice daily (100 mg daily) compared with chlorthalidone 50 mg daily. After 4 weeks of treatment, chlorthalidone reduced mean BP by 18/15 mm Hg, whereas HCTZ reduced mean BP by 22/16 mm Hg (no significant difference between drugs). The percentage of patients with DBP ⪕90 mm Hg was 42% with chlorthalidone and 32% with HCTZ. Serum potassium decreased 0.38 mEq/L with HCTZ and only 0.03 mEq/L with chlorthalidone, but these differences were not statistically significant (P<0.07). Another study suggested that chlorthalidone is more potent than HCTZ (Table 3).69

Inspection of the available studies suggests that 50 mg HCTZ is approximately equivalent to 25 to 37 mg chlorthalidone, similar to that proposed by Ford60 in 1960. The scientific basis for the more recent recommendations that the 2 drugs are equipotent is not clear. We suggest that equivalent doses of chlorthalidone should generally be 50% to 75% of typical HCTZ doses. There is, however, a gap in the data, because comparative doses of 12.5 to 25 mg have not been studied, and it is likely that these doses are on the steeper portions of the dose-response curves.

Discussion

Thiazide diuretics are often considered a class of drugs equivalent to thiazide-like agents, and HCTZ and chlorthalidone are often referred to interchangeably.3 It is, however, clear from this analysis that they are very different compounds. Whether these 2 drugs have different effects on clinical outcomes is unknown.10 Any such difference is probably not due to differences in duration of action, because HCTZ appears to effectively lower BP for 24 hours.

Should one diuretic be preferred on the basis of the scientific evidence? Both HCTZ and chlorthalidone have demonstrated risk reduction in clinical trials. However, the largest trials, including Hypertension Detection and Follow-up Program (HDFP), MRFIT, Systolic Hypertension in the Elderly Program (SHEP), and ALLHAT, primarily used chlorthalidone as the initial therapy and more consistently showed reductions in cardiovascular events than did studies that primarily used HCTZ. Although it is possible that these differences are related to the population demographics, it is equally possible that cited differences account for the differences in outcome. Unfortunately, a randomized trial to prove any differences in outcome will probably never be performed.

At this time, we do not believe there is strong evidence to support the use of chlorthalidone over HCTZ. However, we are convinced that the weight of the scientific evidence suggests that clinicians should use one of these two agents as the preferred diuretic for treating hypertension. The typical starting doses of HCTZ should be 12.5 mg in the elderly and 25 mg in younger patients. Most patients will respond to 12.5 to 25 mg HCTZ, but maximum doses of 50 mg might be necessary for some patients. The typical starting dose of chlorthalidone should be 6.25 mg in the elderly and 12.5 mg in younger patients, with a maximum dose of 25 mg if necessary. Studies should be conducted that compare these 2 agents in lower doses to help elucidate whether one agent is clearly superior for the management of hypertension.

This study was supported in part by grants R01HL70740-01A1 and R01HL069801-01A1 (to Dr Carter) from the National Heart, Lung, and Blood Institute.

Footnotes

Correspondence to Barry L. Carter, PharmD, Professor and Head, Division of Clinical and Administrative Pharmacy, College of Pharmacy, Building S 532, University of Iowa, Iowa City, IA 52242. E-mail [email protected]

References

  • 1 Moser M. Why are physicians not prescribing diuretics more frequently in the management of hypertension? JAMA . 1998; 279: 1813–1816.CrossrefMedlineGoogle Scholar
  • 2 Carter BL, Malone DC, Ellis SL, Dombrowski RC. Antihypertensive drug utilization in hypertensive veterans with complex medication profiles. J Clin Hypertens . 2000; 2: 172–180.Google Scholar
  • 3 Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA . 2003; 289: 2560–2572.CrossrefMedlineGoogle Scholar
  • 4 Leren P, Helgeland A. Oslo Hypertension Study. Drugs . 1986; 31 (suppl 1): 41–45.CrossrefMedlineGoogle Scholar
  • 5 Wikstrand J, Warnold I, Olsson G, Tuomilehto J, Elmfeldt D, Berglund G. Primary prevention with metoprolol in patients with hypertension: mortality results from the MAPHY study. JAMA . 1988; 259: 1976–1982.CrossrefMedlineGoogle Scholar
  • 6 Medical Research Council trial of treatment of hypertension in older adults: principal results. MRC Working Party. BMJ . 1992; 304: 405–412.CrossrefMedlineGoogle Scholar
  • 7 Amery A, Birkenhager W, Brixko P, Bulpitt C, Clement D, Deruyttere M, De Schaepdryver A, Dollery C, Fagard R, Forette F, et al. Mortality and morbidity results from the European Working Party on High Blood Pressure in the Elderly trial. Lancet . 1985; 1: 1349–1354.CrossrefMedlineGoogle Scholar
  • 8 Borhani NO, Mercuri M, Borhani PA, Buckalew VM, Canossa-Terris M, Carr AA, Kappagoda T, Rocco MV, Schnaper HW, Sowers JR, Bond MG. Final outcome results of the Multicenter Isradipine Diuretic Atherosclerosis Study (MIDAS): a randomized controlled trial. JAMA . 1996; 276: 785–791.CrossrefMedlineGoogle Scholar
  • 9 Brown MJ, Palmer CR, Castaigne A, de Leeuw PW, Mancia G, Rosenthal T, Ruilope LM. Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT). Lancet . 2000; 356: 366–372.CrossrefMedlineGoogle Scholar
  • 10 Mortality after 10 1/2 years for hypertensive participants in the Multiple Risk Factor Intervention Trial. Circulation . 1990; 82: 1616–1628.CrossrefMedlineGoogle Scholar
  • 11 Wing LM, Reid CM, Ryan P, Beilin LJ, Brown MA, Jennings GL, Johnston CI, McNeil JJ, Macdonald GJ, Marley JE, Morgan TO, West MJ. A comparison of outcomes with angiotensin-converting–enzyme inhibitors and diuretics for hypertension in the elderly. N Engl J Med . 2003; 348: 583–592.CrossrefMedlineGoogle Scholar
  • 12 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: 2981–2997.CrossrefMedlineGoogle Scholar
  • 13 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 [comment]. JAMA . 2000; 283: 1967–1975.CrossrefMedlineGoogle Scholar
  • 14 Five-year findings of the hypertension detection and follow-up program, I: reduction in mortality of persons with high blood pressure, including mild hypertension. ypertension Detection and Follow-up Program Cooperative Group. JAMA . 1979; 242: 2562–2571.CrossrefMedlineGoogle Scholar
  • 15 Five-year findings of the hypertension detection and follow-up program, III: reduction in stroke incidence among persons with high blood pressure. Hypertension Detection and Follow-up Program Cooperative Group. JAMA . 1982; 247: 633–638.CrossrefMedlineGoogle Scholar
  • 16 Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension: final results of the Systolic Hypertension in the Elderly Program (SHEP). SHEP Cooperative Research Group. JAMA . 1991; 265: 3255–3264.CrossrefMedlineGoogle Scholar
  • 17 Alderman MH. ALLHAT and beyond. Am J Hypertens . 2003; 16: 512–514.CrossrefMedlineGoogle Scholar
  • 18 Spiers DR, Wade RC. Double-blind parallel study of a combination of chlorthalidone 50 mg and triamterene 50 mg in patients with mild and moderate hypertension. Curr Med Res Opin . 1996; 13: 409–415.CrossrefMedlineGoogle Scholar
  • 19 Hort JF, Wilkins HM. Changes in blood pressure, serum potassium and electrolytes with a combination of triamterene and a low dose of chlorthalidone. Curr Med Res Opin . 1991; 12: 430–440.CrossrefMedlineGoogle Scholar
  • 20 Multiclinic comparison of amiloride, hydrochlorothiazide, and hydrochlorothiazide plus amiloride in essential hypertension. Multicenter Diuretic Cooperative Study Group. Arch Intern Med . 1981; 141: 482–486.CrossrefMedlineGoogle Scholar
  • 21 Myers MG. Hydrochlorothiazide with or without amiloride for hypertension in the elderly: a dose-titration study. Arch Intern Med . 1987; 147: 1026–1030.CrossrefMedlineGoogle Scholar
  • 22 Kohvakka A, Salo H, Gordin A, Eisalo A. Antihypertensive and biochemical effects of different doses of hydrochlorothiazide alone or in combination with triamterene. Acta Med Scand . 1986; 219: 381–386.MedlineGoogle Scholar
  • 23 Larochelle P, Logan AG. Hydrochlorothiazide-amiloride versus hydrochlorothiazide alone for essential hypertension: effects on blood pressure and serum potassium level. Can Med Assoc J . 1985; 132: 801–805.MedlineGoogle Scholar
  • 24 Swinyard E. Diuretic drugs. In: Osol A, Hoover JE (eds). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pa: Mack Publishing Co; 1975. Google Scholar
  • 25 Saseen JJ, Carter BL, Brown TE, Elliott WJ, Black HR. Comparison of nifedipine alone and with diltiazem or verapamil in hypertension. Hypertension . 1996; 28: 109–114.CrossrefMedlineGoogle Scholar
  • 26 Carter BL, Noyes MA, Demmler RW, Barnette DJ, Pieper J. Pharmacokinetics of verapamil and its metabolites in elderly and young volunteers. J Appl Ther . 1996; 1: 85–91.Google Scholar
  • 27 Carter BL, Noyes MA, Demmler RW. Differences in serum concentrations of and responses to generic verapamil in the elderly. Pharmacotherapy . 1993; 13: 359–368.MedlineGoogle Scholar
  • 28 Carter BL, Gersema LM, Williams GO, Schabold K. Once-daily propranolol for hypertension: a comparison of regular-release, long-acting, and generic formulations. Pharmacotherapy . 1989; 9: 17–22.CrossrefMedlineGoogle Scholar
  • 29 Carter BL, Frohlich ED, Elliott WJ, Moore MA, Mann RJ, Roberts RW. Selected factors that influence responses to antihypertensives: choosing therapy for the uncomplicated patient. Arch Fam Med . 1994; 3: 528–536.CrossrefMedlineGoogle Scholar
  • 30 Jackson E. Diuretics. In: Hardman JG, Limbird LE, eds. Goodman & Gilman's The Pharmacologic Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill; 2001:757–787.Google Scholar
  • 31 Brater DC. Diuretic therapy. N Engl J Med . 1998; 339: 387–395.CrossrefMedlineGoogle Scholar
  • 32 Howes LG, Conway EL, Phillips PA, Broadbear J, Drummer OH, Louis WJ. Pharmacokinetic comparison of a combination tablet of enalapril and hydrochlorothiazide with enalapril and hydrochlorothiazide tablets administered together and separately. Biopharm Drug Dispos . 1991; 12: 447–455.CrossrefMedlineGoogle Scholar
  • 33 Giudicelli JF, Richer C, Mattei A. Pharmacokinetics and biological effects of captopril and hydrochlorothiazide after acute and chronic administration either alone or in combination in hypertensive patients. Br J Clin Pharmacol . 1987; 23 (suppl 1): 51S–63S.CrossrefMedlineGoogle Scholar
  • 34 Jordo L, Johnsson G, Lundborg P, Persson BA, Regardh CG, Ronn O. Bioavailability and disposition of metoprolol and hydrochlorothiazide combined in one tablet and of separate doses of hydrochlorothiazide. Br J Clin Pharmacol . 1979; 7: 563–567.CrossrefMedlineGoogle Scholar
  • 35 Weir SJ, Dimmitt DC, Lanman RC, Morrill MB, Geising DH. Steady-state pharmacokinetics of diltiazem and hydrochlorothiazide administered alone and in combination. Biopharm Drug Dispos . 1998; 19: 365–371.CrossrefMedlineGoogle Scholar
  • 36 Weimann HJ, Pabst G, Weber W. Lack of pharmacokinetic interaction between moxonidine and hydrochlorothiazide. Eur J Clin Pharmacol . 1992; 43: 209–210.CrossrefMedlineGoogle Scholar
  • 37 Drug Facts and Comparisons. St Louis, Mo: Facts and Comparisons; 2002:656–662.Google Scholar
  • 38 Lutterodt A, Nattel S, McLeod PJ. Duration of antihypertensive effect of a single daily dose of hydrochlorothiazide. Clin Pharmacol Ther . 1980; 27: 324–327.CrossrefMedlineGoogle Scholar
  • 39 De Plaen JF, Vander Elst E, Van Ypersele de Strihou C. Penbutolol or hydrochlorothiazide once a day in hypertension: a controlled study with home measurements. Br J Clin Pharmacol . 1981; 12: 215–221.CrossrefMedlineGoogle Scholar
  • 40 Lacourciere Y, Provencher P. Comparative effects of zofenopril and hydrochlorothiazide on office and ambulatory blood pressures in mild to moderate essential hypertension. Br J Clin Pharmacol . 1989; 27: 371–376.CrossrefMedlineGoogle Scholar
  • 41 Allen JH, McKenney JM, Stratton MA, Link K. Antihypertensive effect of hydrochlorothiazide administered once or twice daily. Clin Pharm . 1982; 1: 239–243.MedlineGoogle Scholar
  • 42 Riess W, Dubach UC, Burckhardt D, Theobald W, Vuillard P, Zimmerli M. Pharmacokinetic studies with chlorthalidone (Hygroton) in man. Eur J Clin Pharmacol . 1977; 12: 375–382.CrossrefMedlineGoogle Scholar
  • 43 McAinsh J, Bastain W, Young J, Harry JD. Bioavailability in man of atenolol and chlorthalidone from a combination formulation. Biopharm Drug Dispos . 1981; 2: 147–156.CrossrefMedlineGoogle Scholar
  • 44 Fleuren HL, Verwey-van Wissen C, van Rossum JM. Dose-dependent urinary excretion of chlorthalidone. Clin Pharmacol Ther . 1979; 25: 806–812.CrossrefMedlineGoogle Scholar
  • 45 Russell JG, Mayhew SR, Humphries IS. Chlorthalidone in mild hypertension: dose response relationship. Eur J Clin Pharmacol . 1981; 20: 407–411.CrossrefMedlineGoogle Scholar
  • 46 Fleuren HL, Thien TA, Verwey-van Wissen CP, van Rossum JM. Absolute bioavailability of chlorthalidone in man: a cross-over study after intravenous and oral administration. Eur J Clin Pharmacol . 1979; 15: 35–50.CrossrefMedlineGoogle Scholar
  • 47 Collste P, Garle M, Rawlins MD, Sjoqvist F. Interindividual differences in chlorthalidone concentration in plasma and red cells of man after single and multiple doses. Eur J Clin Pharmacol . 1976; 9: 319–325.CrossrefMedlineGoogle Scholar
  • 48 Tweeddale MG, Ogilvie RI. Improved method for estimating chlorthalidone in body fluids. J Pharm Sci . 1974; 63: 1065–1068.CrossrefMedlineGoogle Scholar
  • 49 Mach RS, Veyrat R. Clinical experiences with some of the newer diuretics, especially chlorthalidone. Ann N Y Acad Sci . 1960; 88: 841–863.CrossrefMedlineGoogle Scholar
  • 50 Bengtsson C, Johnsson G, Sannerstedt R, Werko L. Effect of different doses of chlorthalidone on blood pressure, serum potassium, and serum urate. BMJ . 1975; 1: 197–199.CrossrefMedlineGoogle Scholar
  • 51 McLeod PJ, Ogilvie RI, Ruedy J. Effects of large and small doses of hydrochlorothiazide in hypertensive patients. Clin Pharmacol Ther . 1970; 11: 733–739.CrossrefMedlineGoogle Scholar
  • 52 Freis ED, Reda DJ, Materson BJ. Volume (weight) loss and blood pressure response following thiazide diuretics. Hypertension . 1988; 12: 244–250.LinkGoogle Scholar
  • 53 Degnbol B, Dorph S, Marner T. The effect of different diuretics on elevated blood pressure and serum potassium. Acta Med Scand . 1973; 193: 407–410.CrossrefMedlineGoogle Scholar
  • 54 Beermann B, Groschinsky-grind M. Antihypertensive effect of various doses of hydrochlorothiazide and its relation to the plasma level of the drug. Eur J Clin Pharmacol . 1978; 13: 195–201.CrossrefMedlineGoogle Scholar
  • 55 Cushman WC, Khatri I, Materson BJ, Reda DJ, Freis ED, Goldstein G, Ramirez EA, Talmers FN, White TJ, Nunn S, et al. Treatment of hypertension in the elderly, III: response of isolated systolic hypertension to various doses of hydrochlorothiazide: results of a Department of Veterans Affairs cooperative study. Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents. Arch Intern Med . 1991; 151: 1954–1960.CrossrefMedlineGoogle Scholar
  • 56 Skoularigis J, Strugo V, Chopamba A, Setekge S, Sareli P. Low dose hydrochlorothiazide (12.5 to 25 mg daily) as monotherapy in black patients with mild to moderate hypertension: assessment by ambulatory blood pressure monitoring. Am J Hypertens . 1995; 8 (pt 1): 1046–1050.CrossrefMedlineGoogle Scholar
  • 57 McKenney JM, Goodman RP, Wright JT Jr, Rifai N, Aycock DG, King ME. The effect of low-dose hydrochlorothiazide on blood pressure, serum potassium, and lipoproteins. Pharmacotherapy . 1986; 6: 179–184.CrossrefMedlineGoogle Scholar
  • 58 Jounela AJ, Lilja M, Lumme J, Morlin C, Hoyem A, Wessel-Aas T, Borrild NJ. Relation between low dose of hydrochlorothiazide, antihypertensive effect and adverse effects. Blood Press . 1994; 3: 231–235.CrossrefMedlineGoogle Scholar
  • 59 Kakaviotos N, Finnerty FA Jr. Comparison of chlorthalidone, a long-acting antihypertensive and diuretic agent, with chlorothiazide. Am J Cardiol . 1962; 10: 570–574.CrossrefMedlineGoogle Scholar
  • 60 Ford RV. Therapy of edema and hypertension: comparative clinical effects of chlorothiazide and chlorphthalidolone. Tex State J Med . 1960; 56: 343–346.MedlineGoogle Scholar
  • 61 Tweeddale MG, Ogilvie RI, Ruedy J. Antihypertensive and biochemical effects of chlorthalidone. Clin Pharmacol Ther . 1977; 22 (pt 1): 519–527.CrossrefMedlineGoogle Scholar
  • 62 Materson BJ, Oster JR, Michael UF, Bolton SM, Burton ZC, Stambaugh JE, Morledge J. Dose response to chlorthalidone in patients with mild hypertension: efficacy of a lower dose. Clin Pharmacol Ther . 1978; 24: 192–198.CrossrefMedlineGoogle Scholar
  • 63 Carney S, Gillies AI, Morgan T. Optimal dose of a thiazide diuretic. Med J Australia . 1976; 2: 692–693.CrossrefMedlineGoogle Scholar
  • 64 Wing LM, West MJ, Graham JR, Chalmers JP. Long-acting and short-acting diuretics in mild essential hypertension. Clin Exp Hypertens [A] Theory Pract . 1982; 4: 1429–1441.CrossrefMedlineGoogle Scholar
  • 65 Grimm RH Jr, Neaton JD, McDonald M, Case J, McGill E, Allen R, Bailey-Hoffman G, Kousch D, Childs J, Hulley SB. Beneficial effects from systematic dosage reduction of the diuretic, chlorthalidone: a randomized study within a clinical trial. Am Heart J . 1985; 109: 858–864.CrossrefMedlineGoogle Scholar
  • 66 Morledge JH, Ettinger B, Aranda J, McBarron F, Barra P, Gorwit J, Davidov M. Isolated systolic hypertension in the elderly: a placebo-controlled, dose-response evaluation of chlorthalidone. J Am Geriatr Soc . 1986; 34: 199–206.CrossrefMedlineGoogle Scholar
  • 67 Bowlus WE, Langford HG. A comparison of the antihypertensive effect of chlorthalidone and hydrochlorothiazide. Clin Pharmacol Ther . 1964; 5: 708–711.CrossrefMedlineGoogle Scholar
  • 68 Finnerty FA Jr. A double-blind study of chlorthalidone and hydrochlorothiazide in an outpatient population of moderate hypertensives. Angiology . 1976; 27: 738–744.CrossrefMedlineGoogle Scholar
  • 69 van Soeren F. The antihypertensive and biochemical effects of hydrochlorothiazide/amiloride (Moduretic) versus chlorthalidone. J Int Med Res . 1980; 8: 132–135.CrossrefMedlineGoogle Scholar
  • 70 Clark EC, Podolsky S, Thompson EJ. Double-blind comparison of hydrochlorothiazide plus triameterene therapy versus chlorthalidone therapy in hypertension. South Med J . 1979; 72: 798–802.CrossrefMedlineGoogle Scholar

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Source: https://www.ahajournals.org/doi/full/10.1161/01.hyp.0000103632.19915.0e