EBM Consult

Differences in Chlorthalidone's Mechanism of Action vs Hydrochlorothiazide and Its Clinical Relevance


  • Hydrochlorothiazide is the more commonly prescribed thiazide diuretic, but chlorthalidone may have greater benefits.

  • Chlorthalidone is more potent and exhibits both a longer duration of action and elimination half-life compared to hydrochlorothiazide. 

  • It is hypothesized that the greater inhibition of carbonic anhydrase associated with chlorthalidone is the reason for possible improved cardiovascular benefits.

  • Studies have found chlorthalidone to provide greater blood pressure lowering effects over a 24-hour period.  Some trials associate chlorthalidone with greater cardiovascular event reduction outcomes, but not in the older patient population. 
  • Overall, both agents have a similar drug interaction and adverse drug reaction profile. 

  • Additional head-to-head evaluations are needed to determine the difference in cardiovascular benefits and risk of hypokalemia between hydrochlorothiazide and chlorthalidone.

Carolyn J. Steber, PharmD
Anthony J. Busti, MD, PharmD, FNLA, FAHA
Content Editors:
Donald S. Nuzum, PharmD, BCACP, BC-ADM, CDE, CPP and Sabrina W. Cole, PharmD, BCPS
Last Reviewed: August 2015



    The most recent guidelines for the management of hypertension recommend thiazide diuretics without noting any differences between individual agents.1  Despite numerous trials demonstrating the effectiveness of chlorthalidone, hydrochlorothiazide remains the most commonly prescribed thiazide diuretic.2  Additionally, recent studies have raised the question that chlorthalidone may pose greater benefits compared to hydrochlorothiazide.3

    Differences in Mechanisms

    Both hydrochlorothiazide and chlorthalidone are thiazide diuretics that have FDA-approved indications for the treatment of hypertension (both as mono or as part of dual therapy) and edema.  Thiazide diuretics prevent reabsorption of sodium and chloride by interfering with the Na+/Cl- transporter in the distal convoluted tubule.4  These two agents vary in pharmacokinetic profiles.  Chlorthalidone has an elimination half-life of 40 to 60 hours compared to 6 to 15 hours of hydrochlorothiazide.  In addition to a longer half-life, chlorthalidone also has a longer duration of action lasting 24 to 72 hours, is approximately twice as potent as hydrochlorothiazide, and has a greater degree of protein binding.2

    Althoughthiazide and thiazide-like diuretics often get grouped together, significant structural differences exist.  The only common structure between the two drugs is the sulfonamide group (SO2NH2), which inhibits carbonic anhydrase activity.3  The molecular structure of chlorthalidone outside of the sulfonamide group allows additional inhibition of carbonic anhydrase compared to hydrochlorothiazide, resulting in differences in intracellular pH and cell volume.3  The discovery of greater inhibition of carbonic anhydrase associated with chlorthalidone has created the investigation of potential greater cardiovascular benefits since inhibition of carbonic anhydrase by other drug classes has been associated with proven cardiovascular effects and platelet function.3  In-vitro studies have shown chlorthalidone to decrease platelet aggregation associated with epinephrine and also amplify angiogenesis to a greater extent compared to a true thiazide diuretic.5

    Chlorthalidone vs Hydrochlorthiazide Structure Image 


    Clinical Relevance

    The blood-pressure-lowering effects and cardiovascular outcomes of each agent have been evaluated in separate clinical trials, but limited head-to-head trials comparing the efficacy of these drugs make concrete comparison difficult.   In a small, randomized, 8-week crossover study comparing low-dose chlorthalidone to low-dose hydrochlorothiazide, chlorthalidone showed a decrease in nighttime blood pressure compared to hydrochlorothiazide (-13.5 mmHg vs. -6.4 mmHg respectively, P=0.009), suggesting that chlorthalidone is more effective in providing 24-hour blood pressure control.2  Chlorthalidone showed greater reduction in systolic pressure during the 2-week office measurements compared to hydrochlorothiazide; although, the only statistically significant difference was noted at the initial 2-week follow-up (-15.7 mmHg vs. -4.5 mmHg respectively, P < 0.001).2  A systematic review and network meta-analyses concluded chlorthalidone provided greater cardiovascular protection compared to hydrochlorothiazide by discovering a 21% relative risk reduction in cardiovascular events for chlorthalidone compared to hydrochlorothiazide (95% CI, 12-28; P < 0.0001).1  A cohort study evaluating the use of these 2 thiazide diuretics in older adults, did not find a significantly lower risk in death or hospitalization due to myocardial infarction, heart failure, or stroke with chlorthalidone verse hydrochlorothiazide once the data were adjusted for differences in baseline characterisitcs.7

    Other Effects

    Hypokalemia is associated with thiazide diuretic use, with the risk increasing with larger diuretic doses.2  The main concern of hypokalemia is the link to hospitalizations and cardiovascular events.2  There have been mixed results in evaluating which thiazide diuretic carries the greatest risk of hypokalemia.  In head-to-head trials, chlorthalidone has shown to lower serum potassium concentration less than hydrochlorothiazide, although none of the results were statistically significant when comparing monotherapy of the two agents alone.2  Contrary, chlorthalidone use in older adults has been associated with greater incidence of hospitalization due to electrolyte abnormality over hydrochlorothiazide.8

    Both agents have the majority of the same significant drug interactions.  One exception is the concomitant use of hydrochlorothiazide and benazepril (worsening of nephrotoxic effects of ACEi) - which is not seen with chlorthalidone.  A benefit of hydrochlorothiazide is its availability in combination with other antihypertensive agents.

    1. Roush GC, Hoford TR, Guddati AK.  Chlorthalidone Compared With Hydrochlorothiazide in Reducing Cardiovascular Events: Systematic Review & Network  Meta-Analyses.  Hypertension AHA.  2012;59:1110-1117.
    2. Neff KM, Nawarskas JJ.  Hydrochlorothiazide Versus Chlorthalidone in the Management of Hypertension.  Cardiology in Review.  2010; 18: 51-56.
    3. Kurtz TW.  Chlorthalidone: Don't Call It "Thiazide-Like" Anymore.  Hypertension 2010;56:335-337. Katzung BG.  Basic and Clinical Pharmacology.  10th ed.  New York: McGraw Hill; 2007.  244 p.
    4. Wood R, Brown C, Lockette W.  Chlorthalidone decreases platelet aggregation and vascular permeability and promotes angiogenesis.  Hypertension  2010;56:463-470.
    5. Carter BL, Ernst ME, Cohen JD.  Hydrochlorothiazide Versus Chlorthalidone: Evidence Supporting Their Interchangeability.  Hypertension  2004; 43: 4-9.
    6. Dhalla IA, Gomes T, Yao Z, et al.  Chlorthalidone Versus Hydrochlorothiazide for the Treatment of Hypertension in Older Adults.  Ann Intern Med  2013;158:447-455.
    7. Hydrochlorothiazide [package insert].  Eatontown, NJ: West-Ward; 2006. Chlorthalidone [package insert].  Libertyville, IL: A-S Medication Solutions; 2013.

MESH Terms & Keywords

  • Hydrochlorothiazide, chlorthalidone, HCTZ, thiazide diuretics, hctz vs chlorthalidone, differences in mechanism of action, carbonic anhydrase inhibition, chlorthalidone mechanism of action, hydrochlorothiazide mechanism of action