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Chlorthalidone: Mechanisms of Action and Effect on Cardiovascular Events

  • Hypertension Management and Antihypertensive Drugs (HM Siragy and B Waeber, Section Editors)
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Abstract

How chlorthalidone (CTDN) reduces risk for cardiovascular events (CVEs) can be considered in light of its ability to lower blood pressure (BP) and its non-BP related, pleiotropic effects. The mechanism by which CTDN lowers BP is unclear but may include alterations in whole body regulation and vasodilatory actions on vasculature, possibly mediated via its inhibitory effects on carbonic anhydrase. Additionally, CTDN has potentially beneficial, non-BP related, pleiotropic effects that include improvements in endothelial function, anti-platelet activity, and oxidative status. CTDN reduces pulse wave velocity, predictor of CVEs and a measure of central aortic stiffness associated with endothelial dysfunction. On the other hand, CTDN fosters hypokalemia, hyperglycemia, sympathetic discharge, and the renin–angiotensin–aldosterone system, but these potentially harmful effects do not appear to materially reduce CTDN’s ability to prevent CVEs. Further, CTDN reduces and regresses left ventricular hypertrophy (LVH), an important BP-dependent predictor of CVEs. Consistent with this finding, CTDN was more effective than amlodipine in reducing congestive heart failure (CHF) in the Anti-hypertensive and Lipid-lowering Treatment to Prevent Heart Attach Trial (ALLHAT). In reducing CVEs, CTDN was superior to lisinopril in ALLHAT and superior to hydrochlorthiazide in observational cohort analyses and in network analyses of randomized trials. A statistical synthesis of randomized trials suggests that the reduction in cardiovascular risk from CTDN can be explained primarily on the basis of its ability to lower blood pressure rather than its influence upon non-BP related, pleiotropic effects.

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Conflict of Interest

George C. Roush has received compensation and reimbursement for travel expenses from Farme for lecturing on chlorthalidone and hydrochlorothiazide.

Venkata Buddharaju, Michael E. Ernst, and Theodore R. Holford declare that they have no conflict of interest.

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Authors and Affiliations

  1. UCONN School of Medicine and St. Vincent’s Medical Center, 2800 Main Street, Bridgeport, CT, 06606, USA

    George C. Roush & Venkata Buddharaju

  2. Department of Family Medicine, 01291-APFP, University of Iowa Hospitals and Clinics, 200 Hawkins Dr, Iowa City, IA, USA

    Michael E. Ernst

  3. Department of Biostatistics, Yale School of Public Health, New Haven, CT, USA

    Theodore R. Holford

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  1. George C. Roush
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Correspondence to George C. Roush.

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Roush, G.C., Buddharaju, V., Ernst, M.E. et al. Chlorthalidone: Mechanisms of Action and Effect on Cardiovascular Events. Curr Hypertens Rep 15, 514–521 (2013). https://doi.org/10.1007/s11906-013-0372-1

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