Chlorthalidone: Don’t Call It “Thiazide-Like” Anymore

Abstract

HomeHypertensionVol. 56, No. 3Chlorthalidone: Don’t Call It “Thiazide-Like” Anymore Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBChlorthalidone: Don’t Call It “Thiazide-Like” Anymore Theodore W. Kurtz Theodore W. KurtzTheodore W. Kurtz From the Department of Laboratory Medicine, University of California, San Francisco, Calif. Search for more papers by this author Originally published12 Jul 2010https://doi.org/10.1161/HYPERTENSIONAHA.110.156166Hypertension. 2010;56:335–337Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: July 12, 2010: Previous Version 1 Recently, there has been growing interest in the idea that chlorthalidone should be preferred over thiazides when it comes to selecting a nonloop diuretic for treatment of hypertension.1–4 Depending on how these drugs are dosed, it is believed that the nonthiazide diuretic chlorthalidone might provide greater cardiovascular protection than thiazide diuretics because of its more potent and prolonged effects on blood pressure. However, given that the chemical structure of chlorthalidone is clearly distinct from the basic chemical structure of the thiazides (Figure), it is possible that the nonthiazide chlorthalidone might also differ from thiazides with respect to effects on determinants of cardiovascular disease other than just blood pressure. Yet, few if any studies have ever directly compared the effects of the nonthiazide chlorthalidone versus thiazides on potential cellular or molecular mechanisms of cardiovascular morbidity and mortality independent of blood pressure. Download figureDownload PowerPointFigure. The nonthiazide diuretic chlorthalidone and the thiazides, including hydrochlorothiazide, have sulfonamide groups (denoted within the unshaded ovals) that interact with the Zn(II) ion in the active site cleft of CA and with amino acid residues in the enzyme as well. A sulfonamide moiety is also present in the nonthiazide diuretics metolazone and indapamide (not shown), and these agents are also known to affect CA activity. However, the nonthiazide diuretics chlorthalidone, metolazone, and indapamide do not have the benzothiadiazine dioxide scaffold that is characteristic of the thiazides (denoted within the shaded oval). The structures of the nonthiazide diuretics beyond the sulfonamide group are clearly different from those of the thiazides and contribute to different effects of the various diuretics on CA isozyme activity profiles and perhaps to different effects on cardiovascular outcomes as well.Chlorthalidone Versus Thiazide Diuretics: Distinctly Different Impacts on Cellular and Molecular Mechanisms Relevant to Pathogenesis of Cardiovascular DiseaseIn this issue of Hypertension, Woodman et al5 report novel in vitro experiments in which chlorthalidone was found to reduce epinephrine-induced platelet aggregation and increase angiogenesis much more than bendroflumethiazide, a thiazide diuretic that is widely used in the United Kingdom. Given that Woodman et al5 performed their studies in cells incubated with chlorthalidone or bendroflumethiazide, rather than in cells obtained from patients treated with either drug, the observed effects on platelet aggregation and angiogenesis could not be secondary to differential effects of the 2 agents on blood pressure. If the greater effects of chlorthalidone on platelet aggregation and angiogenesis are also obtained in vivo, they could conceivably contribute to greater protection against stroke and myocardial infarction with chlorthalidone compared with bendroflumethiazide, and perhaps other thiazides as well.In cultured vascular smooth muscle cells, Woodman et al5 also found that chlorthalidone reduced expression of mRNAs for vascular endothelial growth factor C and transforming growth factor-β3 much more than bendroflumethiazide.5 These proteins have potential to affect a variety of factors that could influence pathogenesis of cardiovascular disease, including interstitial fluid volume balance and cardiac fibrosis and remodeling.6,7 Thus, the results of Woodman et al5 raise the possibility that chlorthalidone differs from thiazides with respect to many mechanisms that could theoretically influence a host of cardiovascular outcomes in patients with hypertension.Different Cellular and Molecular Effects of Chlorthalidone Versus Thiazides: Are Different Effects on Carbonic Anhydrase Isoenzyme Activity the Key?What could explain the different cellular and molecular effects that Woodman et al5 observed between chlorthalidone and the thiazide diuretic they tested? One possible explanation put forth by the authors is that chlorthalidone has a greater ability to inhibit carbonic anhydrase (CA) activity than thiazides and that this could cause alterations in intracellular pH, cell volume regulation, and other biological processes of potential functional significance. CAs are widely distributed zinc metalloenzymes that catalyze the conversion of carbon dioxide and water to carbonic acid and ultimately bicarbonate ions and protons.8 It has long been recognized that CA inhibitors like acetazolamide and ethoxzolamide can have effects on cardiovascular and platelet functions of potential clinical significance. For example, acetazolamide was shown years ago to cause marked increases in cerebral blood flow, and ethoxzolamide was shown to significantly inhibit the velocity of thrombin-induced platelet aggregation.9,10Chlorthalidone and the thiazide diuretics inhibit CA activity through interaction of their sulfonamide moieties with the Zn(II) ion in the CA active site cleft and with specific amino acid residues in the enzyme as well.11 However, beyond the sulfonamide group, the scaffold structure of chlorthalidone is very different from that of the thiazides (Figure), and this can further influence CA activity by affecting molecular interactions with amino acids that line the active site cleft in the enzyme. When the sulfonamide diuretics became clinically available, only 1 CA isozyme was well known.11 However, it is now appreciated that ≥16 different CA isozymes or CA-related proteins exist and that the inhibitory profile of the nonthiazide chlorthalidone on these CA isozymes is markedly different from that of the thiazides because of chemical structural differences beyond the sulfonamide group (Table and Figure).8,11 The potential importance of these observations is highlighted by growing interest in the development of novel chemical modulators of many different CA isoforms for a variety of therapeutic purposes.11,12Table. Inhibition Profiles of Hydrochlorothiazide and Chlorthalidone Against Different Isozymes of CACA IsozymeInhibition Constant, nMHydrochlorothiazideChlorthalidoneAdapted with permission from Temperini et al.11*Data show inhibition constant values >1 order of magnitude lower for chlorthalidone than hydrochlorothiazide.CA I328348CA II290138CA III790 00011 000*CA IV427196CA VA4225917CA VB6039*CA VI36551347CV VII50102.8*CA IX36723*CA XII3554.5*CA XIII388515*CA XIV41054130Chlorthalidone Is a Strong Inhibitor of Multiple Isoforms of CAChlorthalidone inhibits the activity of most CA isozymes much more potently than hydrochlorothiazide when tested at concentrations within ranges that can be achieved in plasma with suitable oral dosing (Table); the inhibitory potency of chlorthalidone against some CA isozymes (eg, CA VII) is >1000-fold greater than that of hydrochlorothiazide.11 Bendroflumethiazide, the thiazide tested by Woodman et al,5 is said to be relatively devoid of inhibitory activity on CA, although its effects on various isozymes of CA require further study. Indapamide, another nonthiazide sulfonamide diuretic, is a potent inhibitor of some isoforms of CA with an inhibition profile that is also very different from the thiazides. For example, the inhibitory potency of indapamide against the CA VII isozyme is >10 000-fold greater than that of hydrochlorothiazide, whereas its inhibitory potency against CA I is >100-fold lower than that of hydrochlorothiazide.11Considering the importance of CA in multiple biological processes, as well as the diverse nature and distribution of CA isozymes,8,12,13 one can readily imagine how the contrasting actions of nonthiazide versus thiazide diuretics on CA isozyme activity might give rise to different effects on a variety of mechanisms relevant to the pathogenesis of cardiovascular disease, including those that regulate blood pressure. For example, the antihypertensive effects of nonthiazide diuretics like chlorthalidone and thiazide diuretics like hydrochlorothiazide are believed to primarily depend on their ability to inhibit the renal Na+-Cl− cotransporter and initially reduce plasma volume and cardiac output. However, the reductions in plasma volume and cardiac output induced by these agents are not fully maintained over time, and it has long been suspected that vasodilator effects of nonthiazide and thiazide diuretics might also contribute to their antihypertensive effects in the long term.14 It has been proposed that vasodilator effects of these drugs may be related to inhibition of vascular CA activity or to direct effects on vascular ion channels or both.14Could Effects on NO Production Also Be Involved?Recently, it has been found that CA can generate NO from nitrite at high rates.15 Surprisingly, it appears that some CA inhibitors, including acetazolamide, can increase CA-mediated production of vasoactive NO despite inhibiting CA-mediated interconversion of carbon dioxide and bicarbonate.15 Thus, the ability of CA inhibitors to increase production of vasoactive NO might also help to explain the known vasodilatory effects of these drugs. This raises the possibility that a special effect of chlorthalidone on CA isoenzymatic profiles might be contributing to its presumed cardioprotective superiority not only by affecting the cellular and molecular pathways identified by Woodman et al,5 but perhaps by influencing NO activity in certain organs as well.PerspectivesAlthough chlorthalidone is not a thiazide, it is frequently referred to as “thiazide-like” because chlorthalidone and the thiazide diuretics all inhibit the Na+-Cl− cotransporter in the distal tubule. Referring to chlorthalidone in this imprecise fashion makes about as much sense as referring to amlodipine as a “benzothiazepine-like” or a “diltiazem-like” calcium antagonist simply because amlodipine and the benzothiazepines including diltiazem block l-type calcium channels in the vasculature (although amlodipine is a dihydropyridine and not a benzothiazepine).Unfortunately, the imprecise description of chlorthalidone as “thiazide like” has led many to assume that chlorthalidone and the thiazides are alike with respect to all actions that might possibly influence cardiovascular outcomes in patients with hypertension. In fact many writers, including the authors of the seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, lapse into dropping the qualifier “thiazide like” or “thiazide type” and on occasion simply call or classify chlorthalidone as a “thiazide diuretic” although it is clearly not a thiazide (eg, Table 10 in the seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure).16By placing nonthiazide molecules including chlorthalidone in a class labeled “thiazide diuretics,”16 the seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure tacitly encouraged the belief that nonthiazide diuretics such as chlorthalidone and thiazide diuretics such as hydrochlorothiazide are equivalent with respect to their therapeutic effects on all of the important mechanisms of hypertension-related cardiovascular disease. From both a clinical perspective1–4 and now a mechanistic perspective,5 it would appear that lumping all of these heterogeneous molecules into a single therapeutic class may have been misguided.The novel studies of Woodman et al,5 together with evolving research on inhibitors of CA isozyme activity,8,11,12 highlight distinct cellular, biochemical, and molecular effects of chlorthalidone that are of potential cardiovascular significance and that clearly distinguish chlorthalidone from at least some of the thiazides. Such observations suggest that when evaluating the relative benefit of antihypertensive agents, the results with chlorthalidone in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial should not be extrapolated to hydrochlorothiazide, nor should the results with hydrochlorothiazide in the Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension Trial be extrapolated to chlorthalidone. The findings of Woodman et al5 raise the possibility that, even if one happens to achieve the same degree of blood pressure control by using a thiazide diuretic instead of chlorthalidone, one may not achieve the same degree of cardiovascular protection with these 2 different types of agents. As emphasized by Woodman et al,5 it is time to abandon use of the term “thiazide like” when referring to chlorthalidone.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.DisclosuresT.W.K. has received speaker honoraria and consulting fees from, and is a stockholder in, companies with financial interests in the use of thiazide diuretics, nonthiazide diuretics, and/or other antihypertensive agents in the treatment of hypertension.FootnotesCorrespondence to Theodore W. Kurtz, Department of Laboratory Medicine, University of California, San Francisco, 185 Berry St, Suite 290, San Francisco, CA 94107. E-mail [email protected] References 1 Elliott WJ, Grimm RH Jr. Using diuretics in practice: one opinion. J Clin Hypertens (Greenwich). 2008; 10: 856–862.CrossrefMedlineGoogle Scholar2 Ernst ME, Carter BL, Basile JN. All thiazide-like diuretics are not chlorthalidone: putting the ACCOMPLISH study into perspective. J Clin Hypertens (Greenwich). 2009; 11: 5–10.CrossrefMedlineGoogle Scholar3 Kaplan NM. The choice of thiazide diuretics: why chlorthalidone may replace hydrochlorothiazide. Hypertension. 2009; 54: 951–953.LinkGoogle Scholar4 Sica DA. Chlorthalidone: a renaissance in use? Expert Opin Pharmacother. 2009; 10: 2037–2039.CrossrefMedlineGoogle Scholar5 Woodman R, Brown C, Lockette W. Chlorthalidone decreases platelet aggregation and vascular permeability and promotes angiogenesis. Hypertension. 2010; 56: 463–470.LinkGoogle Scholar6 Machnik A, Neuhofer W, Jantsch J, Dahlmann A, Tammela T, Machura K, Park JK, Beck FX, Muller DN, Derer W, Goss J, Ziomber A, Dietsch P, Wagner H, van Rooijen N, Kurtz A, Hilgers KF, Alitalo K, Eckardt KU, Luft FC, Kerjaschki D, Titze J. Macrophages regulate salt-dependent volume and blood pressure by a vascular endothelial growth factor-C-dependent buffering mechanism. Nat Med. 2009; 15: 545–552.CrossrefMedlineGoogle Scholar7 Bujak M, Frangogiannis NG. The role of TGF-β signaling in myocardial infarction and cardiac remodeling. Cardiovasc Res. 2007; 74: 184–195.CrossrefMedlineGoogle Scholar8 Supuran CT. Carbonic anhydrases: an overview. Curr Pharm Des. 2008; 14: 603–614.CrossrefMedlineGoogle Scholar9 Cotev S, Lee J, Severinghaus JW. The effects of acetazolamide on cerebral blood flow and cerebral tissue PO2. Anesthesiology. 1968; 29: 471–477.CrossrefMedlineGoogle Scholar10 Siffert W, Fox G, Gros G. The effect of carbonic anhydrase inhibition on the velocity of thrombin-stimulated platelet aggregation under physiological conditions. Biochem Biophys Res Commun. 1984; 121: 266–270.CrossrefMedlineGoogle Scholar11 Temperini C, Cecchi A, Scozzafava A, Supuran CT. Carbonic anhydrase inhibitors: sulfonamide diuretics revisited–old leads for new applications? Org Biomol Chem. 2008; 6: 2499–2506.CrossrefMedlineGoogle Scholar12 Supuran CT. Carbonic anhydrases: novel therapeutic applications for inhibitors and activators. Nat Rev Drug Discov. 2008; 7: 168–181.CrossrefMedlineGoogle Scholar13 Berg JT, Ramanathan S, Gabrielli MG, Swenson ER. Carbonic anhydrase in mammalian vascular smooth muscle. J Histochem Cytochem. 2004; 52: 1101–1106.CrossrefMedlineGoogle Scholar14 Hughes AD. How do thiazide and thiazide-like diuretics lower blood pressure? J Renin Angiotensin Aldosterone Syst. 2004; 5: 155–160.CrossrefMedlineGoogle Scholar15 Aamand R, Dalsgaard T, Jensen FB, Simonsen U, Roepstorff A, Fago A. Generation of nitric oxide from nitrite by carbonic anhydrase: a possible link between metabolic activity and vasodilation. Am J Physiol Heart Circ Physiol. 2009; 297: H2068–H2074.CrossrefMedlineGoogle Scholar16 Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ, for the Joint National Committee on Prevention, Detection, and Treatment of High Blood Pressure, National Heart, Lung, and Blood Institute, and National High Blood Pressure Education Program Coordinating Committee. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003; 42: 1206–1252.LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Kehrenberg M and Bachmann H (2022) Diuretics: a contemporary pharmacological classification?, Naunyn-Schmiedeberg's Archives of Pharmacology, 10.1007/s00210-022-02228-0, 395:6, (619-627), Online publication date: 1-Jun-2022. Roush G and Messerli F (2021) Chlorthalidone versus hydrochlorothiazide: major cardiovascular events, blood pressure, left ventricular mass, and adverse effects, Journal of Hypertension, 10.1097/HJH.0000000000002771, 39:6, (1254-1260), Online publication date: 1-Jun-2021. Dineva S, Uzunova K, Pavlova V, Filipova E, Kalinov K and Vekov T (2019) Comparative efficacy and safety of chlorthalidone and hydrochlorothiazide—meta-analysis, Journal of Human Hypertension, 10.1038/s41371-019-0255-2, 33:11, (766-774), Online publication date: 1-Nov-2019. Meadows C and Khitan Z (2018) Which thiazide to choose—A “dynamic” question with a mundane answer?, The Journal of Clinical Hypertension, 10.1111/jch.13419, 20:12, (1748-1748), Online publication date: 1-Dec-2018. Huang C, Leu H, Huang P, Lin L, Wu T, Lin S and Chen J (2015) Hypertension subtypes modify metabolic response to thiazide diuretics, European Journal of Clinical Investigation, 10.1111/eci.12571, 46:1, (80-91), Online publication date: 1-Jan-2016. Pareek A, Messerli F, Chandurkar N, Dharmadhikari S, Godbole A, Kshirsagar P, Agarwal M, Sharma K, Mathur S and Kumbla M (2016) Efficacy of Low-Dose Chlorthalidone and Hydrochlorothiazide as Assessed by 24-h Ambulatory Blood Pressure Monitoring, Journal of the American College of Cardiology, 10.1016/j.jacc.2015.10.083, 67:4, (379-389), Online publication date: 1-Feb-2016. Vongpatanasin W (2015) Hydrochlorothiazide is not the most useful nor versatile thiazide diuretic, Current Opinion in Cardiology, 10.1097/HCO.0000000000000178, 30:4, (361-365), Online publication date: 1-Jul-2015. Roush G, Ernst M, Kostis J, Kaur R and Sica D (2015) Not Just Chlorthalidone: Evidence-Based, Single Tablet, Diuretic Alternatives to Hydrochlorothiazide for Hypertension, Current Hypertension Reports, 10.1007/s11906-015-0540-6, 17:4, Online publication date: 1-Apr-2015. Ma W and Ackermann L (2015) Cobalt(II)-Catalyzed Oxidative C–H Alkenylations: Regio- and Site-Selective Access to Isoindolin-1-one, ACS Catalysis, 10.1021/acscatal.5b00322, 5:5, (2822-2825), Online publication date: 1-May-2015. Oparil S, Cushman W and Lederle F (2014) Chlorthalidone Versus Hydrochlorothiazide in Hypertension Treatment: Do We Have the Evidence to Decide?, American Journal of Kidney Diseases, 10.1053/j.ajkd.2013.11.009, 63:3, (387-389), Online publication date: 1-Mar-2014. Roush G, Buddharaju V, Ernst M and Holford T (2013) Chlorthalidone: Mechanisms of Action and Effect on Cardiovascular Events, Current Hypertension Reports, 10.1007/s11906-013-0372-1, 15:5, (514-521), Online publication date: 1-Oct-2013. Peterzan M, Hardy R, Chaturvedi N and Hughes A (2012) Meta-Analysis of Dose-Response Relationships for Hydrochlorothiazide, Chlorthalidone, and Bendroflumethiazide on Blood Pressure, Serum Potassium, and Urate, Hypertension, 59:6, (1104-1109), Online publication date: 1-Jun-2012.Roush G, Holford T and Guddati A (2012) Chlorthalidone Compared With Hydrochlorothiazide in Reducing Cardiovascular Events, Hypertension, 59:6, (1110-1117), Online publication date: 1-Jun-2012. Germino F (2012) Which Diuretic Is the Preferred Agent for Treating Essential Hypertension: Hydrochlorothiazide or Chlorthalidone?, Current Cardiology Reports, 10.1007/s11886-012-0307-5, 14:6, (673-677), Online publication date: 1-Dec-2012. DiNicolantonio J (2012) Hydrochlorothiazide: is it a wise choice?, Expert Opinion on Pharmacotherapy, 10.1517/14656566.2012.670636, 13:6, (807-814), Online publication date: 1-Apr-2012. Brook R and Weder A (2011) Initial hypertension treatment: one combination fits most?, Journal of the American Society of Hypertension, 10.1016/j.jash.2011.01.002, 5:2, (66-75), Online publication date: 1-Mar-2011. Rosendorff C (2011) Why Are We Still Using Hydrochlorothiazide?, The Journal of Clinical Hypertension, 10.1111/j.1751-7176.2011.00566.x, 13:12, (867-869), Online publication date: 1-Dec-2011. Ernst M and Mann S (2011) Diuretics in the Treatment of Hypertension, Seminars in Nephrology, 10.1016/j.semnephrol.2011.09.004, 31:6, (495-502), Online publication date: 1-Nov-2011. Düsing R (2011) Therapie der Hypertonie mit DiuretikaDiuretics in the treatment of hypertension, Der Internist, 10.1007/s00108-011-2915-3, 52:12, (1484-1491), Online publication date: 1-Dec-2011. Musini V, Nazer M, Bassett K and Wright J (2014) Blood pressure-lowering efficacy of monotherapy with thiazide diuretics for primary hypertension, Cochrane Database of Systematic Reviews, 10.1002/14651858.CD003824.pub2 Bubnova M (2015) Modern approaches to the treatment and long-term management of arterial hypertension in clinical practice. Pharmacological and clinical characteristics of angiotensin II receptor blockers: focus on azilsartan medoxomil. Part II, CardioSomatics, 10.26442/CS45157, 6:3, (58-69) Ernst M and Fravel M (2022) Thiazide and the Thiazide-Like Diuretics: Review of Hydrochlorothiazide, Chlorthalidone, and Indapamide, American Journal of Hypertension, 10.1093/ajh/hpac048 Chazova I and Martyniuk T (2016) Diuretics in combination antihypertensive therapy: focus on forecast, Systemic Hypertension, 10.26442/SG29120, 13:2, (6-10) Düsing R (2012) Diuretika in der Bluthochdruck-Therapie, Humanmedizin kompakt, 10.1007/s40355-012-0002-1 Baranauskiene L, Škiudaitė L, Michailovienė V, Petrauskas V, Matulis D and Hofmann A (2021) Thiazide and other Cl-benzenesulfonamide-bearing clinical drug affinities for human carbonic anhydrases, PLOS ONE, 10.1371/journal.pone.0253608, 16:6, (e0253608) Verdecchia P, Cavallini C and Angeli F (2022) Advances in the Treatment Strategies in Hypertension: Present and Future, Journal of Cardiovascular Development and Disease, 10.3390/jcdd9030072, 9:3, (72) September 2010Vol 56, Issue 3 Advertisement Article InformationMetrics https://doi.org/10.1161/HYPERTENSIONAHA.110.156166PMID: 20625074 Originally publishedJuly 12, 2010 PDF download Advertisement SubjectsTreatment