Chlortalidone

{{Short description|Thiazide-like diuretic drug}} {{Use dmy dates|date=October 2022}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Drugbox | Watchedfields = changed | verifiedrevid = 460034023 | image = Chlortalidone.svg | image_class = skin-invert-image | alt = | chirality = Racemic mixture | image2 = Chlortalidone ball-and-stick 3F4X.png | image_class2 = bg-transparent | alt2 =

<!-- Clinical data --> | tradename = Hygroton, Thalitone, others | Drugs.com = {{drugs.com|monograph|chlorthalidone}} | MedlinePlus = a682342 | DailyMedID = Chlorthalidone | pregnancy_AU = C | pregnancy_category = | routes_of_administration = By mouth | class = Thiazide-like diuretic | ATC_prefix = C03 | ATC_suffix = BA04

| legal_UK = POM | legal_US = Rx-only | legal_US_comment = <ref>{{cite web | title=Thalitone- chlorthalidone tablet; Thalitone- chlorthalidone tablet | website=DailyMed | date=30 December 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=bc5a0299-115b-4e60-bb3f-c75a95c51c15 | access-date=7 July 2025}}</ref><ref>{{cite web | title=Hemiclor- chlorthalidone tablet | website=DailyMed | date=27 March 2025 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3f0f3ee0-f5a6-4bda-8160-a77744e9fa46 | access-date=7 July 2025}}</ref>

<!-- Pharmacokinetic data --> | bioavailability = | protein_bound = 75% | metabolism = | elimination_half-life = 40 hours | excretion = Kidney

<!-- Identifiers --> | IUPHAR_ligand = 7147 | CAS_number_Ref = {{cascite|correct|??}} | CAS_number = 77-36-1 | PubChem = 2732 | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = DB00310 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 2631 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = Q0MQD1073Q | KEGG_Ref = {{keggcite|correct|kegg}} | KEGG = D00272 | ChEBI_Ref = {{ebicite|correct|EBI}} | ChEBI = 3654 | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 1055

<!-- Chemical data --> | IUPAC_name = (''RS'')-2-Chloro-5-(1-hydroxy-3-oxo-2,3-dihydro-1''H''-isoindol-1-yl)benzene-1-sulfonamide | C=14 | H=11 | Cl=1 | N=2 | O=4 | S=1 | smiles = O=S(=O)(N)c1c(Cl)ccc(c1)C2(O)c3ccccc3C(=O)N2 | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 1S/C14H11ClN2O4S/c15-11-6-5-8(7-12(11)22(16,20)21)14(19)10-4-2-1-3-9(10)13(18)17-14/h1-7,19H,(H,17,18)(H2,16,20,21) | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = JIVPVXMEBJLZRO-UHFFFAOYSA-N }} <!-- Definition and medical uses --> '''Chlortalidone''', also known as '''chlorthalidone''', is a thiazide-like diuretic drug<ref name=Ace2019/> used to treat high blood pressure, swelling (such as occurs in heart failure, liver failure, and nephrotic syndrome), diabetes insipidus, and renal tubular acidosis.<ref name=AHFS2019/><ref name=BNF76/> Because chlortalidone is effective in most patients with high blood pressure, it is considered a preferred initial treatment.<ref>{{cite journal | vauthors = Ernst ME, Fravel MA | title = Thiazide and the Thiazide-Like Diuretics: Review of Hydrochlorothiazide, Chlorthalidone, and Indapamide | journal = American Journal of Hypertension | volume = 35 | issue = 7 | pages = 573–586 | date = July 2022 | pmid = 35404993 | doi = 10.1093/ajh/hpac048 | doi-access = free }}</ref><ref name=AHFS2019/> It is also used to prevent calcium-based kidney stones.<ref name=AHFS2019/> It is taken by mouth.<ref name=AHFS2019>{{cite web |title=Chlorthalidone Monograph for Professionals |url=https://www.drugs.com/monograph/chlorthalidone.html |website=Drugs.com |publisher=American Society of Health-System Pharmacists |access-date=18 April 2019 }}</ref> Effects generally begin within three hours and last for up to three days.<ref name=AHFS2019/> Long-term treatment with chlortalidone is more effective than hydrochlorothiazide for prevention of heart attack or stroke.<ref>{{cite journal | vauthors = Roush GC, Messerli FH | title = Chlorthalidone versus hydrochlorothiazide: major cardiovascular events, blood pressure, left ventricular mass, and adverse effects | journal = Journal of Hypertension | volume = 39 | issue = 6 | pages = 1254–1260 | date = June 2021 | pmid = 33470735 | doi = 10.1097/HJH.0000000000002771 | s2cid = 231649367 }}</ref>

<!-- Adverse effects and mechanism --> Common adverse effects include low blood potassium, low blood sodium, high blood sugar, dizziness, and erectile dysfunction.<ref name=AHFS2019/><ref name=BNF76/><ref>{{cite journal | vauthors = Liamis G, Filippatos TD, Elisaf MS | title = Thiazide-associated hyponatremia in the elderly: what the clinician needs to know | journal = Journal of Geriatric Cardiology | volume = 13 | issue = 2 | pages = 175–82 | date = February 2016 | pmid = 27168745 | pmc = 4854958 | doi = 10.11909/j.issn.1671-5411.2016.02.001 | doi-broken-date = 11 July 2025 }}</ref> Other adverse effects may include gout, low blood magnesium, high blood calcium, allergic reactions, and low blood pressure.<ref name=AHFS2019/><ref name=BNF76/><ref>{{cite web |title=Chlorthalidone |url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/019574s016lbl.pdf |archive-url=https://web.archive.org/web/20200327061646/https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/019574s016lbl.pdf |archive-date=27 March 2020 |website=FDA |access-date=27 March 2020}}</ref> Some reviews have found chlortalidone and hydrochlorothiazide to have a similar risk of adverse effects,<ref name=Din2019>{{cite journal | vauthors = Dineva S, Uzunova K, Pavlova V, Filipova E, Kalinov K, Vekov T | title = Comparative efficacy and safety of chlorthalidone and hydrochlorothiazide-meta-analysis | journal = Journal of Human Hypertension | volume = 33 | issue = 11 | pages = 766–774 | date = November 2019 | pmid = 31595024 | pmc = 6892412 | doi = 10.1038/s41371-019-0255-2 }}</ref><!-- Quote = "Our meta-analysis has demonstrated a slight superiority for CTLD regarding blood pressure control. At the same time, the two medications do not show significant differences in their safety profile." --><ref name=Rou2018>{{cite journal | vauthors = Roush GC, Abdelfattah R, Song S, Ernst ME, Sica DA, Kostis JB | title = Hydrochlorothiazide vs chlorthalidone, indapamide, and potassium-sparing/hydrochlorothiazide diuretics for reducing left ventricular hypertrophy: A systematic review and meta-analysis | journal = Journal of Clinical Hypertension | volume = 20 | issue = 10 | pages = 1507–1515 | date = October 2018 | pmid = 30251403 | doi = 10.1111/jch.13386 | pmc = 8030834 | doi-access = free }}</ref><!-- Quote = Chlorthalidone, indapamide, and HCTZ have similar effects on serum potassium. --> while other reviews have found chlortalidone to have a higher risk.<ref name=Ace2019/><!-- Quote = However, chlorthalidone use is more frequently associated with adverse metabolic effects, particularly hypokalemia and hyponatremia, compared with HCTZ. --><ref name=Spr2015>{{cite journal | vauthors = Springer K | title = Chlorthalidone vs. Hydrochlorothiazide for Treatment of Hypertension | journal = American Family Physician | volume = 92 | issue = 11 | pages = 1015–6 | date = December 2015 | pmid = 26760416 }}</ref> While it may be used in pregnancy it is a less preferred option.<ref name=AHFS2019/> How it works is not completely clear but is believed to involve increasing the amount of sodium and water lost by the kidneys.<ref name=AHFS2019/>

<!-- Society and culture --> Chlortalidone was patented in 1957 and came into medical use in 1960.<ref>{{cite book | vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery |date=2006 |publisher=John Wiley & Sons |isbn=978-3-527-60749-5 |page=457 |url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA457 }}</ref> It is on the World Health Organization's List of Essential Medicines.<ref name="WHO23rd">{{cite book | title = The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023) | year = 2023 | hdl = 10665/371090 | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2023.02 | hdl-access=free }}</ref> It is available as a generic medication.<ref name=BNF76>{{cite book|title=British national formulary: BNF 76|date=2018|publisher=Pharmaceutical Press|isbn=978-0-85711-338-2|pages=229–230|edition=76}}</ref> In 2023, it was the 124th most commonly prescribed medication in the United States, with more than 5{{nbsp}}million prescriptions.<ref name="Top 300">{{cite web | title=Top 300 of 2023 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=12 August 2025 | archive-date=12 August 2025 | archive-url=https://web.archive.org/web/20250812130026/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title = Chlorthalidone Drug Usage Statistics, United States, 2014 - 2023 | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Chlorthalidone | access-date = 18 August 2025 }}</ref>

==Medical use== ===High blood pressure=== Chlortalidone is considered a first-line medication for treatment of high blood pressure.<ref name=AHFS2019/> Some recommend chlortalidone over hydrochlorothiazide.<ref name=Ace2019>{{cite journal |vauthors=Acelajado MC, Hughes ZH, Oparil S, Calhoun DA |title=Treatment of Resistant and Refractory Hypertension |journal=Circ. Res. |volume=124 |issue=7 |pages=1061–1070 |date=March 2019 |pmid=30920924 |pmc=6469348 |doi=10.1161/CIRCRESAHA.118.312156 |quote=A long-acting thiazide-like diuretic, specifically chlorthalidone, if available, is recommended over hydrochlorothiazide (HCTZ) given its superior efficacy and clear benefit demonstrated in multiple outcome studies of hypertension.}}</ref><ref>{{cite journal |vauthors=Vongpatanasin W |title=Hydrochlorothiazide is not the most useful nor versatile thiazide diuretic |journal=Curr. Opin. Cardiol. |volume=30 |issue=4 |pages=361–5 |date=July 2015 |pmid=26049382 |pmc=4460599 |doi=10.1097/HCO.0000000000000178 }}</ref> A meta-analysis of randomized controlled trials found that chlortalidone is more effective than hydrochlorothiazide for lowering blood pressure, while the two drugs have similar toxicity.<ref>{{cite journal |vauthors=Dineva S, Uzunova K, Pavlova V, Filipova E, Kalinov K, Vekov T |title=Comparative efficacy and safety of chlorthalidone and hydrochlorothiazide-meta-analysis |journal=J Hum Hypertens |volume=33 |issue=11 |pages=766–774 |date=November 2019 |pmid=31595024 |pmc=6892412 |doi=10.1038/s41371-019-0255-2 }}</ref><ref>{{cite journal |vauthors=Carey RM, Whelton PK |title=Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: Synopsis of the 2017 American College of Cardiology/American Heart Association Hypertension Guideline |journal=Ann. Intern. Med. |volume=168 |issue=5 |pages=351–358 |date=March 2018 |pmid=29357392 |doi=10.7326/M17-3203 |doi-access=free }}</ref><ref name=Ace2019/><!-- Quote = However, chlorthalidone use is more frequently associated with adverse metabolic effects, particularly hypokalemia and hyponatremia, compared with HCTZ. --><ref name=Spr2015/>

Trials of chlortalidone for high blood pressure found that lower doses of chlortalidone (e.g., 12.5&nbsp;mg daily in ALLHAT study) had maximal blood pressure lowering effect and that higher doses did not lower it more. Chlortalidone and other thiazide diuretics are effective for lowering high blood pressure in persons with chronic kidney disease, although the risk of adverse effects is higher.<ref>{{cite journal |vauthors=Pourafshar N, Alshahrani S, Karimi A, Soleimani M |title=Thiazide Therapy in Chronic Kidney Disease: Renal and Extra Renal Targets |journal=Curr. Drug Metab. |volume=19 |issue=12 |pages=1012–1020 |date=2018 |pmid=29962339 |doi=10.2174/1389200219666180702104559 |s2cid=49650101 }}</ref><ref>{{cite journal |vauthors=Sinha AD, Agarwal R |title=Thiazide Diuretics in Chronic Kidney Disease |journal=Curr. Hypertens. Rep. |volume=17 |issue=3 |article-number=13 |date=March 2015 |pmid=25749608 |doi=10.1007/s11906-014-0525-x |s2cid=6108618 }}</ref><ref>{{cite journal |vauthors=Musini VM, Nazer M, Bassett K, Wright JM |title=Blood pressure-lowering efficacy of monotherapy with thiazide diuretics for primary hypertension |journal=Cochrane Database Syst Rev |issue=5 |article-number=CD003824 |date=May 2014 |volume=2014 |pmid=24869750 |doi=10.1002/14651858.CD003824.pub2 |pmc=10612990 }}</ref><ref>{{cite journal |vauthors=Sinha AD, Agarwal R |title=Clinical Pharmacology of Antihypertensive Therapy for the Treatment of Hypertension in CKD |journal=Clin J Am Soc Nephrol |volume=14 |issue=5 |pages=757–764 |date=May 2019 |pmid=30425103 |pmc=6500954 |doi=10.2215/CJN.04330418 |quote=thiazides either alone or in combination with a loop diuretic in advanced CKD, and all show some degree of efficacy, whether for hypertension or diuresis}}</ref>

===Left ventricular hypertrophy=== Chlortalidone is used to treat enlargement of the left ventricle of the heart; it works chiefly by lowering blood pressure, and thereby reducing systemic vascular resistance. There is evidence that chlortalidone is superior to hydrochlorothiazide for reducing the mass of the left ventricle of the heart in persons with enlargement of the left ventricle of the heart.<ref>{{cite journal |vauthors=Roush GC, Abdelfattah R, Song S, Ernst ME, Sica DA, Kostis JB |title=Hydrochlorothiazide vs chlorthalidone, indapamide, and potassium-sparing/hydrochlorothiazide diuretics for reducing left ventricular hypertrophy: A systematic review and meta-analysis |journal=The Journal of Clinical Hypertension |volume=20 |issue=10 |pages=1507–1515 |date=October 2018 |pmid=30251403 |doi=10.1111/jch.13386 |pmc=8030834 |doi-access=free }}</ref> Chlortalidone is superior to angiotensin converting enzyme Inhibitors or angiotensin II receptor blockers for inducing regression of enlargement of the left ventricle, which is the main pumping chamber of the heart.<ref>{{cite journal |vauthors=Roush GC, Abdelfattah R, Song S, Kostis JB, Ernst ME, Sica DA |title=Hydrochlorothiazide and alternative diuretics versus renin-angiotensin system inhibitors for the regression of left ventricular hypertrophy: a head-to-head meta-analysis |journal=J. Hypertens. |volume=36 |issue=6 |pages=1247–1255 |date=June 2018 |pmid=29465713 |doi=10.1097/HJH.0000000000001691 |s2cid=3423953 }}</ref>

===Swelling=== Chlortalidone reduces edema (swelling) by increasing urinary salt and water excretion, lowering intravascular hydrostatic pressure and thereby lowering transcapillary pressure (see Starling Equation). Edema may be caused by either increased hydrostatic pressure or reduced oncotic pressure in the blood vessels. Edema due to increased hydrostatic pressure may be a result of serious cardiopulmonary disease (which reduces glomerular perfusion in the kidney) or to kidney injury or disease (which may reduce glomerular excretion of salt and water by the kidney) or due to relatively benign conditions such as menstrual-related fluid retention, or as an adverse effect of dihydropyridine calcium channel blockers, which commonly cause swelling of the feet and lower legs. Edema due to decreased oncotic pressure may be a result of leaking of blood proteins through the glomeruli of an injured kidney<ref>{{cite journal |vauthors=Khan S, Floris M, Pani A, Rosner MH |title=Sodium and Volume Disorders in Advanced Chronic Kidney Disease |journal=Adv Chronic Kidney Dis |volume=23 |issue=4 |pages=240–6 |date=July 2016 |pmid=27324677 |doi=10.1053/j.ackd.2015.12.003 }}</ref> or a result of diminished synthesis of blood proteins by a damaged liver. Regardless of cause, chlortalidone may reduce the severity of edema by reducing intravascular volume and thereby reducing intravascular hydrostatic pressure.<ref>{{cite journal |vauthors=O'Brien JG, Chennubhotla SA, Chennubhotla RV |title=Treatment of edema |journal=Am Fam Physician |volume=71 |issue=11 |pages=2111–7 |date=June 2005 |pmid=15952439 }}</ref>

===Bone fracture prevention=== Chlortalidone decreases mineral bone loss by promoting calcium retention by the kidney, and by directly stimulating osteoblast differentiation and bone mineral formation.<ref name="pmid17656470">{{cite journal | vauthors = Dvorak MM, De Joussineau C, Carter DH, Pisitkun T, Knepper MA, Gamba G, Kemp PJ, Riccardi D | title = Thiazide diuretics directly induce osteoblast differentiation and mineralized nodule formation by interacting with a sodium chloride co-transporter in bone | journal = Journal of the American Society of Nephrology | volume = 18 | issue = 9 | pages = 2509–16 | date = September 2007 | pmid = 17656470 | pmc = 2216427 | doi = 10.1681/ASN.2007030348 | url = http://jasn.asnjournals.org/cgi/pmidlookup?view=long&pmid=17656470 }}</ref> A Cochrane review found tentative evidence that thiazide exposure was associated with a reduced risk of hip fracture.<ref>{{cite journal | vauthors = Aung K, Htay T | s2cid = 28866803 | title = Thiazide diuretics and the risk of hip fracture | journal = The Cochrane Database of Systematic Reviews | issue = 10 | article-number = CD005185 | date = October 2011 | pmid = 21975748 | doi = 10.1002/14651858.CD005185.pub2 }}</ref> A secondary analysis of data from the ALLHAT study found that chlortalidone reduced risk of hip and pelvis fracture.<ref>{{cite journal|author2-link=Barry R. Davis |author4-link=Paul Whelton| vauthors = Puttnam R, Davis BR, Pressel SL, Whelton PK, Cushman WC, Louis GT, Margolis KL, Oparil S, Williamson J, Ghosh A, Einhorn PT, Barzilay JI | title = Association of 3 Different Antihypertensive Medications With Hip and Pelvic Fracture Risk in Older Adults: Secondary Analysis of a Randomized Clinical Trial | journal = JAMA Internal Medicine | volume = 177 | issue = 1 | pages = 67–76 | date = January 2017 | pmid = 27893045 | doi = 10.1001/jamainternmed.2016.6821 | doi-access = free | hdl = 10453/125448 | hdl-access = free }}</ref>

===Kidney stone prevention=== Chlortalidone reduces the amount of calcium excreted in urine, reducing the risk of calcium oxalate kidney stones.<ref>{{cite journal |vauthors=Pearle MS, Roehrborn CG, Pak CY |s2cid=2514178 |title=Meta-analysis of randomized trials for medical prevention of calcium oxalate nephrolithiasis |journal=J. Endourol. |volume=13 |issue=9 |pages=679–85 |date=November 1999 |pmid=10608521 |doi=10.1089/end.1999.13.679 }}</ref> In people who have had multiple episodes of calcium oxalate kidney stones, chlortalidone lowers the risk of having another episode of kidney stones.<ref>{{cite journal |vauthors=Fink HA, Wilt TJ, Eidman KE, Garimella PS, MacDonald R, Rutks IR, Brasure M, Kane RL, Ouellette J, Monga M |title=Medical management to prevent recurrent nephrolithiasis in adults: a systematic review for an American College of Physicians Clinical Guideline |journal=Ann. Intern. Med. |volume=158 |issue=7 |pages=535–43 |date=April 2013 |pmid=23546565 |doi=10.7326/0003-4819-158-7-201304020-00005 |doi-access=free }}</ref> Chlortalidone is more effective than hydrochlorothiazide for lowering urine calcium levels and is therefore probably more effective.<ref>{{cite journal |vauthors=Wolfgram DF, Gundu V, Astor BC, Jhagroo RA |title=Hydrochlorothiazide compared to chlorthalidone in reduction of urinary calcium in patients with kidney stones |journal=Urolithiasis |volume=41 |issue=4 |pages=315–22 |date=August 2013 |pmid=23660825 |doi=10.1007/s00240-013-0568-5 |s2cid=10227907 }}</ref>

===Ménière's disease=== Chlortalidone reduces the endolymph volume which reduces the hydrostatic pressure in the inner ear chambers; elevated endolymph pressure in the inner ear is thought to be the cause of Ménière's disease or 'Endolymphatic hydrops.' Synthesis of evidence from multiple small, low-quality studies indicates that chlortalidone or other thiazide diuretics are effective for Ménière's Disease.<ref>{{cite journal |vauthors=Crowson MG, Patki A, Tucci DL |s2cid=24741244 |title=A Systematic Review of Diuretics in the Medical Management of Ménière's Disease |journal=Otolaryngol Head Neck Surg |volume=154 |issue=5 |pages=824–34 |date=May 2016 |pmid=26932948 |doi=10.1177/0194599816630733 }}</ref>

===Diabetes insipidus=== Chlortalidone (or other thiazide medication) is a key component of treatment of nephrogenic diabetes insipidus. Nephrogenic diabetes insipidus occurs when the kidney is unable to concentrate urine because it has an inadequate response to vasopressin-dependent removal of free water from the renal tubular filtrate. By blocking sodium ion resorption in the distal convoluted tubule, chlortalidone induces an increase in excretion of sodium ion in urine (natriuresis). Giving chlortalidone while simultaneously restricting dietary sodium intake causes mild hypovolemia (low intravascular volume), which induces isotonic reabsorption of solute from the proximal renal tubule, reducing solute delivery in the renal collecting tubule and renal medullary collecting duct. This reduced delivery of solute to the collecting tubule and medullary collecting duct allows increased water resorption and higher concentration of urine, which leads to reversal of nephrogenic diabetes insipidus by a means that is independent of vasopressin.<ref>{{cite journal |vauthors=Verbalis JG |title=Diabetes insipidus |journal=Rev Endocr Metab Disord |volume=4 |issue=2 |pages=177–85 |date=May 2003 |pmid=12766546 |doi= 10.1023/a:1022946220908|s2cid=33533827 }}</ref>

==Adverse effects== Some reviews have found a similar risk as hydrochlorothiazide,<ref name=Din2019/><!-- Quote = "Our meta-analysis has demonstrated a slight superiority for CTLD regarding blood pressure control. At the same time, the two medications do not show significant differences in their safety profile." --><ref name=Rou2018/><!-- Quote = Chlorthalidone, indapamide, and HCTZ have similar effects on serum potassium. --> while other reviews found a higher risk of side effects.<ref name=Ace2019/><!-- Quote = However, chlorthalidone use is more frequently associated with adverse metabolic effects, particularly hypokalemia and hyponatremia, compared with HCTZ. --><ref name=Spr2015/>

* Hypokalemia (low blood potassium) occurs occasionally; the risk of hypokalemia is higher in persons who are magnesium deficient<ref>{{cite journal |vauthors=DiNicolantonio JJ, O'Keefe JH, Wilson W |title=Subclinical magnesium deficiency: a principal driver of cardiovascular disease and a public health crisis |journal=Open Heart |volume=5 |issue=1 |article-number=e000668 |date=2018 |pmid=29387426 |pmc=5786912 |doi=10.1136/openhrt-2017-000668 }}</ref> * Hypomagnesemia (low blood magnesium) a review of four clinical trials found that low blood magnesium occurred in 20% of persons within a few weeks of beginning treatment with 50&nbsp;mg of chlortalidone daily.<ref>{{cite journal |vauthors=Pak CY |title=Correction of thiazide-induced hypomagnesemia by potassium-magnesium citrate from review of prior trials |journal=Clin. Nephrol. |volume=54 |issue=4 |pages=271–5 |date=October 2000 |pmid=11076102 }}</ref> The risk of chlortalidone-associated hypomagnesemia is higher in persons with diabetes mellitus who have low dietary magnesium intake. * Hyponatremia (low blood sodium) occurred in 4.1% of subjects randomized to chlortalidone in the Systolic Hypertension in the Elderly Trial, compared to 1.3% of control subjects.<ref>{{cite journal |title=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 |journal=JAMA |volume=265 |issue=24 |pages=3255–64 |date=June 1991 |pmid=2046107 |doi= 10.1001/jama.1991.03460240051027}}</ref> The risk of hyponatremia varies from 5 per 100,000 person-years for those younger than 40 years of age to 730 per 100,000 person-years in those older than 80 years of age.<ref>{{cite journal |vauthors=Barber J, McKeever TM, McDowell SE, Clayton JA, Ferner RE, Gordon RD, Stowasser M, O'Shaughnessy KM, Hall IP, Glover M |title=A systematic review and meta-analysis of thiazide-induced hyponatraemia: time to reconsider electrolyte monitoring regimens after thiazide initiation? |journal=Br J Clin Pharmacol |volume=79 |issue=4 |pages=566–77 |date=April 2015 |pmid=25139696 |pmc=4386942 |doi=10.1111/bcp.12499 }}</ref><ref>{{cite journal |vauthors=van Blijderveen JC, Straus SM, Rodenburg EM, Zietse R, Stricker BH, Sturkenboom MC, Verhamme KM |title=Risk of hyponatremia with diuretics: chlorthalidone versus hydrochlorothiazide |journal=Am. J. Med. |volume=127 |issue=8 |pages=763–71 |date=August 2014 |pmid=24811554 |doi=10.1016/j.amjmed.2014.04.014 }}</ref> Hyponatremia is more likely in persons with certain genetic variants of the prostaglandin transporter SLCO2A1 associated with elevated urinary PGE₂ and inappropriately low plasma ADH levels in the setting of low plasma osmolality.<ref>{{cite journal |vauthors=Ware JS, Wain LV, Channavajjhala SK, Jackson VE, Edwards E, Lu R, Siew K, Jia W, Shrine N, Kinnear S, Jalland M, Henry AP, Clayton J, O'Shaughnessy KM, Tobin MD, Schuster VL, Cook S, Hall IP, Glover M |title=Phenotypic and pharmacogenetic evaluation of patients with thiazide-induced hyponatremia |journal=J. Clin. Invest. |volume=127 |issue=9 |pages=3367–3374 |date=September 2017 |pmid=28783044 |pmc=5669583 |doi=10.1172/JCI89812 }}</ref> Thiazide-associated hyponatremia is often more severe than loop diuretic-associated hyponatremia because the predominant action of thiazides occurs late in the tubular flow, reducing opportunity to apply additional corrective action further along the tubule.<ref>{{cite book | vauthors = Peri A | title = Disorders of fluid and electrolyte metabolism: focus on hyponatremia | publisher = Karger | location = Basel New York | year = 2019 | isbn = 978-3-318-06383-7 }}</ref> * Hypercalcemia (high blood calcium level) can occur in normal persons exposed to chlortalidone but is more likely to occur when persons with sub-clinical hyperparathyroidism are exposed to chlortalidone.<ref>{{cite journal |vauthors=Griebeler ML, Kearns AE, Ryu E, Thapa P, Hathcock MA, Melton LJ, Wermers RA |title=Thiazide-Associated Hypercalcemia: Incidence and Association With Primary Hyperparathyroidism Over Two Decades |journal=J. Clin. Endocrinol. Metab. |volume=101 |issue=3 |pages=1166–73 |date=March 2016 |pmid=26751196 |pmc=4803175 |doi=10.1210/jc.2015-3964 }}</ref> * Hyperuricemia, high levels of uric acid in the blood * Hyperlipidemia, high cholesterol and triglycerides * Headache * Nausea/vomiting * Photosensitivity increased susceptibility to sunburn of skin with sun exposure * Photoonycholysis detachment of nails from nailbed with sun exposure<ref>{{cite book | vauthors = Rubin A | title = Scher and Daniel's nails: diagnosis, surgery, therapy | pages = 453–489 | publisher = Springer | location = Cham | year = 2018 | isbn = 978-3-319-65647-2 }}</ref> * Weight gain * Gout; approximately doubles the risk<ref>{{cite journal |vauthors=Evans PL, Prior JA, Belcher J, Mallen CD, Hay CA, Roddy E |title=Obesity, hypertension and diuretic use as risk factors for incident gout: a systematic review and meta-analysis of cohort studies |journal=Arthritis Res. Ther. |volume=20 |issue=1 |article-number=136 |date=July 2018 |pmid=29976236 |pmc=6034249 |doi=10.1186/s13075-018-1612-1 |doi-access=free }}</ref> * Pancreatitis

==Mechanism of action== Chlortalidone reduces reabsorption of sodium and chloride primarily through inhibition of the Na⁺/Cl⁻ symporter in the apical membrane of distal convoluted tubule cells in the kidney.<ref>{{cite journal |vauthors=Gamba G |title=The thiazide-sensitive Na+-Cl- cotransporter: molecular biology, functional properties, and regulation by WNKs |journal=Am. J. Physiol. Renal Physiol. |volume=297 |issue=4 |pages=F838–48 |date=October 2009 |pmid=19474192 |pmc=3350128 |doi=10.1152/ajprenal.00159.2009 }}</ref> Although chlortalidone is often referred to as a "thiazide-like" diuretic, it is unlike thiazide diuretics in that, in addition to its inhibition of the Na⁺/Cl⁻ symporter, it also strongly inhibits multiple isoforms of carbonic anhydrase.<ref>{{cite journal |vauthors=Kurtz TW |title=Chlorthalidone: don't call it "thiazide-like" anymore |journal=Hypertension |volume=56 |issue=3 |pages=335–7 |date=September 2010 |pmid=20625074 |doi=10.1161/HYPERTENSIONAHA.110.156166 |doi-access=free }}</ref> Some of chlortalidone's diuretic effect is also due to this inhibition of carbonic anhydrase in the proximal tubule.<ref>{{cite journal |vauthors=Johnston MM, Li H, Mufson D |title=Chlorthalidone analysis using carbonic anhydrase inhibition |journal=J Pharm Sci |volume=66 |issue=12 |pages=1735–8 |date=December 1977 |pmid=411910 |doi= 10.1002/jps.2600661220 |bibcode=1977JPhmS..66.1735J }}</ref>

There is uncertainty about the mechanism of the blood pressure-lowering effect that occurs during chronic exposure to chlortalidone.<ref>{{cite journal |vauthors=Shahin MH, Johnson JA |title=Mechanisms and pharmacogenetic signals underlying thiazide diuretics blood pressure response |journal=Curr Opin Pharmacol |volume=27 |pages=31–7 |date=April 2016 |pmid=26874237 |pmc=4915478 |doi=10.1016/j.coph.2016.01.005 }}</ref>

==Pharmacokinetics== Chlortalidone is slowly absorbed from the gastrointestinal tract after oral ingestion. It has a long half-life and therefore a prolonged diuretic action, which results in continued diuretic effects despite a skipped dose. This prolonged action of chlortalidone despite missing doses may account for the higher efficacy of chlortalidone compared to the shorter half-life medication, hydrochlorothiazide. Chlortalidone is eliminated from the body mostly by the kidney, as unchanged drug. Thus, in persons with diminished kidney function, the clearance of chlortalidone is reduced and the elimination half-life is increased.<ref name = "Singer_1985" />

As with other thiazide diuretics, chlortalidone crosses the placenta and is excreted in breast milk.<ref>{{cite journal |vauthors=Mulley BA, Parr GD, Pau WK, Rye RM, Mould JJ, Siddle NC |title=Placental transfer of chlorthalidone and its elimination in maternal milk |journal=Eur. J. Clin. Pharmacol. |volume=13 |issue=2 |pages=129–31 |date=May 1978 |pmid=658109 |doi= 10.1007/bf00609757|s2cid=22930934 }}</ref> Chlortalidone may suppress lactation, and has been used for this indication. Due to its long half-life, chlortalidone may accumulate in newborns via breast milk, despite receiving only about 6% of the maternal weight-adjusted dose.<ref name="lactmed">{{cite journal |title= Chlorthalidone |url=https://www.ncbi.nlm.nih.gov/books/NBK501562/ | journal = Drugs and Lactation Database (LactMed) [Internet] | location = Bethesda (MD) | author = National Institute of Child Health and Human Development |date=2006 |access-date=13 December 2018| id = NBK501562 | pmid = 30000622 }}</ref>

==Chemistry== Chlortalidone is in the sulfamoylbenzamide class. As it lacks the benzothiadiazine structure of the thiazide-type diuretics, it is called a thiazide-like diuretic.<ref>National Center for Biotechnology Information. PubChem Compound Database; CID=2732, {{cite web | title = Chlorthalidone | url = https://pubchem.ncbi.nlm.nih.gov/compound/2732 | work = PubChem | publisher = U.S. National Library of Medicine }}</ref> Chlortalidone is freely soluble in dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), and methanol; it is also soluble in warm ethanol.<ref name = "Singer_1985">{{cite book | vauthors = Singer JM, O'Hare MJ, Rehm CR, Zarembo JE | chapter = Chlorthalidone | title = Analytical Profiles of Drug Substances | date = January 1985 | volume = 14 | pages = 1–36 | publisher = Academic Press | doi = 10.1016/S0099-5428(08)60575-4 | isbn = 978-0-12-260814-8 }}</ref>

Chlortalidone is the official name of the medication according to the (INN/BAN), which is the medication naming system coordinated by the World Health Organization. Chlorthalidone is the official name of the medication according to the (USAN), which is the medication naming system coordinated by the USAN Council, which is co-sponsored by the American Medical Association (AMA), the United States Pharmacopeial Convention (USP), and the American Pharmacists Association (APhA).

==Society and culture== Chlortalidone is banned for some sports (including cricket) because it is a diuretic, and can be used to reduce body weight or to mask the concomitant use of performance-enhancing drugs.<ref>{{cite journal |vauthors=Cadwallader AB, de la Torre X, Tieri A, Botrè F |title=The abuse of diuretics as performance-enhancing drugs and masking agents in sport doping: pharmacology, toxicology and analysis |journal=Br. J. Pharmacol. |volume=161 |issue=1 |pages=1–16 |date=September 2010 |pmid=20718736 |pmc=2962812 |doi=10.1111/j.1476-5381.2010.00789.x }}</ref> Sports such as wrestling or boxing categorize athletes according to body weight; taking a diuretic such as chlortalidone may lower body weight, and thereby permit an athlete to compete in a lighter weight class, which would provide an advantage. Diuretics such as chlortalidone also reduce the urine concentration of concomitantly-taken performance-enhancing drugs or of their metabolites, thus making it more difficult to detect these drugs using urine testing.<ref>{{cite news|title=Yasir Shah provisionally suspended after failed drugs test|url=https://www.bbc.com/sport/cricket/35185202|work=BBC News|date=27 December 2015}}</ref>

==References== {{reflist}}

{{Symporter inhibitors}} {{Diuretics}} {{Portal bar | Medicine}} {{Authority control}}

Category:Diuretics Category:Sulfonamides Category:Isoindolines Category:Drugs developed by Novartis Category:Chloroarenes Category:Lactams Category:Carbonic anhydrase inhibitors Category:World Anti-Doping Agency prohibited substances Category:Wikipedia medicine articles ready to translate