thiazide

Thiazide diuretics are primarily used to treat the hypertension (high blood pressure) and edema (swelling) caused by water overload as well as certain conditions related to unbalanced calcium metabolism.

There are many causes of hypertension (high blood pressure), including advancing age, smoking and obesity.{{Cite journal|last1=Musini|first1=Vijaya M|last2=Gill|first2=Rupam|last3=Wright|first3=James M|date=2018-04-18|title=First-line drugs for hypertension|journal=The Cochrane Database of Systematic Reviews|volume=2018|issue=4|pages=CD001841|doi=10.1002/14651858.CD001841.pub3|issn=1469-493X|pmc=6513559|pmid=29667175}} Sometimes the underlying cause of hypertension cannot be determined, resulting in a diagnosis of idiopathic hypertension. Regardless of the cause, someone may have very high hypertension without any initial symptoms. Uncontrolled hypertension will eventually cause damage to the heart, kidneys and eyes. Lifestyle changes, including reducing dietary salt, increasing exercise and losing weight can help to reduce blood pressure.

Thiazides and thiazide-like diuretics have been in constant use since their introduction in 1958. Decades as a cornerstone of hypertension treatment show how well these drugs perform for most patients.{{cite journal|vauthors=Moser M, Feig PU|date=November 2009|title=Fifty years of thiazide diuretic therapy for hypertension|journal=Archives of Internal Medicine|publisher=JAMA|volume=169|issue=20|pages=1851–6|doi=10.1001/archinternmed.2009.342|pmid=19901136|doi-access=free}} Low-dose thiazides are tolerated as well as the other classes of medications for hypertension, including ACE inhibitors, beta blockers and calcium channel blockers. In general, the thiazides and thiazide-like diuretics reduce the risk of death, stroke, heart attack, and heart failure due to hypertension.{{cite journal|vauthors=Wright JM, Musini VM, Gill R|date=April 2018|title=First-line drugs for hypertension|journal=The Cochrane Database of Systematic Reviews|volume=2018|issue=4|pages=CD001841|doi=10.1002/14651858.CD001841.pub3|pmc=6513559|pmid=29667175}}

Clinical practice guidelines regarding the use of thiazides vary by geographic region. Guidelines in the United States recommend thiazides as a first-line treatment for hypertension (JNC VIII).{{cite journal|vauthors=James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J, Lackland DT, LeFevre ML, MacKenzie TD, Ogedegbe O, Smith SC, Svetkey LP, Taler SJ, Townsend RR, Wright JT, Narva AS, Ortiz E|date=February 2014|title=2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8)|journal=JAMA|volume=311|issue=5|pages=507–20|doi=10.1001/jama.2013.284427|pmid=24352797|doi-access=free}} A systematic review by the Cochrane Collaboration specifically recommended that low-dose thiazides be used as the initial pharmacological therapy for high blood pressure. Low-dose thiazides are more effective at treating hypertension than beta blockers and are similar to angiotensin-converting enzyme (ACE) inhibitors. Thiazides are a recommended treatment for hypertension in Europe (ESC/ESH).{{cite web|url=http://www.escardio.org/knowledge/guidelines/CVD_Prevention_in_Clinical_Practice.htm|title=escardio.org|archive-url=https://web.archive.org/web/20080517202503/http://www.escardio.org/knowledge/guidelines/CVD_Prevention_in_Clinical_Practice.htm|archive-date=2008-05-17|url-status=dead|access-date=2007-08-30}} Thiazides should be considered as initial treatment if the patient has a high risk of developing heart failure.National Institute for Health and Clinical Excellence (NICE) guideline on the management of primary hypertension in adults (CG127) accessed 5/3/2012 at {{cite web|url=http://publications.nice.org.uk/hypertension-cg127|title=CG127 - Hypertension - National Institute for Health and Clinical Excellence|archive-url=https://web.archive.org/web/20120131225642/http://publications.nice.org.uk/hypertension-cg127|archive-date=2012-01-31|url-status=dead|access-date=2012-03-05}} Thiazides have also been replaced by ACE inhibitors in Australia due to the association between thaizide use and increased risk of developing diabetes mellitus type 2.Guide to management of hypertension 2008. National Heart Foundation Australia. 2008. accessed online at {{cite web|url=http://www.heartfoundation.org.au/SiteCollectionDocuments/HypertensionGuidelines2008to2010Update.pdf|title=Archived copy|archive-url=https://web.archive.org/web/20130515133817/http://www.heartfoundation.org.au/SiteCollectionDocuments/HypertensionGuidelines2008to2010Update.pdf|archive-date=2013-05-15|url-status=dead|access-date=2013-07-10}}

Thiazides can be used to paradoxically decrease urine flow in people with nephrogenic diabetes insipidus.{{Cite journal|last=Magaldi|first=Antonio J.|date=2000-12-01|title=New insights into the paradoxical effect of thiazides in diabetes insipidus therapy|journal=Nephrology Dialysis Transplantation|volume=15|issue=12|pages=1903–1905|doi=10.1093/ndt/15.12.1903|pmid=11096127|issn=0931-0509|doi-access=free}} Thiazides may also be useful in treating hyponatremia (low blood sodium) in infants with central diabetes insipidus.{{Cite journal|last=Welch|first=Thomas R.|date=2015-09-01|title=Diuretics for diabetes insipidus|url=https://www.jpeds.com/article/S0022-3476(15)00751-9/abstract|journal=The Journal of Pediatrics|language=en|volume=167|issue=3|pages=503–505|doi=10.1016/j.jpeds.2015.07.029|issn=0022-3476|doi-access=free}}

Thiazides are useful in treating kidney stones and bladder stones that result from hypercalciuria (high urine calcium levels). Thiazides increase the uptake of calcium in the distal tubules, to moderately reduce urinary calcium. Thiazides combined with potassium citrate, increased water intake and decreased dietary oxalate and sodium can slow or even reverse the formation of calcium-containing kidney stones.{{Cite web|url=https://kidneystones.uchicago.edu/thiazide-diuretics-for-stone-prevention/|title=THIAZIDE DIURETICS FOR STONE PREVENTION {{!}} Kidney Stone Evaluation And Treatment Program|website=kidneystones.uchicago.edu|access-date=2019-07-22}} High-dose therapy with the thiazide-like diuretic indapamide can be used to treat idiopathic hypercalcinuria (high urine calcium with unknown cause).{{Cite journal|last1=Martins|first1=M. C.|last2=Meyers|first2=A. M.|last3=Whalley|first3=N. A.|last4=Margolius|first4=L. P.|last5=Buys|first5=M. E.|date=1996|title=Indapamide (Natrilix): the agent of choice in the treatment of recurrent renal calculi associated with idiopathic hypercalciuria|journal=British Journal of Urology|volume=78|issue=2|pages=176–180|doi=10.1046/j.1464-410X.1996.00633.x|pmid=8813907|issn=1464-410X}}

Hypocalcemia (low blood calcium) can be caused by a variety of conditions that reduce dietary calcium absorption, increase calcium excretion or both. Positive calcium balance occurs when calcium excretion is decreased and intake remains constant so that calcium is retained within the body.Aung K, Htay T. Thiazide diuretics and the risk of hip fracture. Cochrane Database of Systematic Reviews 2011, Issue 10. Art. No.: CD005185. DOI: 10.1002/14651858.CD005185.pub2. Higher levels of retained calcium are associated with increased bone mineral density and fewer fractures in individuals with osteoporosis. By a poorly understood mechanism, thiazides directly stimulate osteoblast differentiation and bone mineral formation, further slowing the course of osteoporosis.{{cite journal|vauthors=Dvorak MM, De Joussineau C, Carter DH, Pisitkun T, Knepper MA, Gamba G, Kemp PJ, Riccardi D|date=September 2007|title=Thiazide diuretics directly induce osteoblast differentiation and mineralized nodule formation by interacting with a sodium chloride co-transporter in bone|url=http://jasn.asnjournals.org/cgi/pmidlookup?view=long&pmid=17656470|journal=Journal of the American Society of Nephrology|volume=18|issue=9|pages=2509–16|doi=10.1681/ASN.2007030348|pmc=2216427|pmid=17656470}}

Thiazides may be used to treat the symptoms of Dent's disease, an X-linked genetic condition that results in electrolyte imbalance with repeated episodes of kidney stones. A case study of two brothers with the condition, two years of treatment with hydrochlorothiazide reduced the incidence of kidney stones and improved kidney function.{{Cite journal|last1=Velasco|first1=Nestor|last2=Jayawardene|first2=Satishkumar A.|last3=Burgess|first3=Helen K.|date=2001-07-01|title=Dent's disease: can we slow its progression?|journal=Nephrology Dialysis Transplantation|volume=16|issue=7|pages=1512–1513|doi=10.1093/ndt/16.7.1512|pmid=11427657|issn=0931-0509|doi-access=free}} The thiazide-like diuretic chlortalidone reduced urine calcium oxalate in seven of the eight males with inactivated CLCN5 gene that participated in the study.{{Cite journal|last1=Scheinman|first1=Steven J.|last2=Asplin|first2=John|last3=Ploutz-Snyder|first3=Robert J.|last4=Why|first4=Scott Van|last5=Goodyer|first5=Paul|last6=Blowey|first6=Douglas|last7=D’Mello|first7=Richard G.|last8=Schurman|first8=Scott|last9=Raja|first9=Khalid A.|date=2002-12-01|title=Responsiveness of Hypercalciuria to Thiazide in Dent's Disease|url=https://jasn.asnjournals.org/content/13/12/2938|journal=Journal of the American Society of Nephrology|volume=13|issue=12|pages=2938–2944|doi=10.1097/01.ASN.0000036869.82685.F6|issn=1046-6673|pmid=12444212|doi-access=free}} Inactivation of the CLCN5 gene causes Dent's disease Type 1.{{Cite web|url=https://rarediseases.org/rare-diseases/dent-disease/|title=Dent Disease|website=NORD (National Organization for Rare Disorders)|access-date=2019-07-22}} The rare nature of Dent's disease makes it difficult to coordinate large controlled studies, so most evidence for thiazide use is with too few patients to make broad recommendations possible. Long-term thiazide use may not be advisable due to the risk of significant adverse side effects.{{cn|date=September 2022}}

Bromine intoxication can be treated by giving intravenous saline with either thiazides or Loop diuretics.{{Cite journal|last1=Trump|first1=D. L.|last2=Hochberg|first2=M. C.|date=April 1976|title=Bromide intoxication|journal=The Johns Hopkins Medical Journal|volume=138|issue=4|pages=119–123|issn=0021-7263|pmid=131871}}

Contraindications include: {{cn|date=September 2022}}

• Hypotension
• Allergy to sulphur-containing medications
• Gout
• Kidney failure
• Lithium therapy
• Hypokalemia
• May worsen diabetes

Thiazides reduce the clearance of uric acid since they compete for the same transporter, and therefore raise the levels of uric acid in the blood. Hence, they are prescribed with caution in patients with gout or hyperuricemia.{{Cite web|url=http://www.medscape.com/viewarticle/421426|title=Medication Update}}{{cite web |url=http://rx-s.net/weblog/more/hydrochlorothiazide_hctz_microzide_contraindications_and_precautions/ |title=Hydrochlorothiazide, HCTZ (Microzide) Contraindications and Precautions |access-date=2010-05-14 |url-status=dead |archive-url=https://web.archive.org/web/20101009210901/http://rx-s.net/weblog/more/hydrochlorothiazide_hctz_microzide_contraindications_and_precautions/ |archive-date=2010-10-09 }}

Chronic administration of thiazides is associated with the increase of insulin resistance which can lead to hyperglycemia.{{Cite journal|last1=Rehman|first1=Abdur|last2=Setter|first2=Stephen M.|last3=Vue|first3=Mays H.|date=2011-11-01|title=Drug-Induced Glucose Alterations Part 2: Drug-Induced Hyperglycemia|url=https://spectrum.diabetesjournals.org/content/24/4/234|journal=Diabetes Spectrum|volume=24|issue=4|pages=234–238|doi=10.2337/diaspect.24.4.234|issn=1040-9165|doi-access=free}}

Thiazides cause loss of blood potassium, while conserving blood calcium.{{cn|date=September 2022}}

Thiazides can decrease placental perfusion and adversely affect the fetus, so should be avoided in pregnancy.{{Cite web|url=http://www.merck.com/mmpe/sec18/ch261/ch261k.html|title = Hypertension in Pregnancy - Gynecology and Obstetrics}}

• File:Kidney nephron molar transport diagram.svgHypokalemia – Thiazide diuretics reduce potassium concentration in blood through two indirect mechanisms: inhibition of sodium-chloride symporter at distal convoluted tubule of a nephron and stimulation of aldosterone that activates Na+/K+-ATPase at collecting duct. Inhibition of sodium-chloride symporter increases availability of sodium and chloride in urine. When the urine reaches the collecting duct, the increase in sodium and chloride availability activates Na+/K+-ATPase, which increases the absorption of sodium and excretion of potassium into the urine. Long term administration of thiazide diuretics reduces total body blood volume. This activates the renin–angiotensin system, stimulates the secretion of aldosterone, thus activating Na+/K+-ATPase, increasing excretion of potassium in urine.{{cite book|last1=Dowd|first1=Frank J|last2=Johnson|first2=Bart|last3=Mariotti|first3=Angelo|title=Pharmacology and Therapeutics for Dentistry - E-Book|date=3 September 2016|publisher=Elsevier Health Sciences|isbn=978-0-323-44595-5|pages=324–326|url=https://books.google.com/books?id=6xT7DAAAQBAJ&pg=PA326|access-date=4 November 2017}} Therefore, ACE inhibitor and thiazide combination is used to prevent hypokalemia.
• Hyperglycemia
• Hyperlipidemia
• Hyperuricemia
• Hypercalcemia
• Hyponatremia
• According to a 2025 retrospective study patients who experience early hyponatremia after beginning thiazide diuretics have a higher risk of mortality compared to those with stable sodium levels.{{Cite web |title=Early hyponatremia after starting thiazide associated with increased mortality risk |url=https://www.healio.com/news/nephrology/20250227/early-hyponatremia-after-starting-thiazide-associated-with-increased-mortality-risk |access-date=2025-02-28 |website=www.healio.com |language=en}} Researchers also found that these patients faced an increased likelihood of complications such as sepsis, pneumonia, urinary tract infections, cellulitis, myocardial infarction, stroke, congestive heart failure, ataxia, and hip fractures.{{Cite journal |last1=Achinger |first1=Steven G. |last2=Ayus |first2=Juan Carlos |last3=Kumar |first3=Ambuj |last4=Tsalatsanis |first4=Athanasios |date=2025-02-01 |title=Thiazide-Associated Hyponatremia and Mortality Risk: A Cohort Study |url=https://www.kidneymedicinejournal.org/article/S2590-0595(24)00152-3/fulltext |journal=Kidney Medicine |language=English |volume=7 |issue=2 |doi=10.1016/j.xkme.2024.100941 |issn=2590-0595 |pmid=39866296|pmc=11759562 }}
• Hypomagnesemia
• Hypocalciuria
• Metabolic alkalosis

File:Gitelman syndrome.jpg

Thiazide diuretics control hypertension in part by inhibiting reabsorption of sodium (Na⁺) and chloride (Cl⁻) ions from the distal convoluted tubules in the kidneys by blocking the thiazide-sensitive Na⁺-Cl⁻ symporter.{{cite journal |vauthors=Duarte JD, Cooper-DeHoff RM |title=Mechanisms for blood pressure lowering and metabolic effects of thiazide and thiazide-like diuretics |journal=Expert Rev Cardiovasc Ther |volume=8 |issue=6 |pages=793–802 |date=June 2010 |pmid=20528637 |pmc=2904515 |doi=10.1586/erc.10.27 }}

The term "thiazide" is also often used for drugs with a similar action that do not have the thiazide chemical structure, such as chlorthalidone, metolazone and indapamide. These agents are more properly termed thiazide-like diuretic. {{cite journal |vauthors=Taler SJ |title= Initial Treatment of Hypertension. |journal= N Engl J Med |volume= 387 |pages= 636–644 |date= 2018 |issue= 7 |pmid=29443671 |

pmc=2904515 |doi= 10.1056/NEJMcp1613481 }}

Anyhow, the results regarding the importance of the kidney alone and the thiazide-sensitive receptor NCC Sodium-chloride symporter in the anti-hypertensive effects of thiazides have been debated for decades providing evidence for the existence of an extrarenal target involved in the thiazide-mediated chronic inhibition of vascular constriction. {{cite journal |vauthors=Rapoport RM, Manoocher S |title= Mechanism of Thiazide Diuretic Arterial Pressure Reduction: The Search Continues. |journal= Front Pharmacol |volume= 387 |date= 2019 |page= 815 |pmid=31543812 |doi= 10.3389/fphar.2019.00815 |doi-access= free |pmc= 6730501 }}

The membrane-associated phospholipase NAPE-PLD (N-acyl phosphatidylethanolamine-specific phospholipase D) of the endocannabinoid system is a renal and extrarenal target of "thiazide-type" (e.g., hydrochlorothiazide) and "thiazide-like" diuretics (e.g., chlorthalidone and indapamide). NAPE-PLD accounts for both their acute (diuresis and accompanying decrease of plasma volume) and chronic (reduction of arterial pressure through vascular dilation) therapeutic effects, as well as for thiazide-associated metabolic abnormalities (e.g., hyperlipidemia and hyperglycemia). {{cite journal | vauthors = Chiarugi S, Margheriti F, De Lorenzi V, Martino E, Garau G | title = NAPE-PLD is target of thiazide diuretics | journal = Cell Chem Biol | date = 2025 | volume = 32 | issue = 3 | pages = 449–462 | pmid = 39999832 | doi = 10.1016/j.chembiol.2025.01.008 }}

File:20250402 155152 NAPE-PLD.jpg

Thiazide diuretics also increase calcium reabsorption at the distal tubule. By lowering the sodium concentration in the tubule epithelial cells, thiazides indirectly increase the activity of the basolateral Na⁺/Ca²⁺ antiporter to maintain intracellular Na⁺ level, facilitating Ca²⁺ to leave the epithelial cells into the renal interstitium. Thus, intracellular Ca²⁺ concentration is decreased, which allows more Ca²⁺ from the lumen of the tubules to enter epithelial cells via apical Ca²⁺-selective channels (TRPV5). In other words, less Ca²⁺ in the cell increases the driving force for reabsorption from the lumen.{{cite book|last=Longo|first=Dan L|title=Harrison's Principals of Internal Medicine, Vol. 2|year=2012|publisher=McGraw-Hill|location=New York|isbn=978-0-07-174887-2|pages=2285|display-authors=etal}}

Thiazides are also thought to increase the reabsorption of Ca²⁺ by a mechanism involving the reabsorption of sodium and calcium in the proximal tubule in response to sodium depletion. Some of this response is due to augmentation of the action of parathyroid hormone.{{cite book|last=Longo|first=Dan L|title=Harrison's Principals of Internal Medicine, Vol. 2|year=2012|publisher=McGraw-Hill|location=New York|isbn=978-0-07-174887-2|pages=3109|display-authors=etal}}

Thiazides pass into breast milk and can decrease the flow of breast milk.{{cite book|author1=Gerald G. Briggs|author2=Roger K. Freeman|author3=Sumner J. Yaffe|title=Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk|url=https://books.google.com/books?id=OIgTE4aynrMC&pg=PA257|year=2011|publisher=Lippincott Williams & Wilkins|isbn=978-1-60831-708-0|pages=257–}} Thiazides have been associated with significant side effects in some nursing infants and should be administered to nursing mothers with caution.{{cite journal |title=Transfer of drugs and other chemicals into human milk |journal=Pediatrics |volume=108 |issue=3 |pages=776–89 | date=September 2001 |pmid=11533352 |doi= 10.1542/peds.108.3.776|author1=American Academy of Pediatrics Committee on Drugs |doi-access=free }}

The thiazide diuretics were developed by scientists Karl H. Beyer, James M. Sprague, John E. Baer, and Frederick C. Novello of Merck and Co. in the 1950s,{{cite journal|vauthors=Beyer KH|year=1993|title=Chlorothiazide. How the thiazides evolved as antihypertensive therapy|journal=Hypertension|volume=22|issue=3|pages=388–91|doi=10.1161/01.hyp.22.3.388|pmid=8349332|doi-access=free}} and led to the marketing of the first drug of this class, chlorothiazide, under the trade name Diuril in 1958.{{cite web |url=http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails |title=Drugs@FDA: FDA Approved Drug Products }} The research leading to the discovery of chlorothiazide, leading to "the saving of untold thousands of lives and the alleviation of the suffering of millions of victims of hypertension" was recognized by a special Public Health Award from the Lasker Foundation in 1975.{{cite web |url=http://www.laskerfoundation.org/awards/formaward.htm |title=The Lasker Foundation - Awards }}

{{reflist|30em}}

{{Diuretics}}

{{Antihypertensives and diuretics}}

{{Membrane transport modulators}}

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Category:Nephrotoxins