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Thiazide

October 15, 2023

Thiazide (/ˈθaɪəzaɪd/) refers to both a class of sulfur-containing organic molecules[1] and a class of diuretics based on the chemical structure of benzothiadiazine.[2] The thiazide drug class was discovered and developed at Merck and Co. in the 1950s.[3] The first approved drug of this class, chlorothiazide, was marketed under the trade name Diuril beginning in 1958.[3] In most countries, thiazides are the least expensive antihypertensive drugs available.[4]

Thiazide
Drug class
Chlorothiazide, the first thiazide drug
Class identifiers
Usehypertension, edema
ATC codeC03A
Biological targetsodium-chloride symporter
External links
MeSHD049971
Legal status
In Wikidata
Benzothiadiazine, the parent structure of this class of molecules

Thiazide organic molecules are bi-cyclic structures that contain adjacent sulfur and nitrogen atoms on one ring.[5] Confusion sometimes occurs because thiazide-like diuretics such as indapamide are referred to as thiazides despite not having the thiazide chemical structure.[6] When used this way, "thiazide" refers to a drug which acts at the thiazide receptor.[7] The thiazide receptor is a sodium-chloride transporter that pulls NaCl from the lumen in the distal convoluted tubule. Thiazide diuretics inhibit this receptor, causing the body to release NaCl and water into the lumen, thereby increasing the amount of urine produced each day.[6] An example of a molecule that is chemically a thiazide but not used as a diuretic is methylchloroisothiazolinone, often found as an antimicrobial in cosmetics.[8]

Medical uses Edit

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.

Water balance Edit

Hypertension Edit

There are many causes of hypertension (high blood pressure), including advancing age, smoking and obesity.[9] Sometimes the underlying cause of hypertension can not 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.[9]

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.[10] Low-dose thiazides are tolerated as well as the other classes of medications for hypertension, including ACE inhibitors, beta blockers and calcium channel blockers.[9] In general, the thiazides and thiazide-like diuretics reduce the risk of death, stroke, heart attack, and heart failure due to hypertension.[11]

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).[12] A systematic review by the Cochrane Collaboration specifically recommended that low-dose thiazides be used as the initial pharmacological therapy for high blood pressure.[9] Low-dose thiazides are more effective at treating hypertension than beta blockers and are similar to angiotensin-converting enzyme (ACE) inhibitors.[9] Thiazides are a recommended treatment for hypertension in Europe (ESC/ESH).[13] However, the UK National Institute for Health and Clinical Excellence recommends ACE inhibitor and calcium channel blockers for first-line treatment of hypertension in adults (CG127).[14] Thiazides should be considered as initial treatment if the patient has a high risk of developing heart failure.[14] 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.[15]

Drug Type Generic Drug Name Low Dose

Threshold

(mg/day)[9]

Thiazide Diuretic Chlorothiazide  500
Hydrochlorothiazide  50
Bendroflumethiazide  5
Methyclothiazide  5
Trichlormethiazide  2
Thiazide-like Diuretic Chlorthalidone  50
Indapamide  5

Diabetes insipidus Edit

Thiazides can be used to paradoxically decrease urine flow in people with nephrogenic diabetes insipidus.[16] Thiazides may also be useful in treating hyponatremia (low blood sodium) in infants with central diabetes insipidus.[17]

Calcium balance Edit

Urinary stones Edit

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.[18] High-dose therapy with the thiazide-like diuretic indapamide can be used to treat idiopathic hypercalcinuria (high urine calcium with unknown cause).[19]

Dent's disease Edit

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.[20] The thiazide-like diuretic chlortalidone reduced urine calcium oxalate in seven of the eight males with inactivated CLCN5 gene that participated in the study.[21] Inactivation of the CLCN5 gene causes Dent's disease Type 1.[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.[22] Long-term thiazide use may not be advisable due to the risk of significant adverse side effects.[citation needed]

Osteoporosis Edit

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.[23] Higher levels of retained calcium are associated with increased bone mineral density and fewer fractures in individuals with osteoporosis.[23] By a poorly understood mechanism, thiazides directly stimulate osteoblast differentiation and bone mineral formation, further slowing the course of osteoporosis.[24]

Other uses Edit

Bromine intoxication can be treated by giving intravenous saline with either thiazides or Loop diuretics.[25]

Contraindications Edit

Contraindications include:[citation needed]

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.[26][27]

Chronic administration of thiazides is associated with the increase of insulin resistance which can lead to hyperglycemia.[28]

Thiazides cause loss of blood potassium, while conserving blood calcium.[citation needed]

Thiazides can decrease placental perfusion and adversely affect the fetus, so should be avoided in pregnancy.[27][29]

Adverse effects Edit

Mechanism of action Edit

 
Illustration of the mechanism of action of thiazide diuretics in the distal convoluted tubule of nephrons.

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.[31] The term "thiazide" is also often used for drugs with a similar action that do not have the thiazide chemical structure, such as chlorthalidone and metolazone. These agents are more properly termed thiazide-like diuretics.[citation needed]

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.[32]

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.[33]

Breastfeeding Edit

Thiazides pass into breast milk and can decrease the flow of breast milk.[34] Thiazides have been associated with significant side effects in some nursing infants and should be administered to nursing mothers with caution.[35]

History Edit

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,[36] and led to the marketing of the first drug of this class, chlorothiazide, under the trade name Diuril in 1958.[37] 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.[38]

References Edit

  1. ^ Thiazides at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
  2. ^ Thiazide+Diuretics at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
  3. ^ a b Beyer KH (September 1993). "Chlorothiazide. How the thiazides evolved as antihypertensive therapy". Hypertension. 22 (3): 388–91. doi:10.1161/01.hyp.22.3.388. PMID 8349332.
  4. ^ Whitworth JA (November 2003). "2003 World Health Organization (WHO)/International Society of Hypertension (ISH) statement on management of hypertension" (PDF). Journal of Hypertension. 21 (11): 1983–92. doi:10.1097/00004872-200311000-00002. PMID 14597836. S2CID 3211922.
  5. ^ "MeSH Browser". meshb.nlm.nih.gov. Retrieved 2019-07-22.
  6. ^ a b Akbari, Pegah; Khorasani-Zadeh, Arshia (2019), "Thiazide Diuretics", StatPearls, StatPearls Publishing, PMID 30422513, retrieved 2019-07-18
  7. ^ thiazide+receptor at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
  8. ^ "6 Final Report on the Safety Assessment of Methylisothiazolinone and Methylchloroisothiazolinone". Journal of the American College of Toxicology. 11 (1): 75–128. 1992-01-01. doi:10.3109/10915819209141993. ISSN 0730-0913. S2CID 208506926.
  9. ^ a b c d e f Musini, Vijaya M; Gill, Rupam; Wright, James M (2018-04-18). "First‐line drugs for hypertension". The Cochrane Database of Systematic Reviews. 2018 (4): CD001841. doi:10.1002/14651858.CD001841.pub3. ISSN 1469-493X. PMC 6513559. PMID 29667175.
  10. ^ Moser M, Feig PU (November 2009). "Fifty years of thiazide diuretic therapy for hypertension". Archives of Internal Medicine. JAMA. 169 (20): 1851–6. doi:10.1001/archinternmed.2009.342. PMID 19901136.
  11. ^ Wright JM, Musini VM, Gill R (April 2018). "First-line drugs for hypertension". The Cochrane Database of Systematic Reviews. 2018 (4): CD001841. doi:10.1002/14651858.CD001841.pub3. PMC 6513559. PMID 29667175.
  12. ^ James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J, et al. (February 2014). "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)". JAMA. 311 (5): 507–20. doi:10.1001/jama.2013.284427. PMID 24352797.
  13. ^ . Archived from the original on 2008-05-17. Retrieved 2007-08-30.
  14. ^ a b National Institute for Health and Clinical Excellence (NICE) guideline on the management of primary hypertension in adults (CG127) accessed 5/3/2012 at . Archived from the original on 2012-01-31. Retrieved 2012-03-05.
  15. ^ Guide to management of hypertension 2008. National Heart Foundation Australia. 2008. accessed online at (PDF). Archived from the original (PDF) on 2013-05-15. Retrieved 2013-07-10.{{cite web}}: CS1 maint: archived copy as title (link)
  16. ^ Magaldi, Antonio J. (2000-12-01). "New insights into the paradoxical effect of thiazides in diabetes insipidus therapy". Nephrology Dialysis Transplantation. 15 (12): 1903–1905. doi:10.1093/ndt/15.12.1903. ISSN 0931-0509. PMID 11096127.
  17. ^ Welch, Thomas R. (2015-09-01). "Diuretics for diabetes insipidus". The Journal of Pediatrics. 167 (3): 503–505. doi:10.1016/j.jpeds.2015.07.029. ISSN 0022-3476.
  18. ^ "THIAZIDE DIURETICS FOR STONE PREVENTION | Kidney Stone Evaluation And Treatment Program". kidneystones.uchicago.edu. Retrieved 2019-07-22.
  19. ^ Martins, M. C.; Meyers, A. M.; Whalley, N. A.; Margolius, L. P.; Buys, M. E. (1996). "Indapamide (Natrilix): the agent of choice in the treatment of recurrent renal calculi associated with idiopathic hypercalciuria". British Journal of Urology. 78 (2): 176–180. doi:10.1046/j.1464-410X.1996.00633.x. ISSN 1464-410X. PMID 8813907.
  20. ^ Velasco, Nestor; Jayawardene, Satishkumar A.; Burgess, Helen K. (2001-07-01). "Dent's disease: can we slow its progression?". Nephrology Dialysis Transplantation. 16 (7): 1512–1513. doi:10.1093/ndt/16.7.1512. ISSN 0931-0509. PMID 11427657.
  21. ^ Scheinman, Steven J.; Asplin, John; Ploutz-Snyder, Robert J.; Why, Scott Van; Goodyer, Paul; Blowey, Douglas; D’Mello, Richard G.; Schurman, Scott; Raja, Khalid A. (2002-12-01). "Responsiveness of Hypercalciuria to Thiazide in Dent's Disease". Journal of the American Society of Nephrology. 13 (12): 2938–2944. doi:10.1097/01.ASN.0000036869.82685.F6. ISSN 1046-6673. PMID 12444212.
  22. ^ a b "Dent Disease". NORD (National Organization for Rare Disorders). Retrieved 2019-07-22.
  23. ^ a b 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.
  24. ^ Dvorak MM, De Joussineau C, Carter DH, Pisitkun T, Knepper MA, Gamba G, Kemp PJ, Riccardi D (September 2007). "Thiazide diuretics directly induce osteoblast differentiation and mineralized nodule formation by interacting with a sodium chloride co-transporter in bone". Journal of the American Society of Nephrology. 18 (9): 2509–16. doi:10.1681/ASN.2007030348. PMC 2216427. PMID 17656470.
  25. ^ Trump, D. L.; Hochberg, M. C. (April 1976). "Bromide intoxication". The Johns Hopkins Medical Journal. 138 (4): 119–123. ISSN 0021-7263. PMID 131871.
  26. ^ "Medication Update".
  27. ^ a b . Archived from the original on 2010-10-09. Retrieved 2010-05-14.
  28. ^ Rehman, Abdur; Setter, Stephen M.; Vue, Mays H. (2011-11-01). "Drug-Induced Glucose Alterations Part 2: Drug-Induced Hyperglycemia". Diabetes Spectrum. 24 (4): 234–238. doi:10.2337/diaspect.24.4.234. ISSN 1040-9165.
  29. ^ "Hypertension in Pregnancy - Gynecology and Obstetrics".
  30. ^ Dowd, Frank J; Johnson, Bart; Mariotti, Angelo (3 September 2016). Pharmacology and Therapeutics for Dentistry - E-Book. Elsevier Health Sciences. pp. 324–326. ISBN 9780323445955. Retrieved 4 November 2017.
  31. ^ Duarte JD, Cooper-DeHoff RM (June 2010). "Mechanisms for blood pressure lowering and metabolic effects of thiazide and thiazide-like diuretics". Expert Rev Cardiovasc Ther. 8 (6): 793–802. doi:10.1586/erc.10.27. PMC 2904515. PMID 20528637.
  32. ^ Longo, Dan L; et al. (2012). Harrison's Principals of Internal Medicine, Vol. 2. New York: McGraw-Hill. p. 2285. ISBN 978-0-07-174887-2.
  33. ^ Longo, Dan L; et al. (2012). Harrison's Principals of Internal Medicine, Vol. 2. New York: McGraw-Hill. p. 3109. ISBN 978-0-07-174887-2.
  34. ^ Gerald G. Briggs; Roger K. Freeman; Sumner J. Yaffe (2011). Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk. Lippincott Williams & Wilkins. pp. 257–. ISBN 978-1-60831-708-0.
  35. ^ American Academy of Pediatrics Committee on Drugs (September 2001). "Transfer of drugs and other chemicals into human milk". Pediatrics. 108 (3): 776–89. doi:10.1542/peds.108.3.776. PMID 11533352.
  36. ^ Beyer KH (1993). "Chlorothiazide. How the thiazides evolved as antihypertensive therapy". Hypertension. 22 (3): 388–91. doi:10.1161/01.hyp.22.3.388. PMID 8349332.
  37. ^ "Drugs@FDA: FDA Approved Drug Products".
  38. ^ "The Lasker Foundation - Awards".


October 15, 2023
thiazide, refers, both, class, sulfur, containing, organic, molecules, class, diuretics, based, chemical, structure, benzothiadiazine, thiazide, drug, class, discovered, developed, merck, 1950s, first, approved, drug, this, class, chlorothiazide, marketed, und. Thiazide ˈ 8 aɪ e z aɪ d refers to both a class of sulfur containing organic molecules 1 and a class of diuretics based on the chemical structure of benzothiadiazine 2 The thiazide drug class was discovered and developed at Merck and Co in the 1950s 3 The first approved drug of this class chlorothiazide was marketed under the trade name Diuril beginning in 1958 3 In most countries thiazides are the least expensive antihypertensive drugs available 4 ThiazideDrug classChlorothiazide the first thiazide drugClass identifiersUsehypertension edemaATC codeC03ABiological targetsodium chloride symporterExternal linksMeSHD049971Legal statusIn WikidataBenzothiadiazine the parent structure of this class of moleculesThiazide organic molecules are bi cyclic structures that contain adjacent sulfur and nitrogen atoms on one ring 5 Confusion sometimes occurs because thiazide like diuretics such as indapamide are referred to as thiazides despite not having the thiazide chemical structure 6 When used this way thiazide refers to a drug which acts at the thiazide receptor 7 The thiazide receptor is a sodium chloride transporter that pulls NaCl from the lumen in the distal convoluted tubule Thiazide diuretics inhibit this receptor causing the body to release NaCl and water into the lumen thereby increasing the amount of urine produced each day 6 An example of a molecule that is chemically a thiazide but not used as a diuretic is methylchloroisothiazolinone often found as an antimicrobial in cosmetics 8 Contents 1 Medical uses 1 1 Water balance 1 1 1 Hypertension 1 1 2 Diabetes insipidus 1 2 Calcium balance 1 2 1 Urinary stones 1 2 2 Dent s disease 1 2 3 Osteoporosis 1 3 Other uses 2 Contraindications 3 Adverse effects 4 Mechanism of action 5 Breastfeeding 6 History 7 ReferencesMedical uses EditThiazide 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 Water balance Edit Hypertension Edit There are many causes of hypertension high blood pressure including advancing age smoking and obesity 9 Sometimes the underlying cause of hypertension can not 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 9 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 10 Low dose thiazides are tolerated as well as the other classes of medications for hypertension including ACE inhibitors beta blockers and calcium channel blockers 9 In general the thiazides and thiazide like diuretics reduce the risk of death stroke heart attack and heart failure due to hypertension 11 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 12 A systematic review by the Cochrane Collaboration specifically recommended that low dose thiazides be used as the initial pharmacological therapy for high blood pressure 9 Low dose thiazides are more effective at treating hypertension than beta blockers and are similar to angiotensin converting enzyme ACE inhibitors 9 Thiazides are a recommended treatment for hypertension in Europe ESC ESH 13 However the UK National Institute for Health and Clinical Excellence recommends ACE inhibitor and calcium channel blockers for first line treatment of hypertension in adults CG127 14 Thiazides should be considered as initial treatment if the patient has a high risk of developing heart failure 14 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 15 Drug Type Generic Drug Name Low Dose Threshold mg day 9 Thiazide Diuretic Chlorothiazide lt displaystyle lt nbsp 500Hydrochlorothiazide lt displaystyle lt nbsp 50Bendroflumethiazide lt displaystyle lt nbsp 5Methyclothiazide lt displaystyle lt nbsp 5Trichlormethiazide lt displaystyle lt nbsp 2Thiazide like Diuretic Chlorthalidone lt displaystyle lt nbsp 50Indapamide lt displaystyle lt nbsp 5Diabetes insipidus Edit Thiazides can be used to paradoxically decrease urine flow in people with nephrogenic diabetes insipidus 16 Thiazides may also be useful in treating hyponatremia low blood sodium in infants with central diabetes insipidus 17 Calcium balance Edit Urinary stones Edit 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 18 High dose therapy with the thiazide like diuretic indapamide can be used to treat idiopathic hypercalcinuria high urine calcium with unknown cause 19 Dent s disease Edit 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 20 The thiazide like diuretic chlortalidone reduced urine calcium oxalate in seven of the eight males with inactivated CLCN5 gene that participated in the study 21 Inactivation of the CLCN5 gene causes Dent s disease Type 1 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 22 Long term thiazide use may not be advisable due to the risk of significant adverse side effects citation needed Osteoporosis Edit 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 23 Higher levels of retained calcium are associated with increased bone mineral density and fewer fractures in individuals with osteoporosis 23 By a poorly understood mechanism thiazides directly stimulate osteoblast differentiation and bone mineral formation further slowing the course of osteoporosis 24 Other uses Edit Bromine intoxication can be treated by giving intravenous saline with either thiazides or Loop diuretics 25 Contraindications EditContraindications include citation needed Hypotension Allergy to sulphur containing medications Gout Kidney failure Lithium therapy Hypokalemia May worsen diabetesThiazides 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 26 27 Chronic administration of thiazides is associated with the increase of insulin resistance which can lead to hyperglycemia 28 Thiazides cause loss of blood potassium while conserving blood calcium citation needed Thiazides can decrease placental perfusion and adversely affect the fetus so should be avoided in pregnancy 27 29 Adverse effects Edit nbsp Overview of nephron function and where thiazide diuretics act Hypokalemia 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 30 Therefore ACE inhibitor and thiazide combination is used to prevent hypokalemia Hyperglycemia Hyperlipidemia Hyperuricemia Hypercalcemia Hyponatremia Hypomagnesemia HypocalciuriaMechanism of action Edit nbsp Illustration of the mechanism of action of thiazide diuretics in the distal convoluted tubule of nephrons 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 31 The term thiazide is also often used for drugs with a similar action that do not have the thiazide chemical structure such as chlorthalidone and metolazone These agents are more properly termed thiazide like diuretics citation needed 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 32 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 33 Breastfeeding EditThiazides pass into breast milk and can decrease the flow of breast milk 34 Thiazides have been associated with significant side effects in some nursing infants and should be administered to nursing mothers with caution 35 History EditThe 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 36 and led to the marketing of the first drug of this class chlorothiazide under the trade name Diuril in 1958 37 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 38 References Edit Thiazides at the U S National Library of Medicine Medical Subject Headings MeSH Thiazide Diuretics at the U S National Library of Medicine Medical Subject Headings MeSH a b Beyer KH September 1993 Chlorothiazide How the thiazides evolved as antihypertensive therapy Hypertension 22 3 388 91 doi 10 1161 01 hyp 22 3 388 PMID 8349332 Whitworth JA November 2003 2003 World Health Organization WHO International Society of Hypertension ISH statement on management of hypertension PDF Journal of Hypertension 21 11 1983 92 doi 10 1097 00004872 200311000 00002 PMID 14597836 S2CID 3211922 MeSH Browser meshb nlm nih gov Retrieved 2019 07 22 a b Akbari Pegah Khorasani Zadeh Arshia 2019 Thiazide Diuretics StatPearls StatPearls Publishing PMID 30422513 retrieved 2019 07 18 thiazide receptor at the U S National Library of Medicine Medical Subject Headings MeSH 6 Final Report on the Safety Assessment of Methylisothiazolinone and Methylchloroisothiazolinone Journal of the American College of Toxicology 11 1 75 128 1992 01 01 doi 10 3109 10915819209141993 ISSN 0730 0913 S2CID 208506926 a b c d e f Musini Vijaya M Gill Rupam Wright James M 2018 04 18 First line drugs for hypertension The Cochrane Database of Systematic Reviews 2018 4 CD001841 doi 10 1002 14651858 CD001841 pub3 ISSN 1469 493X PMC 6513559 PMID 29667175 Moser M Feig PU November 2009 Fifty years of thiazide diuretic therapy for hypertension Archives of Internal Medicine JAMA 169 20 1851 6 doi 10 1001 archinternmed 2009 342 PMID 19901136 Wright JM Musini VM Gill R April 2018 First line drugs for hypertension The Cochrane Database of Systematic Reviews 2018 4 CD001841 doi 10 1002 14651858 CD001841 pub3 PMC 6513559 PMID 29667175 James PA Oparil S Carter BL Cushman WC Dennison Himmelfarb C Handler J et al February 2014 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 JAMA 311 5 507 20 doi 10 1001 jama 2013 284427 PMID 24352797 escardio org Archived from the original on 2008 05 17 Retrieved 2007 08 30 a b National Institute for Health and Clinical Excellence NICE guideline on the management of primary hypertension in adults CG127 accessed 5 3 2012 at CG127 Hypertension National Institute for Health and Clinical Excellence Archived from the original on 2012 01 31 Retrieved 2012 03 05 Guide to management of hypertension 2008 National Heart Foundation Australia 2008 accessed online at Archived copy PDF Archived from the original PDF on 2013 05 15 Retrieved 2013 07 10 a href Template Cite web html title Template Cite web cite web a CS1 maint archived copy as title link Magaldi Antonio J 2000 12 01 New insights into the paradoxical effect of thiazides in diabetes insipidus therapy Nephrology Dialysis Transplantation 15 12 1903 1905 doi 10 1093 ndt 15 12 1903 ISSN 0931 0509 PMID 11096127 Welch Thomas R 2015 09 01 Diuretics for diabetes insipidus The Journal of Pediatrics 167 3 503 505 doi 10 1016 j jpeds 2015 07 029 ISSN 0022 3476 THIAZIDE DIURETICS FOR STONE PREVENTION Kidney Stone Evaluation And Treatment Program kidneystones uchicago edu Retrieved 2019 07 22 Martins M C Meyers A M Whalley N A Margolius L P Buys M E 1996 Indapamide Natrilix the agent of choice in the treatment of recurrent renal calculi associated with idiopathic hypercalciuria British Journal of Urology 78 2 176 180 doi 10 1046 j 1464 410X 1996 00633 x ISSN 1464 410X PMID 8813907 Velasco Nestor Jayawardene Satishkumar A Burgess Helen K 2001 07 01 Dent s disease can we slow its progression Nephrology Dialysis Transplantation 16 7 1512 1513 doi 10 1093 ndt 16 7 1512 ISSN 0931 0509 PMID 11427657 Scheinman Steven J Asplin John Ploutz Snyder Robert J Why Scott Van Goodyer Paul Blowey Douglas D Mello Richard G Schurman Scott Raja Khalid A 2002 12 01 Responsiveness of Hypercalciuria to Thiazide in Dent s Disease Journal of the American 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