WordNet

any of a group of drugs commonly used as diuretics in the treatment of hypertension; they block the reabsorption of sodium in the kidneys
a diuretic drug (trade name Microzide, Esidrix, and HydroDIURIL) used in the treatment of hypertension (同)Microzide, Esidrix, HydroDIURIL

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Benzothiadiazine (parent of the class)

Chlorothiazide

Hydrochlorothiazide

Thiazide is a type of molecule^[1] and a class of diuretics^[2] often used to treat hypertension (high blood pressure) and edema (such as that caused by heart, liver, or kidney disease).

The thiazides and thiazide-like diuretics reduce the risk of death, stroke, heart attack, and heart failure due to hypertension.^[3] The class was discovered and developed at Merck and Co. in the 1950s, and the first approved drug of this class, chlorothiazide, was marketed under the trade name Diuril beginning in 1958.^[4] In most countries, the thiazides are the cheapest antihypertensive drugs available.^[5]

Medical uses

Hypertension

Regarding effectiveness in the treatment of hypertension, a systematic review by the Cochrane Collaboration found:^[6]

Chlorthalidone's reduces systolic and diastolic blood pressure by 12.0/4 mmHg and the reduction is not dose related when tested at a range of doses from 12.5 mg to 75 mg/day.
Hydrochlorothiazide's effect is dose related and at a maximum dose of 50 mg/day, the reduction is 11 mmHg/5 mmHg.

Thiazides and thiazidelike diuretics have been in constant use since their introduction in 1958. They "have remained a cornerstone in the management of hypertension for more than half a century since their introduction [...] Very few agents used for the treatment of any disease can boast such staying power, which is a testament both to the efficacy and safety of these compounds." ^[7]

Several clinical practice guidelines address the use of thiazides. They are the recommended first-line treatment in the US (JNC VII)^[8] guidelines for hypertension and a recommended treatment in the European (ESC/ESH)^[9] guidelines. However, the recent 2011 UK National Institute for Health and Clinical Excellence (NICE) guideline on the management of primary hypertension in adults (CG127)^[10] recommend calcium channel blockers (CCBs) as first line agents in hypertension and advise that thiazide-like diuretics should only be used first line if CCBs are not suitable or if the patient has edema or has a high risk of developing heart failure. Thiazides have also been replaced by angiotensin converting enzyme (ACE) inhibitors in Australia due to their propensity to increase risk of diabetes mellitus type 2.^[11]

The mechanism of action of thiazides in lowering blood pressure in the long term is not fully understood. When administered acutely thiazides lower blood pressure by causing diuresis, a fall in plasma volume and a reduction in cardiac output. However, after chronic use thiazides cause a reduction in blood pressure by lowering peripheral resistance (i.e. vasodilation). The mechanism of this effect is uncertain but it may involve effects on 'whole body' or renal autoregulation, or direct vasodilator actions either through inhibition of carbonic anhydrase^[12] or by desensitizing the vascular smooth muscle cells to the rise in intracellular calcium induced by norepinephrine.^[13]

Other

Thiazides also lower urinary calcium excretion, making them useful in preventing calcium-containing kidney stones. This effect is associated with positive calcium balance and is associated with an increase in bone mineral density and reductions in fracture rates attributable to osteoporosis. By a lesser understood mechanism, thiazides directly stimulate osteoblast differentiation and bone mineral formation, further slowing the course of osteoporosis.^[14]

Because of their promotion of calcium retention, thiazides are used in the treatment of

Dent's Disease
Hypocalcemia
Nephrolithiasis (ideopathic hypercalciuria)
Bromide intoxication
Nephrogenic diabetes insipidus

Mechanisms of action

The members of this class of diuretics are derived from benzothiadiazine. They 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.^[15] The term "thiazide" is also often used for drugs with a similar action that do not have the thiazide chemical structure, such as chlortalidone and metolazone. These agents are more properly termed thiazide-like diuretics.

Thiazide diuretics also increase calcium reabsorption at the distal tubule. By lowering the sodium concentration within the epithelial cells, thiazides increase the activity of the Na⁺/Ca²⁺ antiporter on the basolateral membrane to transport more Ca²⁺ into the interstitium. This, in turn, lowers the intracellular Ca²⁺ concentration so that more Ca²⁺ may diffuse into the cell via apical Ca²⁺-selective channels (TRPV5). In other words, less Ca²⁺ in the cell increases the driving force for reabsorption from the lumen.^[16]

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.^[17]

Denomination

That thiazide refers to both the type of molecule and the medication can sometimes lead to confusion, because some molecules (thiazide-like diuretics) are often considered as thiazide diuretics, although they are not thiazides from a chemical perspective. In this context, "thiazide" is taken to refer to a drug which acts at a "thiazide receptor",^[18] which is believed to be a sodium-chloride symporter.

Breast milk

Thiazides pass into breast milk, and can decrease the flow of breast milk.^[19] Thiazides are classed as 'Drugs That Have Been Associated With Significant Effects on Some Nursing Infants and Should Be Given to Nursing Mothers With Caution' by the American Academy of Pediatrics Committee on Drugs.^[20]

Contraindications

Contraindications include:

Hypotension
Allergy to sulphur-containing medications
Gout
Renal 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.^[21]^[22]

Chronic administration is associated with hyperglycemia.

Thiazides cause loss of blood potassium, while conserving blood calcium.

Thiazides can decrease placental perfusion and adversely affect the fetus so should be avoided in pregnancy.^[22]^[23]

Mechanisms of hypokalemia

There are several mechanisms by which thiazide diuretics cause hypokalemia (decreased plasma potassium concentration):

Increased delivery of sodium to the collecting ducts causes increased cellular uptake of Na from the lumen by apical Epithelial Na Channels (ENaCs). This then causes the basolateral Na/K exchanger to more actively exchange Na for K, which is then passively secreted into the lumen through apical channels, resulting in K loss. (Moreover, the increased delivery of K to the collecting ducts facilitates the exchange of K for H by the H/K exchangers on the intercalated alpha cells, resulting in loss of H [metabolic alkalosis].)^{[citation needed]}

Activation of renin-angiotensin-aldosterone system by the diuretic hypovolemia: body responds to hypovolemia by opposing diuresis, one effect of which is to produce aldosterone which stimulates the Na/K exchanger, resulting in further loss of potassium. For this reason, ACE inhibitors, which inhibit angiotensin II production and therefore aldosterone activation, are frequently used in combination with thiazides to combat hypokalemia.
Flow rate in nephron is increased under diuresis, reducing potassium concentration in the lumen, thus increasing the potassium gradient. Potassium loss through the many potassium channels, such as ROMK. These are not exchangers; they allow facilitated diffusion, so the increased gradient is directly responsible for increased diffusion.

Complications

Hyperglycemia
Hyperlipidemia
Hyperuricemia
Hypercalcemia
Hypokalemia
Hyponatremia
Hypomagnesemia
Hypocalciuria

History

The thiazide diuretics were discovered developed by scientists Karl H. Beyer, James M. Sprague, John E. Baer, and Frederick C. Novello of Merck and Co. in the 1950s,^[4] and led to the marketing of the first drug of this class, chlorothiazide, under the trade name Duiril in 1958.^[24] 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.^[25]

References

^ Thiazides at the US National Library of Medicine Medical Subject Headings (MeSH)
^ Thiazide Diuretics at the US National Library of Medicine Medical Subject Headings (MeSH)
^ Wright JM, Musini VM (July 2009). Wright, James M, ed. "First-line drugs for hypertension". Cochrane Database Syst Rev 8 (3): CD001841. doi:10.1002/14651858.CD001841.pub2. PMID 19588327.
^ ^a ^b 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.
^ Whitworth JA, World Health Organization, International Society of Hypertension Writing Group (November 2003). "2003 World Health Organization (WHO)/International Society of Hypertension (ISH) statement on management of hypertension". J Hypertens 21 (11): 1983–92. doi:10.1097/00004872-200311000-00002. PMID 14597836.
^ Musini VM, Nazer M, Bassett K, Wright JM (2014). "Blood pressure-lowering efficacy of monotherapy with thiazide diuretics for primary hypertension.". Cochrane Database Syst Rev 5: CD003824. doi:10.1002/14651858.CD003824.pub2. PMID 24869750.
^ Moser, Marvin; Feig, Peter U. (2009). "Symbiotic Fifty Years of Thiazide Diuretic Therapy for Hypertension". Arch Intern Med (JAMA) 169 (20): 1851–1856. doi:10.1001/archinternmed.2009.342. Retrieved August 14, 2014.
^ "The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7)". Retrieved 2007-08-30.
^ "escardio.org". Retrieved 2007-08-30.
^ National Institute for Health and Clinical Excellence (NICE) guideline on the management of primary hypertension in adults (CG127) accessed 5/3/2012 at [1]
^ Guide to management of hypertension 2008. National Heart Foundation Australia. 2008. accessed online at http://www.heartfoundation.org.au/SiteCollectionDocuments/HypertensionGuidelines2008to2010Update.pdf
^ Hughes AD (2004). "How do thiazide and thiazide-like diuretics lower blood pressure?". J Renin Angiotensin Aldosterone Syst 5 (4): 155–60. doi:10.3317/jraas.2004.034. PMID 15803433.
^ Zhu Z, Zhu S, Liu D, Cao T, Wang L, Tepel M (2005). "Thiazide-like diuretics attenuate agonist-induced vasoconstriction by calcium desensitization linked to Rho kinase". Hypertension 45 (2): 233–9. doi:10.1161/01.HYP.0000152701.97426.5f. PMID 15611360.
^ Dvorak MM, De Joussineau C, Carter DH et al. (2007). "Thiazide diuretics directly induce osteoblast differentiation and mineralized nodule formation by interacting with a sodium chloride co-transporter in bone". J. Am. Soc. Nephrol. 18 (9): 2509–16. doi:10.1681/ASN.2007030348. PMC 2216427. PMID 17656470.
^ 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.
^ 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.
^ 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.
^ thiazide receptor at the US National Library of Medicine Medical Subject Headings (MeSH)
^ 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.
^ "Transfer of drugs and other chemicals into human milk". Pediatrics 108 (3): 776–89. September 2001. PMID 11533352.
^ http://www.medscape.com/viewarticle/421426
^ ^a ^b http://rx-s.net/weblog/more/hydrochlorothiazide_hctz_microzide_contraindications_and_precautions/
^ http://www.merck.com/mmpe/sec18/ch261/ch261k.html
^ "Drugs@FDA: FDA Approved Drug Products".
^ "The Lasker Foundation - Awards".

External links

UpToDate Contents

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1. 原発性（本態性）高血圧患者におけるサイアザイド系利尿薬の使用 use of thiazide diuretics in patients with primary essential hypertension
2. 利尿剤の作用機序 mechanism of action of diuretics
3. 原発性（本態性）高血圧における薬物療法の選択 choice of drug therapy in primary essential hypertension
4. 高血圧治療におけるサイアザイド系利尿剤とループ利尿剤の比較 thiazides versus loop diuretics in treatment of hypertension
5. ループ利尿剤およびサイアザイド系利尿剤によって誘発された電解質の合併症の経過 time course of loop and thiazide diuretic induced electrolyte complications

English Journal

Bartter- and Gitelman-like syndromes: salt-losing tubulopathies with loop or DCT defects.

Seyberth HW, Schlingmann KP.SourceDepartment of Pediatrics and Adolescent Medicine, Philipps University, Marburg, Germany, seyberth@staff.uni-marburg.de.
Pediatric nephrology (Berlin, Germany).Pediatr Nephrol.2011 Oct;26(10):1789-802. Epub 2011 Apr 19.
Salt-losing tubulopathies with secondary hyperaldosteronism (SLT) comprise a set of well-defined inherited tubular disorders. Two segments along the distal nephron are primarily involved in the pathogenesis of SLTs: the thick ascending limb of Henle's loop, and the distal convoluted tubule (DCT). Th
PMID 21503667

Overexpression of the Sodium Chloride Cotransporter Is Not Sufficient to Cause Familial Hyperkalemic Hypertension.

McCormick JA, Nelson JH, Yang CL, Curry JN, Ellison DH.SourceDivision of Nephrology and Hypertension, Oregon Health & Science University, Portland, OR; Veterans Affairs Medical Center, Portland, OR.
Hypertension.Hypertension.2011 Sep 6. [Epub ahead of print]
The sodium chloride cotransporter (NCC) is the primary target of thiazides diuretics, drugs used commonly for long-term hypertension therapy. Thiazides also completely reverse the signs of familial hyperkalemic hypertension (FHHt), suggesting that the primary defect in FHHt is increased NCC activity
PMID 21896937

Japanese Journal

Inheritance of an Autosomal Recessive Disorder, Gitelmans Syndrome, Across Two Generations in One Family

Yagi Hiroki,Yahata Kensei,Usui Takeshi,Hasegawa Chinatsu,Seta Koichi,Sugawara Akira
Internal Medicine 50(11), 1211-1214, 2011
… Clinically, he was diagnosed as GS because of diuretic responsiveness to furosemide but not thiazide. …
NAID 130000770474

サイアザイドによる降圧加療により意識障害を伴う低ナトリウム血症で緊急入院した2症例

竹下雅子,宮尾益理子,水野有三
日本老年医学会雑誌 47(3), 257-261, 2010-05-25
NAID 10026895494

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★リンクテーブル★

リンク元	「チアジド系」「サイアザイド」「サイアザイド系」
拡張検索	「benzylhydrochlorothiazide」「sodium restriction-hydrochlorothiazide-spironolactone loading test」「thiazide derivative」「cyclothiazide」「cyclopenthiazide」