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

PrepTutorEJDIC

排尿促進の,利尿の / 利尿剤

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/02/13 10:13:26」(JST)

wiki en

[Wiki en表示]

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] In most countries, the thiazides are the cheapest antihypertensive drugs available.^[4]

Medical uses[edit]

Hypertension[edit]

Thiazides are often used to treat hypertension, although they are also used to treat congestive heart failure and symptomatic edema. They are the recommended first-line treatment in the US (JNC VII)^[5] guidelines for hypertension and a recommended treatment in the European (ESC/ESH)^[6] guidelines. However, the recent 2011 UK National Institute for Health and Clinical Excellence (NICE) guideline on the management of primary hypertension in adults (CG127)^[7] 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 Thiazides have also been replaced by angiotensin converting enzyme (ACE) inhibitors in Australia due to their propensity to increase risk of diabetes mellitus type 2.^[8] Low-dose Thiazides have been shown to reduce hypertension-related morbidity and mortality,^[3] although how they lower 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^[9] or by desensitizing the vascular smooth muscle cells to the rise in intracellular calcium induced by norepinephrine.^[10]

Other[edit]

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.^[11]

Because of their promotion of calcium retention, thiazides are used in the treatment of Dent's Disease or idiopathic hypercalciuria.

Mechanisms of action[edit]

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.^[12] 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.^[13]

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.^[14]

Denomination[edit]

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",^[15] which is believed to be a sodium-chloride symporter.

Breast milk[edit]

Thiazides pass through breast milk, and in some cases, decrease the flow of breast milk. There is no specific information regarding the use of thiazides in children, but it is still advised that mothers avoid using thiazides during the first month of breast feeding.^{[citation needed]}

Contraindications[edit]

Contraindications include:

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

Thiazides reduce the clearance of uric acid, and raise the levels of uric acid in the blood. Hence they are prescribed with caution in patients with gout or hyperuricemia.^[16]^[17]

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.^[17]^[18]

Mechanisms of hypokalemia[edit]

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[edit]

Hyperglycemia
Hyperlipidemia
Hyperuricemia
Hypercalcemia
Hypokalemia
Hyponatremia

References[edit]

^ 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)
^ ^a ^b Wright JM, Musini VM (July 2009). "First-line drugs for hypertension". In Wright, James M. Cochrane Database Syst Rev 8 (3): CD001841. doi:10.1002/14651858.CD001841.pub2. PMID 19588327.
^ 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.
^ "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)
^ 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

External links[edit]

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

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. ヒドロクロロチアジド：医薬品情報 hydrochlorothiazide drug information
4. 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
5. 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

English Journal

Diuretics: a review and update.

Roush GC, Kaur R, Ernst ME.Author information 1UCONN School of Medicine and St Vincent's Medical Center, Bridgeport, CT, USA.AbstractDiuretics have been recommended as first-line treatment of hypertension and are also valuable in the management of hypervolemia and electrolyte disorders. This review summarizes the key features of the most commonly used diuretics. We then provide an update of clinical trials for diuretics during the past 5 years. Compared to other classes of medications, thiazide diuretics are at least as effective in reducing cardiovascular events (CVEs) in patients with hypertension and are more effective than β-blockers and angiotensin-converting enzyme inhibitors in reducing stroke. Observational cohort data and a network analysis have shown that CVEs are lowered by one-fifth from chlorthalidone when compared to the commonly used thiazide, hydrochlorothiazide. Relative to placebo, chlorthalidone increases life expectancy. In those aged 80 years and older, the diuretic, indapamide, lowers CVEs relative to placebo. The aldosterone antagonist, eplerenone, lowers total mortality in early congestive heart failure. The benefit of eplerenone following acute myocardial infarction (MI) is limited to administration within 3 to 6 days post-MI. Aldosterone antagonists have been shown to lower the incidence of sudden cardiac death and to reduce proteinuria. In the setting of heart failure, long acting loop diuretics azosemide and torasemide are more effective in improving heart failure outcomes than the far more commonly used short acting furosemide. Evening dosing of diuretics appears to lower CVEs relative to morning dosing. In conclusion, diuretics are a diverse class of drugs that remain extremely important in the management of hypertension and hypervolemic states.
Journal of cardiovascular pharmacology and therapeutics.J Cardiovasc Pharmacol Ther.2014 Jan;19(1):5-13. doi: 10.1177/1074248413497257. Epub 2013 Nov 15.
Diuretics have been recommended as first-line treatment of hypertension and are also valuable in the management of hypervolemia and electrolyte disorders. This review summarizes the key features of the most commonly used diuretics. We then provide an update of clinical trials for diuretics during th
PMID 24243991

Pharmacologic inhibition of the renal outer medullary potassium channel causes diuresis and natriuresis in the absence of kaliuresis.

Garcia ML, Priest BT, Alonso-Galicia M, Zhou X, Felix JP, Brochu RM, Bailey T, Thomas-Fowlkes B, Liu J, Swensen A, Pai LY, Xiao J, Hernandez M, Hoagland K, Owens K, Tang H, de Jesus RK, Roy S, Kaczorowski GJ, Pasternak A.Author information Departments of Ion Channels (M.L.G., B.T.P., J.P.F., R.M.B., T.B., B.T.-F., J.L., A.S., G.J.K.), Hypertension (M.A.-G., X.Z., L.-Y.P., J.X., M.H., S.R.), Drug Metabolism (K.O.), and Medicinal Chemistry (H.T., R. K.J., A.P.), Merck Research Laboratories, Rahway, New Jersey; and Safety and Exploratory Pharmacology, Merck Research Laboratories, West Point, Pennsylvania (K.H.).AbstractThe renal outer medullary potassium (ROMK) channel, which is located at the apical membrane of epithelial cells lining the thick ascending loop of Henle and cortical collecting duct, plays an important role in kidney physiology by regulating salt reabsorption. Loss-of-function mutations in the human ROMK channel are associated with antenatal type II Bartter's syndrome, an autosomal recessive life-threatening salt-wasting disorder with mild hypokalemia. Similar observations have been reported from studies with ROMK knockout mice and rats. It is noteworthy that heterozygous carriers of Kir1.1 mutations associated with antenatal Bartter's syndrome have reduced blood pressure and a decreased risk of developing hypertension by age 60. Although selective ROMK inhibitors would be expected to represent a new class of diuretics, this hypothesis has not been pharmacologically tested. Compound A [5-(2-(4-(2-(4-(1H-tetrazol-1-yl)phenyl)acetyl)piperazin-1-yl)ethyl)isobenzofuran-1(3H)-one)], a potent ROMK inhibitor with appropriate selectivity and characteristics for in vivo testing, has been identified. Compound A accesses the channel through the cytoplasmic side and binds to residues lining the pore within the transmembrane region below the selectivity filter. In normotensive rats and dogs, short-term oral administration of compound A caused concentration-dependent diuresis and natriuresis that were comparable to hydrochlorothiazide. Unlike hydrochlorothiazide, however, compound A did not cause any significant urinary potassium losses or changes in plasma electrolyte levels. These data indicate that pharmacologic inhibition of ROMK has the potential for affording diuretic/natriuretic efficacy similar to that of clinically used diuretics but without the dose-limiting hypokalemia associated with the use of loop and thiazide-like diuretics.
The Journal of pharmacology and experimental therapeutics.J Pharmacol Exp Ther.2014 Jan;348(1):153-64. doi: 10.1124/jpet.113.208603. Epub 2013 Oct 18.
The renal outer medullary potassium (ROMK) channel, which is located at the apical membrane of epithelial cells lining the thick ascending loop of Henle and cortical collecting duct, plays an important role in kidney physiology by regulating salt reabsorption. Loss-of-function mutations in the human
PMID 24142912

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).

James PA1, Oparil S2, Carter BL1, Cushman WC3, Dennison-Himmelfarb C4, Handler J5, Lackland DT6, Lefevre ML7, Mackenzie TD8, Ogedegbe O9, Smith SC Jr10, Svetkey LP11, Taler SJ12, Townsend RR13, Wright JT Jr14, Narva AS15, Ortiz E16.Author information 1University of Iowa, Iowa City.2University of Alabama at Birmingham School of Medicine.3Memphis Veterans Affairs Medical Center and the University of Tennessee, Memphis.4Johns Hopkins University School of Nursing, Baltimore, Maryland.5Kaiser Permanente, Anaheim, California.6Medical University of South Carolina, Charleston.7University of Missouri, Columbia.8Denver Health and Hospital Authority and the University of Colorado School of Medicine, Denver.9New York University School of Medicine, New York, New York.10University of North Carolina at Chapel Hill.11Duke University, Durham, North Carolina.12Mayo Clinic College of Medicine, Rochester, Minnesota.13University of Pennsylvania, Philadelphia.14Case Western Reserve University, Cleveland, Ohio.15National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland.16at the time of the project,National Heart, Lung, and Blood Institute, Bethesda, Maryland17currently with ProVation Medical, Wolters Kluwer Health, Minneapolis, Minnesota.AbstractHypertension is the most common condition seen in primary care and leads to myocardial infarction, stroke, renal failure, and death if not detected early and treated appropriately. Patients want to be assured that blood pressure (BP) treatment will reduce their disease burden, while clinicians want guidance on hypertension management using the best scientific evidence. This report takes a rigorous, evidence-based approach to recommend treatment thresholds, goals, and medications in the management of hypertension in adults. Evidence was drawn from randomized controlled trials, which represent the gold standard for determining efficacy and effectiveness. Evidence quality and recommendations were graded based on their effect on important outcomes. There is strong evidence to support treating hypertensive persons aged 60 years or older to a BP goal of less than 150/90 mm Hg and hypertensive persons 30 through 59 years of age to a diastolic goal of less than 90 mm Hg; however, there is insufficient evidence in hypertensive persons younger than 60 years for a systolic goal, or in those younger than 30 years for a diastolic goal, so the panel recommends a BP of less than 140/90 mm Hg for those groups based on expert opinion. The same thresholds and goals are recommended for hypertensive adults with diabetes or nondiabetic chronic kidney disease (CKD) as for the general hypertensive population younger than 60 years. There is moderate evidence to support initiating drug treatment with an angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, calcium channel blocker, or thiazide-type diuretic in the nonblack hypertensive population, including those with diabetes. In the black hypertensive population, including those with diabetes, a calcium channel blocker or thiazide-type diuretic is recommended as initial therapy. There is moderate evidence to support initial or add-on antihypertensive therapy with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker in persons with CKD to improve kidney outcomes. Although this guideline provides evidence-based recommendations for the management of high BP and should meet the clinical needs of most patients, these recommendations are not a substitute for clinical judgment, and decisions about care must carefully consider and incorporate the clinical characteristics and circumstances of each individual patient.
JAMA : the journal of the American Medical Association.JAMA.2013 Dec 18. doi: 10.1001/jama.2013.284427. [Epub ahead of print]
Hypertension is the most common condition seen in primary care and leads to myocardial infarction, stroke, renal failure, and death if not detected early and treated appropriately. Patients want to be assured that blood pressure (BP) treatment will reduce their disease burden, while clinicians want
PMID 24352797

Japanese Journal

病気について知りたい! 臨床講座(77)浮腫

Pharma tribune : なりたい薬剤師になる! 7(5), 5-12, 2015-05
NAID 40020482177

小西賞受賞者高血圧併用療法とCOPE Trial

山口医学 = Yamaguchi medical journal 64(1), 17-23, 2015-02
NAID 120005601212

Effects of Hydrochlorothiazide on Oxidative Stress and Pulse Pressure in Hypertensive Patients with Chronic Stroke: The EMINENT Study

Internal Medicine 54(6), 573-577, 2015
NAID 130004903090

Related Pictures

★リンクテーブル★

リンク元	「チアジド系利尿薬」
関連記事	「diuretic」「thiazide」

「チアジド系利尿薬」

　　[★]

英: thiazide diuretic, benzothiazide diuretic
同: サイアザイド系利尿薬
関: 利尿薬、利尿薬の作用部位、sodium-chloride symporter inhibitor。ギテルマン症候群

特徴

安価である
有効率が高い
遠位尿細管前半部に作用するらしい
Na⁺とCl^-の共輸送体(NCCT)を阻害→Na⁺,Cl^- の再吸収を阻害する

排泄される電解質の変化

Na↑、K↑、H↑、Ca↓、Mg↑、Cl↑、HCO₃↑、H₂PO₄↑

Ca↓

チアジド系利尿薬の慢性使用により体液量が減少し、近位尿細管での再吸収が亢進するため (GOO.755)　？？

チアジド系利尿薬自体のDCTでの作用による；NCCTを阻害すると細胞内のNa濃度低下、これにより側底膜でのNa⁺-Ca²⁺交換系が亢進することでCa²⁺の再吸収↑ (GOO.755)　→　つまり管腔側から受動的に引き込まれるということ。

K↑、滴定酸↑

ループ利尿薬と同様の機序による (GOO.755)