The thiazides and thiazide-like diuretics reduce the risk of death, stroke, heart attack and heart failure due to hypertension. In most countries, the thiazides are the cheapest antihypertensive drugs available.
- 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." 
Several clinical practice guidelines address the use of thiazides. They are the recommended first-line treatment in the US (JNC VII) guidelines for hypertension and a recommended treatment in the European (ESC/ESH) guidelines. However, the recent 2011 UK National Institute for Health and Clinical Excellence (NICE) guideline on the management of primary hypertension in adults (CG127) 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 Thiazides have also been replaced by angiotensin converting enzyme (ACE) inhibitors in Australia due to their propensity to increase risk of diabetes mellitus type 2.
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 or by desensitizing the vascular smooth muscle cells to the rise in intracellular calcium induced by norepinephrine.
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.
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. 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.
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.
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", which is believed to be a sodium-chloride symporter.
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.
- Allergy to sulphur-containing medications
- Renal failure
- Lithium therapy
- 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.
Chronic administration is associated with hyperglycemia.
Thiazides cause loss of blood potassium, while conserving blood calcium.
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].)
- 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.
- 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)
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- 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.
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- 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 
- Guide to management of hypertension 2008. National Heart Foundation Australia. 2008. accessed online at http://www.heartfoundation.org.au/SiteCollectionDocuments/HypertensionGuidelines2008to2010Update.pdf
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- 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.
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- 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.
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- thiazide receptor at the US National Library of Medicine Medical Subject Headings (MeSH)