Thiazide

Thiazide is a term used to describe a type of molecule [MeshName|Thiazides] and a class of diuretic. [MeshName|Thiazide+Diuretics]

The members of this class of diuretics are derived from benzothiadiazine. They inhibit Na⁺/Cl^- reabsorption from the distal convoluted tubules in the kidneys by blocking the thiazide-sensitive Na+-Cl^- symporter. Thiazides also cause loss of potassium and an increase in serum uric acid. The chemical structure of the original thiazide diuretics contained a thiazide ring system; the term is also used for drugs with a similar action that are not chemically thiazides, such as chlortalidone and metolazone, strictly these agents are termed thiazide-like diuretics, but often the term thiazide is used indiscriminately.

Denomination

That thiazide both refers to 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" [MeshName|thiazide+receptor] , which is believed to be a sodium-chloride symporter.

Primary uses

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) [cite web |url=http://www.nhlbi.nih.gov/guidelines/hypertension/ |title=The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) |accessdate=2007-08-30 |format= |work=] guidelines and the National Institute for Health and Clinical Excellence/British Hypertension Society guidelines [cite web |url=http://www.nice.org.uk/CG034|title=Hypertension: management of hypertension in adults in primary care|accessdate=2008-04-25 |format= |work=] and a recommended treatment in the European (ESC/ESH) [cite web |url=http://www.escardio.org/knowledge/guidelines/CVD_Prevention_in_Clinical_Practice.htm |title=escardio.org |accessdate=2007-08-30 |format= |work=] guidelines. They have been shown to prevent hypertension-related morbidity and mortality, 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 anhydrasecite journal |author=Hughes AD |title=How do thiazide and thiazide-like diuretics lower blood pressure?|journal=J Renin Angiotensin Aldosterone Syst|volume=5 |issue=4 |pages=155–60 |year=2004 |pmid=15803433 |doi=10.3317/jraas.2004.034] or by desensitizing the vascular smooth muscle cells to the rise in intracellular calcium induced by norepinephrine.cite journal |author=Zhu Z, Zhu S, Liu D, Cao T, Wang L, Tepel M |title=Thiazide-like diuretics attenuate agonist-induced vasoconstriction by calcium desensitization linked to Rho kinase |journal=Hypertension |volume=45 |issue=2 |pages=233–9 |year=2005 |pmid=15611360 |doi=10.1161/01.HYP.0000152701.97426.5f]

ide effects

Side effects can include hypokalemia, increased serum cholesterol, triglyceride, impaired glucose tolerance, diabetes mellituscite journal |author= Salvetti A, Ghiadoni L.|title=Thiazide diuretics in the treatment of hypertension: an update|journal=1: J Am Soc Nephrol. |volume=17 |issue=4 (Suppl 2) |pages=S25–9 |year=2006 |pmid=16565243|doi=10.1681/ASN.2005121329] and impotence. The side effect of hypokalemia has motivated combining thiazides with potassium chloride supplements, potassium sparing diuretics (eg with amiloride in co-amilozide) and with the newer ACE inhibitors, which also lower blood pressure but cause hyperkalemia as a side effect.

Long-term usage of thiazides is also linked to increased levels of homocysteine, a toxic amino acid byproduct, that has been associated with atherosclerosis but there is no evidence that people receiving long-term thiazide treatments should also receive folic acid supplements. They have been known to cause a paradoxical effect in Diabetes insipidus, where they reduce the volume of urine. Thiazide diuretics are capable of inhibiting urate secretion.

Other uses

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.cite journal |author=Dvorak MM, De Joussineau C, Carter DH, "et al" |title=Thiazide diuretics directly induce osteoblast differentiation and mineralized nodule formation by interacting with a sodium chloride co-transporter in bone |journal=J. Am. Soc. Nephrol. |volume=18 |issue=9 |pages=2509–16 |year=2007 |pmid=17656470 |doi=10.1681/ASN.2007030348 |url=http://jasn.asnjournals.org/cgi/pmidlookup?view=long&pmid=17656470]

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

Thiazide may be combined with ACE inhibitors to increase diuresis without changing plasma potassium concentrations. While ACE inhibitors cause diuresis with potassium retention, thiazide increases potassium excretion. Their combined effects on potassium cancel each other out.

Breast milk

It should be noted that 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.

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 the Na/K exchanger to more actively exchange Na for K 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.

References

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