Thiazide 1179748 226170382 2008-07-17T03:43:41Z Fabrício Kury 71458 /* Mechanisms of hypokalemia */ Information on how increased loss of potassium loss leads to increased loss of hidrogen. [[Image:Chlorothiazide.svg|thumb|[[Chlorothiazide]]]] [[Image:Hydrochlorothiazide-2D-skeletal.png|thumb|[[Hydrochlorothiazide]]]] [[Image:Bendroflumethiazide-2D-skeletal.png|thumb|[[Bendroflumethiazide]]]] '''Thiazide''' is a term used to describe a type of molecule<ref>{{MeshName|Thiazides}}</ref> and a class of [[diuretic]].<ref>{{MeshName|Thiazide+Diuretics}}</ref> The members of this class of [[diuretic]]s are derived from [[benzothiadiazine]]. They inhibit [[sodium|Na]]<sup>+</sup>/[[chloride|Cl]]<sup>-</sup> reabsorption from the [[distal convoluted tubule]]s in the [[kidney]]s by blocking the thiazide-sensitive [[sodium-chloride symporter|Na+-Cl<sup>-</sup> symporter]]. Thiazides also cause loss of [[potassium]] and an increase in [[blood plasma|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"<ref>{{MeshName|thiazide+receptor}}</ref>, 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)<ref>{{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=}}</ref> guidelines and the National Institute for Health and Clinical Excellence/British Hypertension Society guidelines<ref>{{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=}}</ref>and a recommended treatment in the European (ESC/ESH)<ref>{{cite web |url=http://www.escardio.org/knowledge/guidelines/CVD_Prevention_in_Clinical_Practice.htm |title=escardio.org |accessdate=2007-08-30 |format= |work=}}</ref> guidelines. They have been shown to prevent hypertension-related [[morbidity]] and [[death|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 anhydrase]]<ref name="pmid15803433">{{cite 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}}</ref> or by [[desensitization|desensitizing]] the [[vascular smooth muscle]] cells to the rise in intracellular [[calcium]] induced by [[norepinephrine]].<ref name="pmid15611360">{{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}}</ref> ==Side effects== [[Adverse drug reaction|Side effect]]s can include [[hypokalemia]], increased serum [[cholesterol]], [[triglyceride]], [[impaired glucose tolerance]], [[diabetes mellitus]]<ref name="pmid16565243">{{cite 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}}</ref> and [[impotence]]. The side effect of hypokalemia has motivated combining thiazides with potassium chloride supplements, [[potassium sparing diuretic]]s (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.<ref name="pmid17656470">{{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}}</ref> 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 hypokalaemia (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 alcalose].) * Activation of renin-angiotensin-aldosterone system by the diuretic hypovolaemia: body responds to hypovolaemia 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 inhibitor]]s, which inhibit [[angiotensin II]] production and therefore aldosterone activation, are frequently used in combination with thiazides to combat hypokalaemia. * 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== Moreno, E (2006). Affinity-defining Domains in the Na-Cl Cotransporter. J. Biol. Chem. 281, 17266-17275. <references/> ==External links== *[http://www.mayoclinic.com/health/drug-information/DR602123 Thiazide Diuretics] info from the [[Mayo Clinic]] {{pharma-stub}} {{Antihypertensives and diuretics}} [[Category:Thiazides|*]] [[de:Thiaziddiuretika]] [[es:Tiazida]] [[fr:Diurétique thiazidique]] [[pam:Thiazide]] [[no:Tiazid]] [[nn:Tiazid]] [[pl:Tiazydy]] [[pt:Tiazida]] [[sv:Tiazid]]