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07-SEPTEMBER-2008 03:17:44 - Thiazide Chlorothiazide Chlorothiazide Hydrochlorothiazide Hydrochlorothiazide Bendroflumethiazide Bendroflumethiazide Thiazide is a term used to describe a type of molecule1 and a class of diuretic.2 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. Contents 1 Denomination 2 Primary uses 3 Side effects 4 Other uses 5 Breast milk 6 Mechanisms of hypokalemia 7 References 8 External links 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 receptor3, 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 VII4 guidelines and the National Institute for Health and Clinical Excellence/British Hypertension Society guidelines5and a recommended treatment in the European ESC/ESH6 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 anhydrase7 or by desensitizing the vascular smooth muscle cells to the rise in intracellular calcium induced by norepinephrine.8 Side effects Side effects can include hypokalemia, increased serum cholesterol, triglyceride, impaired glucose tolerance, diabetes mellitus9 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.10 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 alcalose. 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 ^ MeSH Thiazides ^ MeSH Thiazide+Diuretics ^ MeSH thiazide+receptor ^ The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure JNC 7. Retrieved on 2007-08-30. ^ Hypertension: management of hypertension in adults in primary care. Retrieved on 2008-04-25. ^ escardio.org. Retrieved on 2007-08-30. ^ 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. ^ Salvetti A, Ghiadoni L. 2006. Thiazide diuretics in the treatment of hypertension: an update. 1: J Am Soc Nephrol. 17 4 Suppl 2: S25-9. doi:10.1681/ASN.2005121329. PMID 16565243. ^ 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. PMID 17656470. External links Thiazide Diuretics info from the Mayo Clinic Tablets This pharmacology-related article is a stub. v d e Antihypertensives C02 and diuretics C03 Sympatholytic agents Centrally acting/antiadrenergics α2 agonist Clonidine, Guanfacine, Methyldopa imidazoline receptor agonist Moxonidine, Rilmenidine adrenergic uptake inhibitor Rescinnamine, Reserpine Ganglion-blocking/nicotinic antagonist Mecamylamine, Trimethaphan Peripherally acting/antiadrenergics α1 blockers: Prazosin Indoramin Trimazosin Doxazosin Urapidil Guanidine derivatives: Betanidine Guanethidine Guanoxan Debrisoquine Guanoclor Guanazodine Guanoxabenz Vasodilators Diazoxide hydrazinophthalazine Hydralazine, Dihydralazine, Endralazine, Cadralazine Minoxidil Nitroprusside Phentolamine Other antihypertensives serotonin antagonist Ketanserin endothelin receptor antagonist Bosentan, Ambrisentan, Sitaxsentan MAOI Pargyline THI Metirosine Diuretics Low ceiling Thiazides at DCT Bendroflumethiazide Hydroflumethiazide Hydrochlorothiazide Chlorothiazide Polythiazide Trichlormethiazide Cyclopenthiazide Methyclothiazide Cyclothiazide Mebutizide Sulfonamides Quinethazone Clopamide Chlortalidone Mefruside Clofenamide Metolazone Meticrane Xipamide Indapamide Clorexolone Fenquizone Other Mersalyl Theobromine Cicletanine osmotic Mannitol, Urea carbonic anhydrase inhibitor at PT Acetazolamide High ceiling Loop diuretic at AL Bumetanide, Furosemide, Torasemide, Ethacrynic acid Potassium-sparing at CD ESC blockers Amiloride, Triamterene, Benzamil aldosterone antagonists Spironolactone, Eplerenone, Potassium canrenoate, Canrenone v d e Membrane transport modulators Channel blocker Calcium Amlodipine Amrinone Anandamide Anipamil Azimilide Bencyclane Benidipine Bepridil Berbamine Bevantolol Canadine Carboxyamido-Triazole Cilnidipine Cinnarizine Clentiazem Conotoxins Darodipine Dauricine Devapamil Diltiazem Dimiapramine Dotarizine Efonidipine Emopamil Enpiperate Eperisone Falipamil Fantofarone Fasudil Felodipine Fenamic acid Fendiline Flunarizine Fosfedil Gabapentin Gallopamil Isradipine Lacidipine Lamotrigine Lercanidipine Lidoflazine Magnesium sulfate Manidipine Manoalide Mepirodipine Mibefradil Monatepil Naftopidil Nicardipine Nifedipine Niguldipine Niludipin Nilvadipine Nimodipine Nisoldipine Nitrendipine Norverapamil Ochratoxin A Octylonium Osthol Oxodipine Perhexiline Pinaverium Piperidine Pranidipine Prenylamine Risedronic acid Ryodipine Sesamodil Stepholidine Terodiline Tetrahydropalmatine Tetrandrine Tolfenamic acid Tranilast Verapamil Potassium 3,4-Diaminopyridine 4-Aminopyridine Dofetilide Linopirdine Maurotoxin Paxilline Tetraethylammonium Charybdotoxin Sodium Amiloride Encainide Pilsicainide Saxitoxin Tetrodotoxin Tocainide Symporter inhibitor Sodium chloride thiazide: Bendroflumethiazide Chlorothiazide Cyclopenthiazide Hydrochlorothiazide Hydroflumethiazide Methyclothiazide Polythiazide Trichlormethiazide other: Chlorthalidone Sodium potassium chloride Bumetanide Furosemide Retrieved from http://en..org/wiki/Thiazide Categories: Pharmacology stubs | Thiazides Views Article Discussion this page History Personal tools Log in / create account Navigation Main page Contents Featured content Current events Random article Search Go Search Interaction Community portal Recent changes Contact Donate to Help Toolbox What links here Related changes Upload file Special pages Printable version Permanent link Cite this page Languages Deutsch Español Français Kapampangan Norsk bokmål Norsk nynorsk Polski Português Svenska This page was last modified on 25 August 2008, at 18:02
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