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Revision as of 12:31, 24 November 2011 editBeetstra (talk | contribs)Edit filter managers, Administrators172,074 edits Saving copy of the {{drugbox}} taken from revid 453889165 of page Metolazone for the Chem/Drugbox validation project (updated: 'DrugBank').		Latest revision as of 16:18, 27 September 2023 edit Boghog (talk | contribs)Autopatrolled, Extended confirmed users, IP block exemptions, New page reviewers, Pending changes reviewers, Rollbackers, Template editors137,925 edits consistent citation formatting
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			{{short description|Chemical compound}}
	{{ambox | text = This page contains a copy of the infobox ({{tl|drugbox}}) taken from revid of page ] with values updated to verified values.}}
			{{distinguish|text=], a muscle relaxant}}
	{{Drugbox		{{Drugbox
	| Watchedfields = changed		| Verifiedfields = changed
	| verifiedrevid = 411405800		| verifiedrevid = 462251857
	| IUPAC_name = 7-chloro-2-methyl-4-oxo-3-o-tolyl-1,2,3,4-tetrahydroquinazoline-6-sulfonamide		| IUPAC_name = 7-chloro-2-methyl-4-oxo-3-o-tolyl-1,2,3,4-tetrahydroquinazoline-6-sulfonamide
	| image = Metolazone.svg		| image = Metolazone.svg
	| image2 =		| image2 = Metolazone ball-and-stick.png
	<!--Clinical data-->		<!--Clinical data-->
	| tradename = Zaroxolyn		| tradename = Zaroxolyn
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	| pregnancy_category = B		| pregnancy_category = B
	| legal_status = Prescription only		| legal_status = Prescription only
	| routes_of_administration = Oral		| routes_of_administration = By mouth
	<!--Pharmacokinetic data-->		<!--Pharmacokinetic data-->
	| bioavailability = ~65%		| bioavailability = ~65%
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	| elimination_half-life = 14 hours		| elimination_half-life = 14 hours
	| excretion = primarily urine		| excretion = primarily urine
	<!--Identifiers-->		<!--Identifiers-->
			| IUPHAR_ligand = 4838
	| CASNo_Ref = {{cascite|correct|CAS}}		| CAS_number_Ref = {{cascite|correct|??}}
	| CAS_number = 17560-51-9		| CAS_number = 17560-51-9
	| ATC_prefix = C03		| ATC_prefix = C03
	| ATC_suffix = BA08		| ATC_suffix = BA08
	| PubChem = 4170		| PubChem = 4170
			| ChEBI_Ref = {{ebicite|changed|EBI}}
			| ChEBI = 64354
	| DrugBank_Ref = {{drugbankcite|correct|drugbank}}		| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
	| DrugBank = DB00524		| DrugBank = DB00524
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	| ChEMBL_Ref = {{ebicite|correct|EBI}}		| ChEMBL_Ref = {{ebicite|correct|EBI}}
	| ChEMBL = 878		| ChEMBL = 878
	<!--Chemical data-->		<!--Chemical data-->
	| C=16 | H=16 | Cl=1 | N=3 | O=3 | S=1		| C=16 | H=16 | Cl=1 | N=3 | O=3 | S=1
	| molecular_weight = 365.835 g/mol
	| smiles = O=S(=O)(c3c(Cl)cc2c(C(=O)N(c1ccccc1C)C(N2)C)c3)N		| smiles = O=S(=O)(c3c(Cl)cc2c(C(=O)N(c1ccccc1C)C(N2)C)c3)N
	| InChI = 1/C16H16ClN3O3S/c1-9-5-3-4-6-14(9)20-10(2)19-13-8-12(17)15(24(18,22)23)7-11(13)16(20)21/h3-8,10,19H,1-2H3,(H2,18,22,23)
	| InChIKey = AQCHWTWZEMGIFD-UHFFFAOYAO
	| StdInChI_Ref = {{stdinchicite|correct|chemspider}}		| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
	| StdInChI = 1S/C16H16ClN3O3S/c1-9-5-3-4-6-14(9)20-10(2)19-13-8-12(17)15(24(18,22)23)7-11(13)16(20)21/h3-8,10,19H,1-2H3,(H2,18,22,23)		| StdInChI = 1S/C16H16ClN3O3S/c1-9-5-3-4-6-14(9)20-10(2)19-13-8-12(17)15(24(18,22)23)7-11(13)16(20)21/h3-8,10,19H,1-2H3,(H2,18,22,23)
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	| melting_point = 260		| melting_point = 260
	}}		}}
			<!-- Definition and medical uses -->
			'''Metolazone''' is a ] marketed under the brand names '''Zytanix''', '''Metoz''', '''Zaroxolyn''', and '''Mykrox'''. It is primarily used to treat ] and ]. Metolazone indirectly decreases the amount of water reabsorbed into the bloodstream by the ], so that blood volume decreases and urine volume increases. This lowers blood pressure and prevents excess fluid accumulation in heart failure. Metolazone is sometimes used together with ]s such as ] or ], but these highly effective combinations can lead to ] and ].
			<!-- Society and culture -->
			It was patented in 1966 and approved for medical use in 1974.<ref>{{cite book | vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery |date=2006 |publisher=John Wiley & Sons |isbn=9783527607495 |page=457 |url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA457 |language=en}}</ref>
			==Medical uses==
			One of the primary uses of metolazone is for treating ] (fluid retention) associated with ] (CHF). In mild heart failure, metolazone or another diuretic may be used alone, or combined with other diuretics for moderate or severe heart failure. In addition to preventing fluid buildup, the use of metolazone may allow the patient to relax the amount of sodium restriction that is required. Although most thiazide diuretics lose their effectiveness in ], metolazone remains active even when the ] (GFR) is below 30–40 mL/min (moderate ]).{{citation needed|date=January 2018}} This gives it a considerable advantage over other thiazide diuretics, since renal and heart failure often coexist and contribute to fluid retention.<ref name="Harrison's">{{cite book | vauthors = Braunwald E | chapter = Heart Failure and Cor Pulmonale | title = ] | edition = 15th | veditors = Kasper DL, etal | location = New York | publisher = ] | date = 2005 }}</ref>
			Metolazone may also be used in kidney disease, such as ] or the ]. Chronic kidney disease causes excess fluid retention that is often treated with ] adjustments and diuretics.<ref name="Harrison's" /> Metolazone may be combined with other diuretics (typically loop diuretics) to treat diuretic resistance in congestive ], chronic kidney disease, and nephrotic syndrome.<ref name="CDT">{{cite journal | vauthors = Rosenberg J, Gustafsson F, Galatius S, Hildebrandt PR | title = Combination therapy with metolazone and loop diuretics in outpatients with refractory heart failure: an observational study and review of the literature | journal = Cardiovascular Drugs and Therapy | volume = 19 | issue = 4 | pages = 301–6 | date = August 2005 | pmid = 16189620 | doi = 10.1007/s10557-005-3350-2 | s2cid = 23704590 }}</ref> Metolazone and a loop diuretic will synergistically enhance diuresis over the use of either agent alone. Using this combination, diuretic effects will occur at two different segments of the nephron; namely, the loop diuretic will act at the ], and metolazone will act at the distal convoluted tubule. Metolazone is frequently prescribed in addition to the loop diuretic. Metolazone may be used for edema caused by liver ] as well.
			The other major use of metolazone is in treating ] (high blood pressure). Thiazide diuretics, though usually not metolazone, are very often used alone as first-line treatment for mild hypertension. They are also used in combination with other drugs for difficult-to-treat or more severe hypertension. "The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure" (JNC 7) recommends thiazide diuretics as the initial medication for treatment of hypertension. ] is by far the most commonly used, as it is both better-studied and cheaper (about four times) than metolazone, although as mentioned above metolazone is used in patients with moderate chronic kidney disease.<ref name="G&G" />
			==Toxicity==
			Since thiazide diuretics affect the transport of ]s and water in the kidney, they can be responsible for abnormalities of water balance and electrolyte levels. Removal of too much fluid can cause ] and ]. Various electrolyte abnormalities may result, including ] (low sodium), ] (low potassium), ] (low chloride), ] (low ]), ] (high ]), and ] (high ]). These may result in ], ], or heart ]s (palpitations).<ref name="G&G" /> Serious, though rare, side effects include ], ], ], and ]. Metolazone, like other thiazide diuretics, may unmask latent ] or exacerbate ], especially by interacting with medicines used to treat gout. In addition, thiazide diuretics, including metolazone, are ]s; those with hypersensitivity to sulfonamides ("sulfa allergy") may also be allergic to metolazone.<ref name="G&G" />
			==Mechanism of action==
			]. The ] and ] are labeled in Latin ("tubulus contortus proximalis" and "tubulus contortus distalis") in this illustration.]]
			The primary target of all thiazide diuretics, including metolazone, is the ], part of the ] in the ], where they inhibit the ].
			In the kidney, blood is filtered into the ], or open space, of the nephron tubule. Whatever remains in the tubule will travel to the ] as ] and eventually be excreted. The cells lining the tubule modify the fluid inside, absorbing some material and excreting others. One side of the cell (the ''apical'' side) faces the lumen; the opposite side (the ''basolateral'' side) faces the ] near blood vessels. The other sides are tightly joined to neighboring cells.
			As with other regions, tubule cells in the distal convoluted tubule possess the ]-powered ]-] ] (]), which uses energy from ATP to transfer three sodium ions out from the basolateral surface (toward ]s) while simultaneously transferring two potassium ions in. The distal convoluted tubule cells also possess a ] on the apical side, which passively allows one sodium ion and one chloride ion to diffuse together in from the lumen (where urine is forming) into the cell interior. As sodium is pumped out of the cell by the ATPase, its intracellular concentration falls, and additional sodium begins to diffuse in from the tubule lumen as replacement. The symporter requires chloride to be transported in as well. Water passively follows to maintain ]; excess chloride and potassium passively diffuse out the cell through basolateral channels into the interstitial space, and water accompanies them. The water and chloride, as well as the sodium pumped out by the ATPase, will be absorbed into the bloodstream.
			Metolazone and the other thiazide diuretics inhibit the function of the sodium-chloride symporter, preventing sodium and chloride, and therefore water too, from leaving the lumen to enter the tubule cell. As a result, water remains in the lumen and is excreted as urine, instead of being reabsorbed into the bloodstream. Since most of the sodium in the lumen has already been reabsorbed by the time the filtrate reaches the distal convoluted tubule, thiazide diuretics have limited effects on water balance and on ] levels.<ref name="G&G" /> Nevertheless, they can be associated with ], ], and ], among other adverse effects.
			==Pharmacokinetics==
			Metolazone is only available in ] preparations. Approximately 65% of the amount ingested becomes available in the bloodstream. Its ] is approximately fourteen hours, similar to indapamide but considerably longer than ]. Metolazone is around ten times as potent as hydrochlorothiazide. The primary form of excretion is in the urine (around 80%); the remaining fifth is evenly split between ] excretion and metabolism into inactive forms.<ref name="G&G" />
			==Chemistry==
			The use of activated anthranilic acid derivatives facilitates the preparation of the
			amides in those cases where the amines are either unreactive or difficult to obtain.
			]
			Thus, reaction of (1) with ] gives the reactive the ] (2). Condensation of that with ] leads to the acylation product (3) formed with a simultaneous loss of carbon dioxide. This is then converted to the ] (4) by heating with ]. Reaction with ] in the presence of ] selectively reduces the double bond to yield the diuretic agent metolazone (5).
			=== Structure and classification ===
			Metolazone is a ], a derivative of the similar diuretic ], as well as a ]. It is related to analogs of 1,2,4-benzothiadizine-1,1-dioxide (]). Such drugs are called ''benzothiadiazides'', or ''thiazides'' for short; however, in terms of chemistry, metolazone is not a substituted benzothiadiazine, and therefore is not technically a ]. Since metolazone (as well as other drugs like ]) acts on the same target as thiazides and behave in a similar pharmacologic fashion, it is, however, considered a "thiazide-like diuretic." Therefore, metolazone and similar drugs are often categorized with thiazide diuretics despite not being thiazides themselves.<ref name="G&G">{{cite book | vauthors = Jackson EK | chapter = Diuretics | title = ] | edition = 11th | veditors = Brunton LL, etal | location = New York | publisher = ] | date = 2006 }}</ref>
			==History==
			Metolazone was developed in the 1970s. Its creator, ]n born chemist ] has been active in helping the ] ] review drug applications, and in the development of new medicines.<ref name="FDA">{{cite journal | vauthors = Katague DB | title = Chemistry Reviewer Still in Lab | journal = News Along the Pike | publisher = ]' s Center for Drug Evaluation and Research | volume = 2 | issue = 10 | url = https://www.fda.gov/cder/pike/nov96.pdf }}</ref>
			Metolazone quickly gained popularity due to its lower kidney toxicity compared to other diuretics (especially thiazides) in patients with ].
			== References ==
			{{Reflist}}
			{{Symporter inhibitors}}
			{{Diuretics}}
			]
			]
			]
			]
			]
			]