Chlortalidone

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Chlortalidone
Chlortalidone.svg
Chlortalidone ball-and-stick.png
Systematic (IUPAC) name
(RS)-2-Chloro-5-(1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl)benzene-1-sulfonamide
Clinical data
Trade names Hygroton, Tenoretic
AHFS/Drugs.com Consumer Drug Information
MedlinePlus a682342
Pregnancy cat.
Legal status
Routes Oral
Pharmacokinetic data
Protein binding 75%
Half-life 40 hours
Excretion Renal
Identifiers
CAS number 77-36-1 YesY
ATC code C03BA04
PubChem CID 2732
DrugBank DB00310
ChemSpider 2631 YesY
UNII Q0MQD1073Q YesY
KEGG D00272 YesY
ChEBI CHEBI:3654 YesY
ChEMBL CHEMBL1055 YesY
Chemical data
Formula C14H11ClN2O4S 
Mol. mass 338.766 g/mol
 YesY (what is this?)  (verify)

Chlortalidone (INN/BAN) or chlorthalidone (USAN) is a diuretic drug used to treat hypertension, originally marketed as Hygroton in the USA. It is described as a thiazide diuretic (or, rather, a thiazide-like diuretic because it acts similarly to the thiazides but does not contain the benzothiadiazine molecular structure). Compared with other medications of the thiazide class, chlortalidone has the longest duration of action but a similar diuretic effect at maximal therapeutic doses. It is often used in the management of hypertension and edema.

Unlike loop diuretics, chlortalidone efficacy is diminished in patients with certain renal diseases (e.g. chronic renal disease). A clinical trial (ALLHAT) in 2002 compared chlortalidone to doxazosin in the treatment of high-risk hypertensive patients. In this study, only chlortalidone significantly reduced the risk of combined cardiovascular disease events, especially heart failure, when compared with drugs such as doxazosin.[1] Chlortalidone was approved by the FDA in 1960. The ALLHAT study conclusions showed that there was no significant difference in all-cause mortality, fatal heart disease, or non-fatal myocardial infarction when chlortalidone was compared with lisinopril or amlodipine but did show decrease rates of heart failure after 6 years when compared with amlodipine and decreased rates of cerebrovascular disease after 6 years when compared with lisinopril leading the study conclusions to say that thiazide-type diuretics are preferred first-step in antihypertensive therapy.

In terms of activity, chlorothalidone is very similar to hydrochlorothiazide[citation needed] and is used as an independent drug or in combination with other antihypertensive agents for lowering arterial blood pressure, and also as an adjuvant drug for treating edema caused by cardiac insufficiency and renal irregularities, including nephrotic syndrome.

Mechanism of action[edit]

Chlortalidone prevents reabsorption of sodium and chloride by inhibiting the Na+/Cl- symporter in the distal convoluted tubule. Thiazides and related compounds also decrease the glomerular filtration rate, which further reduces the drug's efficacy in patients with renal impairment (e.g. renal insufficiency). By increasing the delivery of sodium to the distal renal tubule, chlortalidone indirectly increases potassium excretion via the sodium-potassium exchange mechanism (i.e. apical ROMK/Na channels coupled with basolateral NKATPases). This can result in hypokalemia and hypochloremia as well as a mild metabolic alkalosis; however, the diuretic efficacy of chlortalidone is not affected by the acid-base balance of the patient being treated.

Initially, diuretics lower blood pressure by decreasing cardiac output and reducing plasma and extracellular fluid volume. Eventually, cardiac output returns to normal, and plasma and extracellular fluid volume return to slightly less than normal, but a reduction in peripheral vascular resistance is maintained, thus resulting in an overall lower blood pressure. The reduction in intravascular volume induces an elevation in plasma renin activity and aldosterone secretion, further contributing to the potassium loss associated with thiazide diuretic therapy.

Combination products[edit]

It is also available as a combination product with the beta blocker atenolol, marketed in the UK as co-tenidone and in the US as Tenoretic.

Recently, products containing chlortalidone in combination with angiotensin receptor blockers telmisartan ( Telpres CT 6.25/12.5 in India) (Eritel CH in India), olmesartan (Olmin CH[2] in India) and azilsartan (Edarbyclor) have been marketed .[citation needed]

Synthesis[edit]

1st method[edit]

Chlorothalidone can be synthesized by two proposed methods from 2'-carboxy-4-chlorobenzophenone, which is easily synthesized by acylating chlorobenzol with phthalic anhydride in the presence of aluminium chloride. The resulting benzophenone derivative undergoes nitration by nitric acid, which gives 2'-carboxy-3-nitro-4-chlorobenzophenone. The nitro group in the resulting compound is reduced by tin dichloride to 2'-carboxy-3-amino-4-chlorobenzophenone. Next, subsequent diazotization and reaction with sulfur dioxide in the presence of copper dichloride gives the corresponding sulfonylchloride. Upon reaction with thionyl chloride, this compound undergoes cyclization into a phthalide, which when reacted with aqueous ammonia rearranges into a derivative of isoindoline with simultaneous substitution of the chloride atom in the sulfogroup with an amino group, which results in chlorothalidone.

Cit:[3][4]

2nd method[edit]

A second way of synthesizing it is from 2'-carboxy-4-chlorobenzophenone, which during reduction with zinc in acetic acid transforms into 3-(4'-chlorophenyl)phthalide. Sulfonylchlorination of this gives the corresponding sulfonyl chloride, which upon reaction with phosphorus pentachloride is chlorinated into 3-(4'-chlorophenyl-3'-chlorosulfo)-3-chlorophtalide. This is reacted with aqueous ammonia in the aforementioned manner, and it rearranges into chlorothalidone.

Ref:[5]

3rd method[edit]

A third way of synthesis is started from 2'-carboxy-4-chlorobenzophenone, and it consists of direct cyclization of the indicated carboxy benzophenone into 3-(4-chlorophenyl)phthalimidine. Subsequent sulfochlorination and amination of this product gives 2-chloro-5-(3-oxo-1-isoindolinyl)-benzolsulfonamide, which is oxidized by various oxidizers such as oxygen or hydrogen peroxide in alkaline or chromic acid in acetic acid into chlorothalidone.

Ref:[6][7]

In terms of activity, chlorothalidone is very similar to benzothiadiazide and is used as an independent drug or in combination with other antihypertensive agents for lowering arterial blood pressure, and also as an adjuvant drug for treating edema caused by cardiac insufficiency and renal irregularities, including nephrotic syndrome.

Synonyms of this drug are gigroton, novatalidon, uridon and others.

References[edit]

  1. ^ ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group (18 December 2002). "Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)". JAMA 288 (23): 2981–97. doi:10.1001/jama.288.23.2981. PMID 12479763. 
  2. ^ http://www.mims.com/India/drug/info/OLMIN-CH/OLMIN-CH%20bilayer%20coated%20tab?q=olmin%20ch
  3. ^ W. Graf, E. Schmid, W.G. Stoll, U.S. Patent 3,055,904 (1962)
  4. ^ W. Graf, E. Girod, E. Schmid,W.G. Stoll, Helv. Chim. Acta, 42, 1085 (1959)
  5. ^ T.J. Giacibbe, H.C. White, U.S. Patent 4,188,330 (1980)
  6. ^ J. Auerbach, F.A. Golec, Eur. Pat. Appl. 51.215 (1981)
  7. ^ J. Auerbach, F.A. Golec, Eur. Pat. Appl. 51.217 (1981).