Thiazides structures

SAR of Indapamide. It apparently differs from the thiazides structurally. However, it may be viewed chemically as comprising of a polar sulphamoylchlorobenzamide and a highly lipoidal methylindolyl functional moiety. 

Each era of medicinal chemistry has been marked by intensive concentration on some structural type in a large number of laboratories. One need only look back in this book to the tables of sulfonamides, barbiturates, and thiazide diuretics, noting the small time span covered by the references to each list. The benzodiazepines have provided such a focus for the past decade. 

Agents acting in the proximal tubule are seldom used to treat hypertension. Treatment is usually initiated with a thiazide-type diuretic. Chlorthalidone and indapamide are structurally different from thiazides but are functionally related. If renal function is severely impaired (i.e., serum creatinine above 2.5 mg/dl), a loop diuretic is needed. A potassium-sparing agent may be given with the diuretic to reduce the likelihood of hypokalemia. 

The thiazide diuretics possess antihypertensive properties, in part consequent upon electrolyte and plasma-volume changes but mainly resulting from a direct cardiovascular depressant effect. This is clearly illustrated by the non-diuretic thiazide, diazoxide, which is an effective hypotensive [326b, c]. It is not therefore, surprising that both these properties should be found (in varying proportions) in other, structurally related, compounds. One particular line of research, aimed at modification of the thiazide heterocycle (the o-chlorobenzenesulphonamide moiety was untouched as it was believed essential to activity-the subsequent advent of ethacrynic acid questions this belieO examined first the corresponding... 

Thiazide diuretics consist of two distinct groups those containing a benzothiadiazine ring, such as hydrochlorothiazide and chlorothiazide, referred to as thiazide diuretics, and those that lack this heterocyclic structure but contain an unsubstituted sulfonamide group. The latter are called thiazidelike diuretics they include metolazone, xipamide, and indapamide. The major thiazide and thiazidelike drugs available in the United States are bendrofiumethiazide, benzthiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide, and trichlormethiazide and chlorthalidone, indapamide, metolazone, and quinethazone, respectively. 

In contrast to the structurally related thiazide diuretics, diazoxide causes renal salt and water retention. However, because the drug is used for short periods only, this is rarely a problem. 

Furosemide and thiazide diuretics (Fig. 8.4) have been approved for use in dairy cattle for treatment of postparturient edema of the mammary gland and associated structures (56). Furosemide and hydrochlorothiazide are administered intramuscularly or intravenously at a dosage of 500 and 125-250 mg/animal, respectively. Chlorothiazide and trichlormetliiazide are administered orally at dosage of 2000 and 200 mg/animal, respectively. 

The electronic structures of hydrochlorothiazide 146 and related substances have been determined by the complete neglect of differential overlap (CNDO/2) method (83AF688). The calculation confirms that the diuretic thiazides are electron-accepting, whereas diazoxide 147, a non-... 

The thiazides are the most widely used of the diuretic drugs. They are sulfonamide derivatives and are related in structure to the carbonic anhydrase inhibitors. The thiazides have significantly greater diuretic activity than acetazolamide, and they act on the kidney by different mechanisms. All thiazides affect the distal tubule, and all have equal maximum diuretic effect, differing only in potency, expressed on a per -milligram basis. 

Diuretics related to the thiazides. Several compounds, although strictly not thiazides, share structural similarities with them and probably act at the same site on the nephron they therefore exhibit moderate therapeutic efficacy. Overall, these substances have a longer duration of action, are used for oedema and hypertension and their profile of adverse effects is similar to that of the thiazides. They are listed below. 

Xipamide is structurally related to chlortalidone and to frusemide. It induces a diuresis for about 12 h that is brisker than with thiazides, which may trouble the elderly. 

Mefruside is a diuretic that is structurally related to fur-osemide, but with pharmacological actions more similar to those of the thiazide diuretics (SED-8, 488) (1). Its effects on serum lipids (SEDA-11, 196) and serum magnesium (SEDA-10, 188) are also similar to those of the thiazides. 

Acute thrombocytopenia is rarely associated with the newer sulfonamides (4,93,94). The structurally related sulfonylureas and thiazide diuretics can also cause allergic thrombocytopenia (95). Although some in vitro tests have been reported to predict the occurrence of thrombocytopenia, none of these has been used routinely (96,97). Furthermore, a negative test result with a drug does not definitely exclude it as the responsible allergen. 

Although one thiazide diuretic may be 100 times more potent than another weight for weight, all these drugs have essentially the same properties. Their mechanism of action (inhibition of sodium and chloride reabsorption in the distal convoluted tubule of the kidney) is identical and they can therefore be dealt with as a group. Thiazidelike diuretics, structurally different from the thiazides, have similar actions. Thiazide and thiazide-like diuretics are listed in Table 1. 

This is a dcs-sulfamoyl analogue ol (he benzothiazine di-iielics and has a clo.se. structural similarity to chlorolhiazidc. Il was developed intentionally to increa.se (he anlihypeden-live action of the thiazides and to minimize the diuretic cf-... 

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