Antihypertensives 1.2.4- benzothiadiazine

Changing the substitution pattern on the carbo-cyclic ring of the benzothiadiazine diuretics is well known to have a marked effect on the qualitative biological activity. Thus, the direct analogue of the diuretic chlorothiazide (199) in which chlorine replaces one sulfonamide group, diazoxide (200), shows negligible diuretic activity instead the compound is a potent antihypertensive vasodilator. 

The 1,2,3-benzothiadiazine 1,1-dioxide (7, R = OEt) has diuretic and antihypertensive activity (62HCA996)—pharmacological features more common to a number of 1,2,4-benzothiadiazine 1,1-dioxides (see Section III.D). 

A. J. Wohl, Mol. Pharmacol., 6(3), 195 (1970). Electronic iVlolecular Pharmacology The Benzothiadiazine Antihypertensive agents. II. Multiple Regression Analysis Relating Biological Potency and Electronic Structure. 

The only compound of note is the 4-hydrazino-2//-l,2,3-benzothiadiazine 1,1-dioxide (43) which, like the 1,2,4-thiadiazine 1,1-dioxides (see Chapter 6.14), is reported to have diuretic and antihypertensive activity <62HCA996>. 

Benzothiadiazine 1,1-dioxides have been shown to be useful antihypertensive agents and diuretics and many such compounds have been prepared <62AG(E)235>. 

Benzothiadiazines ( thiazides ) and related diuretics are the most frequently used class of antihypertensive agents in the U.S. Thiazides block the Na+-Q symporter and have the same pharmacological effects and are generally interchangeable with appropriate dose adjustment (see Chapter 28). Since their pharmacokinetics and pharmacodynamics differ, these drugs do not necessarily have the same clinical efficacy in treating hypertension. 

Diazoxide - An Jji vitro pharmacodynamic study was de-signed to specify the type(s) of inhibition involved in the vascular action of diazoxide. The results indicate that diaz> oxide competes with barium for a specific receptor site in the vascular smooth muscle of the rat aorta. The location of this receptor is apparently closer to the process of muscle contraction than the a-adrenergic receptor, and may be a site normally activated by calcium. The specific competitive inhibition of barium-stimulated vasoconstriction by diazoxide may help to explain the mechanism by which diazoxide, and possibly other benzothiadiazine antihypertensive agents, reduce blood pressure. ... 

Accepting their well-known side effects the benzothiadiazine derivatives remain a mainstay in the treatment with diuretics, especially in hypertension. The need for caution before prescribing antihypertensive diuretics to patients with myxoedema is indicated by a case reported by Takeda of an adverse reaction to trichlormethiazide (17 -). In this myxoedemic patient, sinus arrest occurred during treatment with the drug. Renewed treatment with the diuretic after substitution with thyroid hormone was possible without complications. 

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