Benzothiadiazine Diuretics Research Articles

Principles and clinical uses of diuretic therapy

I NDUCTION OF diuresis as a therapeutic modality has long been a mainstay of medical practice. It was advocated by physicians in the Fertile Crescent for the treatment of many renal diseases. Components capable of inducing diuresis have been identified in Sumerian, Assyrian, and Babylonian pharmacopeias.’ More recently, Al-Rhazi (850-932 AD), chief physician in Bagdad in the Abbasid period, prescribed it to prevent obstruction in cases of renal papillary necrosis,’ and Ibn-Sina (Avicenna) (980-1037 AD) incorporated diuresis as an integral part of his regimen for the dissolution of kidney st0nes.j Even Withering prescribed foxglove thinking it was a diuretic. However, modern diuretic therapy finds its origins in fortuitous observations on agents first introduced as antimicrobials. Vogl in I920 reported the diuretic effect of the organomercurial merbaphenum, then a treatment for syphilis. However, mercurials proved to be highly toxic and inconvenient. The need for a safer orally effective diuretic was satisfied with a second astute observation from the field of antimicrobials. Benzothiadiazine diuretics were discovered after the observation of diuresis during antimicrobial therapy with sulphonamides. In 1957, Novello and Sprague synthesized chlorothiazide and ushered the era of widespread use of diuretics into the practice of medicine.

Spectrophotometric determination of some benzothiadiazine diuretics with 7,7,8,8-tetracyanoquinodimethane

A new spectrophotometric method for the determination of some benzothiadiazine drugs is presented, based on reaction with 7,7,8,8-tetracyanoquinodimethane in sodium acetate medium and measurement at 578 nm. Beer's law is obeyed in the concentration range 0.7–6.0 μg/ml for all eight drugs tested.

Bromimetric determination of some benzothiadiazine diuretics in dosage forms.

A simple titrimetric method was developed for the determination of some benzothiadiazine diuretics in dosage forms, involving the use of 1,3-dibromo-5,5-dimethylhydantoin or N-bromosuccinimide as the titrant. A known excess volume of either reagent is added and, after a specified time, the residual reagent is determined iodimetrically. The stoicheiometry of the reaction was assessed and a proposal for the reaction pathway is presented. The reaction products were isolated and identified by NMR and IR spectroscopy. The results were compared statistically with those obtained using N-bromosuccinimide and official methods, and were found to be in good agreement.

Spectrophotometric determination of benzothiadiazines in dosage forms

The analytical utility of ethyl acetoacetate for the spectrophotometric determination of benzothiadiazine diuretics has been studied. The procedure developed is based on coupling of the diazotized drugs with the reagent, which possesses an active methylene group. The stoichiometry of the reaction is presented. The nominal recovery of the drugs from pharmaceutical preparations ranges from 97.6 ± 0.7 to 102.3 ± 0.3%. The suggested method is simple, sensitive and applicable to unit dose analysis.

Arginine reversion and lambda induction in E. coli with benzothiadiazine diuretics irradiated with near-ultraviolet light

Photoinduced genotoxicity of benzothiadiazine diuretics was studied with regard to mutagenic and lambda prophage-inducing activities in E. coli. Irradiation of E. coli with near-ultraviolet light in the presence of hydrochlorothiazide or methyclothiazide caused mutations of strain Hs30R argF(Am) to the prototrophic phenotype and induction of lambda from the lysogenic bacteria AB1157(λ). Both drugs showed nearly the same amount of activity. Penfluzide showed much less mutagenic and much less prophage-inducing activity than did hydrochlorothiazide and methyclothiazide.

Enantiomers of Benzothiadiazine Diuretics by Direct Chromatographic Resolution of the Racemic Drugs

A number of racemic benzothiadiazine diuretics and two carbonyl analogue drugs were resolved into their optical isomers by liquid chromatography on chiral polyacrylamides 1. Enantiomeric resolution, which was, in some cases, almost complete, depended considerably on the substitution of the heterocyclic moiety of the drug molecules. Synthesis of the new adsorbent Ib is described. The enantiomers of the benzothiadiazines penflutizide (2a) and bendroflumethiazide (2b) in high optical purity, as well as enriched (+)-buthiazide (2j) were obtained by repeated chromatography on a semipreparative scale. Chiroptical data, optical purity employing the chromatographic method, and first-order racemization kinetics as a function of pH in aqueous solutions were determined.

An in vitro test for photoinduced toxicity of benzothiadiazine diuretics using bacteriophage lambda.

Abstract— The relative photoinduced toxicity of five benzothiadiazine diuretics was assessed with respect to their potentiality to inactivate bacteriophage lambda by exposure to near‐UV light in a semi‐aqueous solution of 40% N,N‐dimethylformamide. The results showed the following order for the toxicity on a quantum yield basis: penflutizide > trichlormethiazide > methichlothiazide > benzylhydrochlorothiazide > hydrochlorothiazide. Since the bacteriophage was inactivated even when mixed with preirradiated solutions of the diuretics, some photoproducts are responsible for the photoinduced toxicity of the diuretics. Although a lowered pH affected the infectivity, it was a minor factor.

Semiaqueous Potentiometric Determinations of Apparent pKa1 Values for Benzothiadiazines and Detection of Decomposition during Solubility Variation with pH Studies

Apparent acidity constants obtained for various benzothiadiazine diuretics by semiaqueous potentiometric titrations gave satisfactory agreement with many values obtained by aqueous potentiometry. One suitable method for determining the acidity constants of sparingly soluble drugs, the solubility variation with pH technique, does not take into account instability problems. The preparation of decomposition products and the TLC analysis of sample solutions at various time intervals during solubility studies of methyclothiazide and bendroflumethiazide indicated that decomposition takes place during agitation and equilibration. This decomposition in buffers of pH 8 and higher was confirmed with the acidified p-dimethylaminobenzaldehyde test for primary aromatic amines.

GLUCOSE TOLERANCE IN HYPERTENSIVE PATIENTS ON LONG-TERM DIURETIC THERAPY

TWELVE (30%) of forty hypertensive patients who had been treated with benzothiadiazine diuretics for at least 3 years were found to have a diabetic-type glucose-tolerance test. Three patients with the highest blood-sugars had low levels of serum-insulin in response to the glucose load when compared with forty-five healthy controls. Stopping the diuretics caused a fall in blood-sugar in one and a rise in serum-insulin in the two patients re-tested. In seven hypertensive patients with less severe diabetes serum-insulin levels were higher than forty-five healthy controls, but stopping diuretic treatment had no effect on either glucose tolerance or serum-insulin levels. Frusemide caused a slight further impairment of glucose tolerance and a rise in serum-insulin in two of three patients so treated.

The hyperglycemic activity of benzothiadiazine and other diuretics

Considerable evidence is available which demontrates the tendency of certain benzothiadiazine diuretics to elevate blood glucose values in seemingly normal, as well as diabetic or pre-diabetic, individuals (1–5). A recent review (5) concerning the benzothiadiazine diuretics suggest that the hyperglycemic potential of all members of this chemical class is equivalent to their diuretic potency. The paucity of data encouraged us to determine systematically the degree of hyperglycemia elicited in rats by eleven benzothiadiazine diuretics. Chlorthalidone (an isoindoline), quinethazone (a quinazoline), and ethacrnic acid were included in this investigation as examples of diuretics of other chemical types.

Benzothiadiazines and Diabetes Mellitus

To the Editor:— Wolff and his associates ( JAMA 185 :568 [Aug 17] 1963) recently indicated that the induction of diabetes mellitus represents a not infrequent complication associated with the long-term administration of benzothiadiazine diuretics. The evidence consisted of the observation that the fasting blood sugar value in 45 patients averaged 97 mg% during long-term treatment with benzothiadiazines, excluding two hypertensive patients in whom frank clinical diabetes developed. This was compared with a mean fasting blood sugar value of 88.4 mg% in 26 patients receiving placebos. Pretreatment values of fasting blood sugar were not reported. The authors concluded that benzothiadiazines should not be given to young or middle-aged hypertensives in whom there is a lengthy life expectancy.... Since these agents are quite effective and often irreplaceable, either alone or as an adjunct in the treatment of hypertension, the conclusions of Wolff and his co-workers deserve careful consideration. It seemed of interest

Treatment of arterial hypertensive disease with diuretics. II. Effects on electrolytes and uric acid of bendroflumethiazide, potassium chloride, and spironolactone.

The effects of long-term administration of benzothiadiazine diuretics on electrolyte metabolism of hypertensive patients are ill defined. Applying results of acute changes in sodium and potassium balance to conditions of prolonged therapy has led to doubtful assumptions. Sodium loss has been believed responsible for the long-term reduction in blood pressure, whereas potassium wastage presumably represents a major untoward side-effect. This study was designed to delineate the magnitude, frequency, and significance of biochemical alterations during long-term administration of bendroflumethiazide to nonedematous hypertensive patients. It appears reasonable to postulate a compensatory increase in aldosterone secretion in response to sodium loss from diuretic therapy. We studied this by observing the modifying influence of an added aldosterone blocking agent, spironolactone, and of sodium and potassium chloride loading experiments. The effects of these drugs on the blood pressure of these same patients were recorded in a collateral communication.1 Material and Methods I. Electrolyte Balance

A possible mechanism of action of the antidiuretic effect of benzothiadiazine derivatives.

Acute experiments were performed on normal subfects to examine the mechanism of the antidiuretic effect of the benzothiadiazine diuretics which has been observed in animals and confirmed in patients with diabetes insipidus. In essence, the influence of dihydroflumethiazide on water loading was determined. On the basis of the data, it is suggested that the drug increases the permeability of the collecting tubule to water.

6-CHLORO,6-DEHYDRO,17α-ACETOXYPROGESTERONE: ITS POSSIBLE ACTION AS AN ALDOSTERONE ANTAGONIST

6-Chloro,6-dehydro,17α-acetoxyprogesterone (RS-1280) is a potent progestational agent, hence it was studied to determine whether or not it was an aldosterone antagonist. The study was carried out in 5 patients with cirrhosis of the liver and ascites, under constant metabolic conditions, with a previous examination of the renal capacity of each patient to excrete water, sodium and potassium under basal conditions and also when benzothiadiazine and mercurial diuretics were administered. In each case, RS-1280 was administered and its effect compared with that of a known aldosterone antagonist (spironolactone). By this means it was demonstrated that RS-1280 has no anti-aldosterone action, although it has a natriuretic effect in cirrhotic patients with a normal capacity to excrete sodium.

A non-diuretic benzothiadiazine with anti-hypertensive properties.

IN recent years the benzothiadiazine diuretics have become the drugs of choice for treating mild to moderate hypertension. Although their anti-hypertensive effect is relatively weak, they are quite non-toxic and are well absorbed orally. The mechanisms by which these agents reduce blood pressure in hypertensive individuals are not known. Some investigators1,2 have implicated natriuresis as the primary event, whereas others3 have suggested that the concentration of circulating pressor agents is reduced. That benzothiadiazine diuretics do antagonize in vitro intestinal and aortic contractions has already been demonstrated4,5. Consequently, the possibility exists that these agents directly affect the responsiveness of vascular smooth muscle. It was, therefore, considered of interest to try to dissociate the anti-hypertensive and diuretic actions of these compounds and, further, to intensify the former action while minimizing the latter.

Treatment of Hypertension with Benzydroflumethiazide as the Sole Antihypertensive Agent

BENZOTHIADIAZINE diuretics have become increasingly important in the treatment of arterial hypertension since the introduction of chlorothiazide in 1957.1 , 2 Although chlorothiazide is effective and possesses relatively few toxic effects, much effort has been made to improve on this parent compound. Such endeavor has led to the synthesis of the dihydro derivative of chlorothiazide (hydrochlorothiazide), which is at least ten times as potent as chlorothiazide on a milligram basis.3 , 4 In addition, fluorine-containing homologues of both drugs that appear to be similar in effectiveness and potency have been developed.3 , 5 A major difficulty in the use of these benzothiadiazine diuretics has been their . . .

New Diuretics and Antihypertensive Agents

The drugs covered in this volume are restricted to those which have appeared within the past 4 years: the benzothiadiazine, phthalimidine, and spirolactone diuretics, and the antihypertensive agents guanethidine and bretylium, and inhibitors of monoamine oxidase and dopadecarboxylation. The specific investigations reported are introduced by 6 review articles to provide appropriate context. Thus Grollman summarizes the most widely held views of the mechanisms of urine formation and diuretic action; Kirkendall reviews concepts of the mechanisms involved in hypertension; and Imbriglia reviews the pathology of hypertension. In addition, Rennick presents a lucid account of the pharmacodynamics of the new diuretics, based largely on animal studies. Parallel articles for the antihypertensive drugs are presented by Sjoerdsma on monoamine oxidase inhibitors and α-methyl dopa, and by Brodie and Kuntzman on agents selectively depleting catechol amines. Most of the information contained in this volume has been replicated in numerous publications. Bound together as a

New Diuretics and Antihypertensive Agents

The drugs covered in this volume are restricted to those which have appeared within the past four years: the benzothiadiazine, phthalimidine, and spirolactone diuretics, and the antihypertensive agents guanethidine, bretylium, and inhibitors of mononamine oxidase and dopa-decarboxylation. The specific investigations reported are introduced by six review articles to provide appropriate context. Thus Grollman summarizes the most widely held views of the mechanisms of urine formation and diuretic action; Kirkendall reviews concepts of the mechanisms involved in hypertension, and Imbriglia reviews the pathology of hypertension. In addition, Rennick presents a lucid account of the pharmacodynamics of the new diuretics, based largely on animal studies. Parallel articles for the antihypertensive drugs are presented by Sjoerdsma on monoamine oxidase inhibitors and α-methyl dopa and by Brodie and Kuntzman on agents selectively depleting catechol amines. Most of the information contained in this volume has been replicated in numerous publications. Bound together as a series

Comparative effects on urinary electrolyte excretion following two benzothiadiazine diuretics, flumethiazide and chlorothiazide.

Comparative effects on urinary electrolyte excretion following two benzothiadiazine diuretics, flumethiazide and chlorothiazide.