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PubMed1981

The effect of renin and aldosterone inhibition by beta-adrenergic blockade on the response to the new diuretic azosemide.

The effect of repeated Azosemide infusions (20 mg in 500 ml 5% glucose for one h) on urine volume and electrolyte excretion, and on the activity of the renin-angiotensin-aldosterone system (RAAS) was studied in a group of 15 patients with benign essential hypertension before and during treatment with the beta-adrenergic blocker Trimepranol. Azosemide alone had a marked but short-lasting diuretic and natriuretic effect. Repeated administration on three consecutive days led, however, to a progressive decrease in the natriuretic effectiveness of Azosemide, associated with an increase in plasma renin activity (from 0.413 o.032 to 1.631 0.438 pmol/l). Treatment with Trimepranol 20 mg/day enhanced and prolonged the diuretic and natriuretic response to Azosemide concomitantly with a reduction of its stimulatory effect of RAAS. There results suggest that stimulation of the RAAS might be responsible for the diminishing effectiveness of repeated Azosemide infusions and that the stimulation could be, at least partly, inhibited by a beta-blocker Trimepranol, resulting in a greater diuretic and natriuretic effect of Azosemide.

Adrenergic beta-Antagonists↗
PubMed1982

Renin classification for diuretic and beta-blocker treatment of black hypertensive patients.

Renin classification has been proposed to guide initial treatment of hypertensive patients with diuretics vs beta-blockers. Most previous studies evaluating this issue have utilized patient populations that were white or predominantly white. Black hypertensives have been noted to differ from white hypertensives in several respects. To evaluate the clinical utility of renin classification in black hypertensives, we compared the blood pressure response of low vs normal renin patients during double-blind treatment with either hydrochlorothiazide or beta blocker (metoprolol or oxprenolol). Hydrochlorothiazide a significantly (P less than 0.05-0.01) larger blood pressure fall than beta-blocker, though there was no difference in the response of low vs normal renin patients. Thus, renin classification does not appear to guide initial selection of diuretic vs beta blocker therapy of black hypertensives, and diuretic therapy is more effective.

Adrenergic beta-Antagonists↗
PubMed1986

Diuretic-induced laboratory abnormalities that predict ventricular ectopy.

In order to determine which of the many diuretic-induced laboratory changes might be associated with an increased risk of ventricular ectopy (VE), we performed logistic regression analyses of patient data from a large computerized medical record system. Study variables included serum Ca2+, K+, Cl-, HCO-3, glucose, cholesterol, albumin, uric acid, and hematocrit. Controlling variables included race, use of diuretics, blood pressure, smoking history, age, and weight. (In one analysis we also included cardiac drug history and evidence of pre-existing cardiovascular disease). Separate analyses were performed for males and females. For the retrospective cohort-like design, we analyzed data for 9561 patients with complete data. For the case-control design we analyzed data from 4786 patients. Diuretic usage predicted ventricular ectopy in women, but not men. Serum uric acid and hematocrit were the only significant laboratory predictors of ventricular ectopy in each of the four analyses. Abnormalities in these variables might provide an explanation for the greater incidence in sudden (and presumably arrhythmic) deaths reported in MRFIT study patients with mild hypertension.

Arrhythmias, Cardiac↗
PubMed1980

Influence of diuretics on complete denture retention: a preliminary report.

Diuretics were suspected of affecting denture retention. A device was constructed to measure changes in retention. Data were obtained from patients both while they were receiving and not receiving diuretics. Significant changes were noted, and the results indicated that patients taking diuretics are likely to have problems with denture retention.

Denture Retention↗
PubMed1982

Tracheal relaxant and cardiostimulant actions of xanthines can be differentiated from diuretic and CNS-stimulant effects. Role of adenosine antagonism?

Theophylline (1, 3-dimethylxanthine) and enprofylline (3-propylxanthine) have been examined for effects in the rat. Enprofylline was 3.8 times as potent as theophylline as a tracheal relaxant in vitro, and 1.3 times as potent as theophylline to increase the rate of isolated perfused hearts. An oral dose (5 mg/kg) of enprofylline to rats was almost completely recovered in the urine as unchanged drug, showing that this xanthine is well absorbed and negligibly metabolised. Theophylline (10 and 30 mg/kg p.o.) significantly and dose-dependently increased locomotor activity in rats whereas the same doses of enprofylline were without effect on behaviour. Theophylline ( 5-20 mg/kg p.o.) produced significant and dose-dependent natriuretic and volume diuretic effect with little augmentation of potassium excretion. Enprofylline up to 10 mg/kg was without diuretic effects. At the large dose of 20 mg/kg enprofylline decreased sodium excretion and produced some volume diuresis. It is suggested that lack of diuretic and CNS-stimulant behavioural effects by enprofylline is due to its low ability to antagonise adenosine receptor stimulation. Pharmacodynamic differences between enprofylline and the potent adenosine antagonist theophylline may indicate a functional importance of endogenous adenosine.

Adenosine↗
PubMed1983

Reversal of diuretic-induced secondary hyperaldosteronism and hypokalemia by enalapril (MK-421): a new angiotensin-converting enzyme inhibitor.

The study reported here prospectively evaluated the prevention of diuretic-induced secondary hyperaldosteronism and hypokalemia by a converting enzyme inhibitor, enalapril (MK 421). Eighteen normal subjects were randomized into three groups: (1) a HCTZ group (hydrochlorothiazide (HCTZ) 50 mg/day); (2) a MK-421 group (MK-421 10 mg/day); and (3) a HCTZ + MK-421 group [HCTZ 50 mg/day plus MK-421 10 mg/day]. Following a five-day control and a 28-day treatment period, the HCTZ group demonstrated an attenuated but persistent secondary hyperaldosteronism and hypokalemia, the MK-421 group manifested a gradual decline in aldosterone secretion, and the HCTZ + MK-421 group had a delayed but effective correction of secondary hyperaldosteronism and hypokalemia at 28 days but not before. In conclusion, MK-421 reversed diuretic-induced secondary hyperaldosteronism and hypokalemia after 28 days of hydrochlorothiazide therapy. Therefore, converting enzyme inhibitors, such as enalapril, provide useful adjunctive therapy in diuretic-treated patients, but potassium supplementation may be required before the start of four weeks of combined therapy.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1976

Inhibition of renal PGE2-9-ketoreductase by diuretics.

The metabolism of PGE2 by extracts of renal cortex is species dependent. In the rat PGE2-15-hydroxydehydrogenase initiates metabolism whereas in the rabbit PGE2-9-ketoreductase predominates. In man both mechanisms may operate. Each of the metabolic enzymes, which limits the vasodilator-diuretic actions of PGE2, was inhibited by ethacrynic acid, furosemide and indomethacin. Some inhibition of PGE2-9-ketoreductase was also observed with chlorthalidone, hydralazine and phentolamine but the thiazide diuretics and a number of other cardiovascular-active agents were without significant effect. We conclude that the inhibition of PGE2-9-ketoreductase and PGE2-15-hydroxydehydrogeanse could contribute to the mechanism of action of the non-thiaxide diuretics in man.

Alcohol Oxidoreductases↗
PubMed1991

Behavioral effects of chronic, orally administered diuretic and verapamil in baboons.

Behavioral performances of six baboons were tested during chronic oral dosing with diuretic (hydrochlorothiazide/triamterene), a calcium channel blocker (verapamil), and a combination of the two drugs. Reaction times and color matching-to-sample performances as well as physiological measures were obtained in deoxycorticosterone acetate (DOCA)-salt baboons and in renovascular hypertensive baboons. Combined diuretic and verapamil impaired color matching to a small degree in comparison to baseline performance, while drug administered alone had no effect. Weekly systolic and diastolic blood pressures decreased maximally from baseline during the drug combination period, and were accompanied by maximal increases in serum sodium. The largest behavioral impairments during combination dosing were observed for colors that were most difficult to discriminate during baseline. Significant positive correlations were found between systolic blood pressure and color matching accuracy. No differences between the animal hypertension groups were found as a function of drug condition either in physiological or behavioral responses. Only the combination of diuretic and verapamil produced a deleterious effect on color discrimination, which suggests further study of commonly administered drug combination therapies in hypertension.

Animals↗
PubMed1984

A method for screening diuretic agents in the rat.

A reproducible screening method for diuretic agents has been developed based upon the selection of a group of homogenous rats with a similar excretory pattern of water and electrolytes. Normal saline (4% body weight) was used as a hydrating fluid to select appropriate rats and to validate the diuretic activity of standard diuretics. The method required only a small number of rats for screening compounds and produced consistent responses in increasing water and electrolyte excretion.

Animals↗
PubMedDate not supplied

Pharmacokinetics of diuretics in geriatric patients.

Pharmacokinetics of three diuretics (furosemide, spironolactone, and triamterene) were investigated in 70 geriatric patients. Comparing the data with the corresponding values of young healthy volunteers, mean plasma concentrations of furosemide and spironolactone (and peak concentrations of triamterene) were markedly higher in the geriatric patients. Different concomitant diuretic therapy (hydrochlorothiazide vs. piretanide) seems to influence the kinetic parameters of triamterene and its active metabolite in the geriatric patients. In elderly patients reduction or correction of the dosage seems to be necessary for all three diuretics investigated in our studies.

Aged↗
PubMed1995

Diuretic activity of C-terminal group analogues of the insect kinins in Acheta domesticus.

A series of insect kinin analogues, AFFPWG-X, modified at the C-terminal group, were evaluated in a cricket Malpighian tubule secretion bioassay. The results were compared with activity profiles observed in a cockroach hindgut myotropic bioassay for these analogues. Although the replacement of the C-terminal amide group with a negatively charged acid leads to a precipitious drop in diuretic activity, it can be partially restored with the introduction of ester groups such as methyl or benzyl. The presence of branched chain character in the C-terminal group or a C-terminal alpha-carbon-amide distance spanning five methylene group spacers is incompatible with the receptor interaction required for biological activity. Significant diuretic activity is retained with four or fewer methylene groups in this region. C-terminal group analogues containing -SCH3, -NHCH2CH2OCH3, or -OCH2(C6H5) offered the greatest retention of diuretic activity while providing increased hydrophobicity and/or steric bulk. The data are of potential value in the development of mimetic analogues of this insect neuropeptide family. Mimetic analogues are potentially valuable tools to insect neuroendocrinologists studying diuresis and/or engaged in the development of future pest management strategies.

Amino Acid Sequence↗
PubMed1988

Acute diuretic effects in conscious rats produced by some medicinal plants used in the state of São Paulo, Brasil.

Extracts of 32 medicinal plants used popularly for their presumed diuretic and/or antihypertensive properties were tested for diuretic effects in conscious unrestrained rats. Extracts were made using aqueous ethanol (50:50, v/v) at 4-10 degrees C. When given orally at a dose of 40 ml/kg, a majority of the ethanol-free extracts produced a more pronounced diuresis than would be expected from the potassium concentration of the extracts. The most significant diuretic effect was observed with Hedychium coronarium sheath and leaf-blade extracts.

Animals↗
PubMed1991

The influence of diuretics on the excretion and metabolism of doping agents--V. Dimefline.

A sensitive method for the quantitative determination of the respiratory stimulant dimefline in 5 ml urine using capillary gas chromatography with nitrogen specific detection is presented. After the oral administration of a therapeutical amount of 16 mg dimefline to five subjects only 0.26 +/- 0.16% of the dose is excreted as the conjugated drug in 24 h. The maximum excretion rate occurred 3 h after dosing, the peak concentration being 154 +/- 60 ng ml-1. The influence of diuretics taken 2 h after the administration of dimefline was studied in three subjects. From these results it appeared that the use of acetazolamide and hydrochlorthiazide in order to circumvent a positive dimefline doping case is questionable. Due to the potent diuretic effect of furosemide, the intake of this diuretic could result in a suppression of the dimefline concentration below the detection limit of 10 ng ml-1.

Acetazolamide↗
PubMed1993

Clinical trials of diuretic therapy in heart failure: research directions and clinical considerations.

Diuretic drugs have historically been developed for the treatment of sodium and water retention in edematous disorders. The latter have traditionally been an amalgam of congestive heart failure, nephrotic syndrome, cirrhosis and chronic renal failure. With a > 50-year tradition of this approach to development, diuretic drugs have not been evaluated specifically for their safety and efficacy profile in patients with congestive heart failure. Yet, they are the most frequently prescribed drug class for this disorder. Furthermore, they remain the only drug class in congestive heart failure not subjected to large scale clinical trials. Sodium and water retention within this group of patients is related primarily to functional rather than to structural renal abnormalities. The reduction of glomerular filtration rate, increase in aldosterone secretion and abnormal profile of atrial natriuretic factor, all produce sodium retention and can be related to the severity of heart failure. Diuretic drugs have not been scrutinized in a manner similar to that of other drugs for the management of heart failure. Controversy persists regarding direct vascular effects, objective end points of assessment and the magnitude of adverse effects such as activation of neurohormonal pathways. These issues may be addressed by the establishment of reasonable objective end points, better stratification of patients in clinical trials and prospective trials in large clinical series. Even mortality studies should be considered.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2005

Long-term effect of diuretic-based therapy on fatal outcomes in subjects with isolated systolic hypertension with and without diabetes.

Diuretic-based antihypertensive therapy is associated with the development of diabetes but with improved clinical outcomes. It has been proposed that the duration of clinical trials has been too short to detect the adverse effects of diabetes. We assessed the long-term mortality rate of subjects in the Systolic Hypertension in the Elderly Program (n = 4,732) who were randomized to stepped-care therapy with 12.5 to 25.0 mg/day of chlorthalidone or matching placebo. If blood pressure remained above the goal, atenolol or matching placebo was added. At a mean follow-up of 14.3 years, cardiovascular (CV) mortality rate was significantly lower in the chlorthalidone group (19%) than in the placebo group (22%; adjusted hazard ratio [HR] 0.854, 95% confidence interval [CI] 0.751 to 0.972). Diabetes at baseline (n = 799) was associated with increased CV mortality rate (adjusted HR 1.659, 95% CI 1.413 to 1.949) and total mortality rate (adjusted HR 1.510, 95% CI 1.347 to 1.693). Diabetes that developed during the trial among subjects on placebo (n = 169) was also associated with increased CV adverse outcome (adjusted HR 1.562, 95% CI 1.117 to 2.184) and total mortality rate (adjusted HR 1.348, 95% CI 1.051 to 1.727). However, diabetes that developed among subjects during diuretic therapy (n = 258) did not have significant associations with CV mortality rate (adjusted HR 1.043, 95% CI 0.745 to 1.459) or total mortality rate (adjusted HR 1.151, 95% CI 0.925 to 1.433). Diuretic treatment in subjects who had diabetes was strongly associated with lower long-term CV mortality rate (adjusted HR 0.688, 95% CI 0.526 to 0.848) and total mortality rate (adjusted HR 0.805, 95% CI 0.680 to 0.952). Thus, chlorthalidone-based treatment improved long-term outcomes, especially among subjects who had diabetes. Subjects who had diabetes associated with chlorthalidone had no significant increase in CV events and had a better prognosis than did those who had preexisting diabetes.

Aged↗
PubMed2004

Effects of pH and the presence of micelles on the resolution of diuretics by reversed-phase liquid chromatography.

A comparative study on the performance of two RPLC modes on the separation of 18 diuretics with diverse acid-base behaviour (acetazolamide, althiazide, amiloride, bendroflumethiazide, benzthiazide, bumetanide, canrenoic acid, chlorothiazide, chlorthalidone, ethacrynic acid, furosemide, hydrochlorothiazide, piretanide, probenecid, spironolactone, triamterene, trichloromethiazide and xipamide) was carried out. A conventional octadecylsilane column and acidic acetonitrile-water mobile phases, in the absence and presence of micelles of the anionic surfactant sodium dodecyl sulphate (SDS), were used. The effects of pH and the modifiers acetonitrile and SDS on peak asymmetry, efficiency, selectivity, resolution and analysis time, were examined. The comparison of both RPLC modes (aqueous- and micellar-organics) was done using the same processing tools, applying several polynomial and mechanistic equations to describe the retention. The best separations were obtained by maximising the product of peak purities, considering a wide range of experimental conditions. The study illustrates that, despite the theoretical and practical complexity of the problem, the predicted optimal chromatograms can be reproduced experimentally with great accuracy. None of the examined RPLC modes was able to yield baseline separation of the 18 diuretics. However, their selectivity was complementary, being appropriate for different combinations of a smaller number of the assayed diuretics.

Chromatography, Liquid↗
PubMed2005

Hypotension is associated with diuretic resistance in severe chronic heart failure, independent of renal function.

BACKGROUND: Diuretic resistance and systemic hypotension are common in chronic heart failure (CHF), however, the two have not been associated. AIMS: Since blood pressure (BP) might be an important determinant of sodium excretion, we searched for an association between BP and diuretic dosage in severe CHF. METHODS: Our heart failure database was retrospectively reviewed for patients with severe left ventricular systolic dysfunction. The 54-patient cohort was divided on the basis of frusemide dosage (high-dose > or = 250 mg daily, n=26). RESULTS: Patients taking high-dose frusemide had higher serum creatinine, and lower systolic and diastolic BP. On logistic regression analysis, increased serum creatinine and reduced diastolic BP were independent predictors of the use of high-dose frusemide. Grouping these variables into tertiles, the odds ratio for the use of high-dose frusemide was 4.0 as diastolic BP decreased (p<0.01), and 6.8 as serum creatinine increased (p<0.001). CONCLUSIONS: We have found an association between hypotension and the use of high-dose frusemide in severe CHF, which is independent of renal function, and which may be an important physiologic mechanism of diuretic resistance in severe CHF.

Aged↗
PubMed2005

Physicochemical evaluation of PVP-thiazide diuretic interactions in co-spray-dried composites--analysis of glass transition composition relationships.

The aim of this study was to evaluate the possible interactions in the solid state between the thiazide diuretics: bendroflumethiazide (BFMT), hydroflumethiazide (HFMT) and hydrochlorothiazide (HCT) and polyvinylpyrrolidone (PVP) following processing. The glass transition temperatures (T(g)s) of a range of binary co-spray-dried PVP-thiazide composites were determined and compared to the predictions of the Gordon-Taylor, Fox, Couchman-Karasz, Kwei and Schneider equations. The solid composites of the thiazide diuretics and PVP were prepared by a spray drying technique. Properties of composites were determined with the use of helium pycnometry and FTIR spectroscopy. For many systems studied the experimentally detected T(g)s exhibited large positive deviations when compared with the values predicted by the Gordon-Taylor, Fox and Couchman-Karasz equations. The data was better fitted by the Schneider equation consistent with a drug-polymer interaction. FTIR analysis revealed that strong hydrogen bonding between the sulphonamide groups of the thiazide diuretics and the PVP molecule was responsible for the increase in the T(g)s. Additionally, in the case of BFMT-PVP composites, an interaction between the phenyl group and polymer ring was apparent. Glass transition-composition behaviour for amorphous drug-PVP composites deviated from the predictions of the commonly used Gordon-Taylor equation. Deviations were consistent with interactions between the components in the amorphous mixtures. The Schneider equation may be successfully applied to fit the Tg-composition profiles obtained, where other models fail to give good predictions.

Benzothiadiazines↗