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PubMed1990

Diuretics and transmembrane ionic exchanges: structure-activity relations and clinical applications.

The study of membrane ion transport has facilitated the discovery of potent and quite specific inhibitory drugs. Some of these compounds are therapeutic agents acting on basic transport mechanisms as in the case of the cardiac glycosides on the myocardial sodium ion (Na+), potassium ion (K+) pump, and the loop diuretics on the renal Na+, K+, chloride (Cl-) co-transport system. The development of inhibitors for other transport systems such as Na+/hydrogen ion (H+), Na+/calcium ion (Ca2+) and bicarbonate (HCO3-)/Cl- exchangers requires the screening of a large number of molecules. For several reasons, the human red blood cell is one of the best models for screening the effect of drugs on ion transport mechanisms. The use of human red cells for pharmacologic studies of ion transport has increased the understanding of the structure-activity relations of diuretics. For instance, loop diuretics that are chemically neutral were considered for many years as drugs that act similarly to classic acid loop diuretics. They are now considered as potent inhibitors of HCO3-/Cl- anion exchange. A brief summary of the more recent results is given together with the perspectives of new fundamental and therapeutic applications of these compounds.

Diuretics↗

PubMed1976

Elevation of serum lipid levels during diuretic therapy of hypertension.

In a study attempting to improve coronary risk status, serum cholesterol and triglyceride levels were measured before and during treatment of 74 patients with mild primary hypertension. In 35 patients there was a satisfactory reduction in elevated blood pressure levels with diet therapy alone. In the remaining 39 patients a diuretic drug was required in addition to the diet. Diet therapy alone was followed by a decrease of 11 mg/100 ml in mean serum cholesterol (p less than 0.01 versus pretreatment value) and no change in serum triglyceride. The sue of diuretics was accompanied by an average increase of 11 mg/100 ml in serum cholesterol and of 34 mg/100 ml in serum triglyceride (p less than 0.01 versus pretreatment level for both). In a subgroup of 21 patients with greatest elevations in lipid levels during the administration of diuretics, little improvement in coronary risk status occurred because the increase in serum cholesterol balanced the decrease in systolic blood pressure, according to Framingham risk tables. If the level of serum lipids is a factor in the pathogenesis of coronary atherosclerosis then the observed effect of diuretic drugs to elevate serum cholesterol and triglyceride levels may explain, in part, the continuing high rate of occurrence of myocardial infarction during the treatment of hypertension.

Adult↗

PubMed1986

Cumulative experience with terazosin administered in combination with diuretics.

The short-term antihypertensive efficacy and safety of terazosin when administered with a diuretic were assessed in three randomized, double-blind, placebo-controlled studies. In all studies, adding terazosin to an established diuretic regimen resulted in significant incremental decreases in blood pressure from baseline to the final visit, with an overall satisfactory response rate of 56 percent versus 29 percent for control subjects. Mean decreases in supine diastolic blood pressure in the terazosin-treated groups ranged from 4.5 to 8.9 mm Hg, compared with mean decreases of 0.4 to 5.8 mm Hg in the placebo-treated groups; these differences generally achieved statistical significance. There were no clinically or statistically significant changes in pulse rates, physical examinations, or electrocardiographic tracings. Results of clinical laboratory tests revealed no evidence of drug-induced toxicity. Patients receiving the terazosin plus diuretic combination had a slight tendency to gain weight. The most common adverse effects reported by this group were dizziness, headache, and asthenia. The results of these studies indicate that combination therapy with terazosin plus a diuretic is both safe and effective for the treatment of hypertension.

Adrenergic alpha-Antagonists↗

PubMed1987

Diuretics and potassium/magnesium depletion. Directions for treatment.

The effects of diuretics on renal handling of potassium and magnesium can result in depletion of these electrolytes. Associations between these deficits and the occurrence of increased ventricular ectopy raise the issue of potential relationships to increased risk of sudden unexpected death in hypertensive patients taking diuretics, especially patients with electrocardiographic and electrolyte abnormalities. Review of diuretic effects on the kidneys provides evidence that diuretic regimens that conserve potassium also conserve magnesium, and suggests the important role of these agents in protecting against potassium and magnesium abnormalities.

Amiloride↗

PubMed1984

Stimulation of K+ fluxes by diuretic drugs in human red cells.

Two different families of diuretic drugs--(i) (aryloxy)acetic acid diuretics (ethacrynic acid, tienilic acid and (--)-indacrinone) and (ii) furopyridines [(+/-)-BN 50157 and (+/-)-cycletanide]--stimulate K+ movements across human red cell membranes. The kinetic properties of this effect (K+-specificity, saturability, optical isomerism, antagonism by structural analogues, etc.) strongly suggest that it is mediated by a K+-transport system with a specific binding site for some diuretic drugs. The stimulated K+ fluxes are resistant to ouabain, bumetanide and quinine, thus suggesting that they are not mediated by the Na+,K+-pump, Na+,K+-cotransport or by the Ca2+-dependent K+-permeability ('Gardos effect'). The replacement of Cl- by NO3- ions can either decrease, increase or have no effect on the stimulated K+ fluxes, depending on the diuretic drug. Although not conclusive, these observations suggest that the K+ fluxes are not mediated by stimulation of a chloride-dependent K+ carrier. The study of structural analogues showed that the intensity of the stimulation of K+ fluxes is strongly correlated with the magnitude of the natriuretic effect. Curiously, some antiallergic furopyridines are able to inhibit K+ fluxes.

Bumetanide↗

PubMed1986

Liver carbonic anhydrase and urea synthesis. The effect of diuretics.

In isolated perfused rat liver, urea synthesis is rapid and reversibly inhibited not only by the well-known carbonic anhydrase inhibitors acetazolamide, methazolamide and ethoxzolamide, but also by diuretics, like xipamide, mefruside, chlortalidone, and chlorothiazide. Furosemide was without effect. Similar to findings with isolated perfused rat liver, acetazolamide inhibits urea synthesis from ammonium ions in normal and cirrhotic human liver slices. Inhibition of urea synthesis by xipamide and acetazolamide is accompanied by a 70% decrease of the cellular citrulline content and the tissue levels of 2-oxoglutarate and citrate, suggesting a block of urea synthesis at a step prior to citrulline formation. At a constant extracellular pH (7.4), inhibition of urea synthesis by xipamide, mefruside and acetazolamide was overcome by increasing the extracellular concentrations of HCO3- and CO2 to above twice the normal values. This shows that inhibition of urea synthesis by these diuretics is not due to an unspecific inhibition of one of the urea cycle enzymes but is due to an inhibition of mitochondrial carbonic anhydrase and therefore due to an impaired HCO3- provision for mitochondrial carbamoylphosphate synthesis. It is concluded that the activity of mitochondrial carbonic anhydrase is required for urea synthesis also in human liver and that several diuretics impair urea synthesis by inhibition of mitochondrial carbonic anhydrase. The pathophysiological significance of these data is discussed with respect to the development of diuretics-induced hyperammonemia and alkalosis in liver disease.

Acetazolamide↗

PubMed1989

Mechanism of diuretic action of U-62,066E, a kappa opioid receptor agonist.

The mechanism of the diuretic action of U-62,066E, a highly selective kappa opioid agonist, was examined in unanesthetized rats and in isolated perfused inner medullary collecting ducts (IMCD). In Long-Evans rats, U-62,066E caused a dose-dependent increase in urine flow and a decrease in urine osmolality without affecting urinary excretion of Na+. The diuretic effect of U-62,066E was blocked by MR-2266, a kappa opioid receptor antagonist. U-62,066E showed no diuretic effect in homozygous hereditary diabetes insipidus rats (Brattleboro strain). In water-deprived rats, U-62,066E markedly inhibited plasma arginine vasopressin (AVP) levels through a kappa receptor-mediated mechanism. In rat IMCD perfused in vitro, 10(-5) M U-62,066E did not inhibit either the baseline or the AVP-stimulated osmotic water permeability. We conclude that the inhibition of the release of AVP is the major if not the entire mechanism of the diuretic action of U-62,066E in rats. Although we ruled out the effect of this drug on the water permeability of IMCD, possible direct effects on other nephron structures remain to be established.

Animals↗

PubMed1987

Comparison of paracentesis and diuretics in the treatment of cirrhotics with tense ascites. Results of a randomized study.

To investigate whether paracentesis could be an alternative therapy for ascites, 117 cirrhotics with tense ascites were randomly allocated into two groups. Fifty-eight patients (group 1) were treated with paracentesis (4-6 L/day until disappearance of ascites) and intravenous albumin infusion (40 g after each tap). Fifty-nine patients (group 2) were treated with spironolactone (200-400 mg/day) plus furosemide (40-240 mg/day). Patients from group 2 not responding to diuretics were treated with a LeVeen shunt. After disappearance of ascites, patients from both groups were discharged from hospital and were instructed to take diuretics. Patients developing tense ascites during follow-up were readmitted to hospital and treated according to their initial schedule. Paracentesis was effective in eliminating the ascites in 56 patients from group 1 (96.5%) and did not induce significant changes in renal and hepatic function, plasma volume, cardiac index, peripheral resistance, plasma renin activity, plasma norepinephrine and antidiuretic hormone concentration, and urinary excretion of prostaglandin E2 and 6-keto-prostaglandin F1 alpha. Diuretics were effective in eliminating the ascites in 43 patients from group 2 (72.8%) (p less than 0.05). Ten patients in group 1 and 36 in group 2 developed complications during their first hospital stay (p less than 0.001). This difference was due to the significantly higher incidence of hepatic encephalopathy, renal impairment, and electrolyte disturbances occurring in patients treated with diuretics. The duration of hospital stay was 11.7 +/- 1.5 days for patients from group 1 and 31 +/- 2.8 days for patients from group 2 (p less than 0.001). The two groups did not differ significantly with respect to the probability of requiring readmission to hospital during follow-up, reasons for readmission, survival probability after entry into the study, and causes of death. These results indicate that paracentesis associated with intravenous albumin infusion is a fast, effective, and safe therapy for ascites in patients with cirrhosis.

Albumins↗

PubMed1993

Screening for diuretics in urine and blood serum by capillary zone electrophoresis.

Diuretics are therapeutic agents used to promote the excretion of bodily fluids and salts. They are also misused by some athletes to decrease body mass or to mask the use of anabolic steroids and other drugs. We have developed a method that screens for diuretics in urine and blood serum. Two successive runs were required because of the heterogeneity of this group of compounds. Screening for diuretics that contained sulphonamide and/or carboxylic groups was done at pH 10.6 with 3-(cyclohexylamino)-1-propane-sulphonic acid (0.06 M) as buffer. Diuretics that contained primary, secondary or tertiary amine groups were investigated at pH 4.5 with an acetate (0.07 M)-betaine (0.5 M) buffer system. Hydrostatic injection mode for 5 s gave the best efficiency. Longer injection times were acceptable but efficiency was then somewhat reduced. Detection limits at the low femtomole level are achievable for most compounds with a UV-Vis detector operating at 220 and 215 nm. Temperature affected the separation, and 20 degrees C proved best. All compounds were separated in less than 30 mins. A confirmation analysis of all compounds was done by GC-MS.

Chromatography, Liquid↗

PubMed1996

Capillary electrophoresis of diuretics.

The review surveys the application of capillary electrophoresis to the screening, identification and determination of diuretics and probenecid. The number of publications is still limited, but the studies already published clearly show that capillary zone electrophoresis (CZE) and micellar electrokinetic chromatography are excellent alternatives for the investigation of diuretics. High accuracy identifications of diuretics and probenecid, even in urine samples, can be obtained when CZE is used with the marker techniques. This review paper has been written from the viewpoint of practical use and some hints are given for future CE studies on diuretics.

Diuretics↗

PubMed1989

Reversal of diuretic-induced secondary hyperaldosteronism and hypokalemia by trilostane, an inhibitor of adrenal steroidogenesis.

Correction of diuretic-induced hypokalemia is usually accomplished by potassium supplementation or antagonism of aldosterone's renal action. This study sought to determine if inhibition of aldosterone biosynthesis could reverse diuretic-induced hypokalemia and whether trilostane would be clinically useful in this regard. Essential hypertensives (n = 22) were treated with hydrochlorothiazide (HCTZ) 50 mg/d, and patients who became hypokalemic were randomly assigned to receive in addition to HCTZ either a placebo (n = 7), trilostane 240 mg/d (Trilo 240) (n = 7), or trilostane 60 mg/d (Trilo 60) (n = 3). Following 12 weeks of therapy the placebo patients remained hypokalemic with hyperaldosteronism, while the patients who received Trilo 240 had a correction of hypokalemia and hyperaldosteronism (P less than .05) along with a reduction in diastolic blood pressure (P less than .05). The Trilo 60 patients, however, remained hypokalemic with no significant reduction in aldosterone excretion or blood pressure compared with HCTZ. Body weight and urinary free cortisol levels along with routine biochemical tests were unchanged during this study. Three Trilo 240 patients developed diarrhea but did not discontinue the study. These results demonstrate that trilostane can correct diuretic-induced hypokalemia by lowering aldosterone secretion. Furthermore, this reduction in aldosterone may enhance the antihypertensive effects of diuretic therapy.

Aldosterone↗

PubMed1992

Preventable sudden death in patients receiving angiotensin converting enzyme inhibitors and loop/potassium sparing diuretic combinations.

Angiotensin-converting-enzyme inhibitors are frequently used in conjunction with diuretics in the treatment of congestive cardiac failure. We report two cases in which use of a proprietary combination diuretic containing a loop diuretic and potassium sparing agent with an angiotensin converting enzyme inhibitor was associated with hyperkalaemic cardiac arrest. Successful resuscitation from the arrest permitted elucidation of its mechanism. We believe that this outcome has not previously been reported, and emphasise the importance of electrolyte monitoring in patients receiving angiotensin converting enzyme inhibitors particularly if prescribed in addition to fixed combination proprietary diuretics.

Aged↗

PubMed1984

Diuretics in pregnancy: a case study of a worthless therapy.

In the 1960s and 1970s diuretics were used during pregnancy to prevent and treat toxemia, but this therapy is now widely condemned as ineffective and harmful. The purpose of this paper was to study this example, to learn from it and to help to prevent further such examples. Data sources included selected articles in medical journals and text-books; in Finland drug catalogues, handbooks, unpublished sales data and interviews and questionnaires to physicians; in Sweden drug catalogues and sales data; controlled clinical trials were also analyzed. Analysis of the controlled clinical trials suggested that the whole episode of wide-spread diuretic use in pregnancy could have been avoided, if the available information had been used. A reason for the neglect of the critical information was apparently that the use of diuretics was in accordance with the common medical reasoning which values changes in clinical signs rather than looking for better health indicators. Use of diuretics was condemned in Finland later than, for example, in the United States, and decline in use occurred prior to the warnings in the local literature. Changes in practice seem to have occurred hierarchially and locally: opinions of a few leading obstetricians were crucial and they were rapidly and effectively disseminated to the providers of antenatal care in the domain of each obstetrician. This hierarchial dissemination of information has profound consequences for the attempts of understanding and influencing the prescribing habits of physicians.

Adolescent↗

PubMed1991

Analysis of diuretic doping agents by HPLC screening and GC-MSD confirmation.

The simultaneous analysis of 14 diuretics in human urine (belonging to five different pharmacological groups) by reversed-phase high-performance liquid chromatography (HPLC) with a diode-array detector was developed by using a gradient elution with acetonitrile and phosphate buffer containing propylamine hydrochloride on a Bondclone-ODS (10 microns) column. The method was applied to the screening test of several diuretics abused by athletes. The confirmation analysis was performed by gas chromatography-mass spectrometry with ion-selective detection (GC-MSD). The characteristic mass fragment ions obtained by electron-impact (EI) ionization (70 eV) provided sufficient identification of these diuretic agents. During the 1990 weight-lifting contest of Asia in Kao-Hsiung, Republic of China, one urine sample was found positive for the diuretic hydrochlorothiazide.

Chromatography, High Pressure Liquid↗

PubMed1996

Current use of thiazide diuretics and prevention of femur fractures.

A case control study of a defined population from The Netherlands was performed to evaluate the risk of femur fractures associated with the use of thiazide diuretics. Included were 386 patients hospitalized for femur fractures between 1986 and 1990 who were residents and 45 years of age and older. Per case, one age-, sex-, pharmacy-, and general practitioner-matched control was chosen from the general population. Drug use was ascertained from computerized pharmacy records. The adjusted odds ratio of current use of thiazide diuretics was 0.5 (95% confidence interval, 0.3-0.9). The protective effect of thiazide diuretics was greatest for use of 1 year or longer at relatively high doses of thiazides (odds ratio, 0.3; 95% confidence interval, 0.1-0.9). We also found that patients who discontinued thiazide use longer than 2 months were not protected against femur fractures. These results support the hypothesis that use of thiazide diuretics protects against femur fractures.

Aged↗

PubMed2005

Antioxidative protection in hypertensive patients treated with diuretics.

BACKGROUND: Recently results of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) showed that a thiazide diuretic was unsurpassed by any other drug class studied in achieving the level of cardiovascular protection, a finding reflected in the recent Seventh Report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure (JNC7) recommendations. Oxidative stress has been found to be one of the key players in the pathophysiology of cardiovascular disease at large. The objective of this study was to check the hypothesis that diuretics may favorably affect the oxidative status of plasma, which could account in part for the results of recent trials. METHODS: In addition to the routine workup in a series of 39 medically treated hypertensive patients, we analyzed the level of antioxidative protection afforded by the ferric-reducing ability of plasma (FRAP), according to class of drug used. RESULTS: We found that patients taking diuretics had significantly better antioxidative protection expressed by the higher levels of FRAP. Although the limited number of patients did not allow us to exclude the influence of other variables in the multiple regression analysis, we did not observe any differences in the level of FRAP when the group was divided according to the other drug classes, gender (men versus women), smoking, diabetes mellitus, duration of treatment, concomitant therapy, or level of uric acid. CONCLUSIONS: The use of thiazide diuretics seems to be associated with better antioxidative protection. This observation may add to the explanation of the results of recent trials in hypertension.

Adrenergic beta-Antagonists↗

PubMed2006

Diuretic use, progressive heart failure, and death in patients in the DIG study.

BACKGROUND: Nonpotassium-sparing diuretics (NPSDs), have been associated with increased sudden cardiac death (SCD) and progressive heart failure (HF) death in HF patients. METHODS AND RESULTS: In 6797 Digitalis Investigation Group study patients, risk ratios were calculated for death, cardiovascular death (CVD), death from worsening HF, SCD, and HF hospitalization among those taking a potassium-sparing (PSD), NPSD, or no diuretic. Compared with not taking diuretic, risk of death (relative risk [RR] 1.36, 95% confidence interval [CI] 1.17-1.59, P < .0001), CVD (RR = 1.38, 95% CI 1.17-1.63, P = .0001), progressive HF death (RR = 1.41, 95% CI 1.06-1.89, P = .02), SCD (RR = 1.67, 95% CI 1.23-2.27, P = .001), and HF hospitalization (RR = 1.68, 95% CI 1.41-1.99, P < .0001) were increased with NPSD. There was no significant difference in any end point for patients taking only PSD compared to no diuretic. PSD only subjects were less likely than NPSD subjects to be hospitalized for HF (RR = 0.71, 95% CI 0.52-0.96, P = .02). CONCLUSION: NPSDs are associated with increased risk of death, CVD, progressive HF death, SCD, and HF hospitalization. A randomized trial is needed to assess the role of NPSDs versus PSDs in HF patients.

Aged↗

PubMed2007

Use of diuretics in the treatment of heart failure in the elderly.

Diuretics are tools of considerable therapeutic importance. First, they effectively reduce blood pressure, while at the same time decreasing the morbidity and mortality associated with hypertension. Diuretics are currently recommended as first-line therapy for the treatment of hypertension. In addition, they remain an important component of heart failure therapy, in that they improve the symptoms of congestion, which typify the more advanced stages of heart failure. This article reviews the mode of action of the various diuretic classes and the physiologic adaptations that follow; sets up the basis for their use in the treatment of volume-retaining states, particularly as applies to the elderly; and reviews diuretic-related side effects that are normally encountered.

Aged↗