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PubMed2003

Application of high-performance liquid chromatography-mass spectrometry to detection of diuretics in human urine.

A rapid, sensitive and reliable high-performance liquid chromatographic-mass spectrometric method for the detection of 25 diuretics in human urine has been developed. Atmosphere pressure chemical ionization (APCI) and electrospray ionization (ESI) modes were evaluated. A 2-ml volume of urine was extracted under basic conditions and separated on an Agilent Zorbax SB-C(18) column (150 x 2.1 mm, 5 microm). The mobile phase consisted of formic ammonium-formic acid buffer (pH 3.5) and acetonitrile. The effects of capillary temperature, sheath gas pressure and compositions of mobile phase on the sensitivity were studied. The recoveries of most of the diuretics were 75-95%. In the full scan mode, the limits of detection of the 25 diuretics were 0.25-25 ng/ml for APCI and 0.6-250 ng/ml for ESI. Under the optimal conditions, 14 diuretics from authentic urine samples were detected successfully by LC-APCI-MS. To obtain more fragmentation information on the chemical structure for positive confirmation, tandem mass analysis was also investigated.

Chromatography, High Pressure Liquid↗
PubMed1978

Diuretic activity of Mannich base derivatives of ethacrynic acid and certain ethacrynic acid analogues.

Various Mannich base derivatives of selected phenoxyacetic acid type diuretics were synthesized and their diuretic potency was evaluated in dogs. It is concluded that the Mannich bases possess little, if any, diuretic activity of their own. Those Mannich bases that do possess diuretic activity undoubtedly do so as a consequence of an elimination reaction (a retro-Michael type reaction) which yields the corresponding pharmacologically active alpha,beta-unsaturated ketone.

Animals↗
PubMed1985

[(Aminomethyl)arloxy]acetic acid esters. A new class of high-ceiling diuretics. 3. Variation in the bridge between the aromatic rings to complete mapping of the receptor.

Continued structural evaluation of the [(aminomethyl)aryloxy]acetic ester diuretics has produced a series of compounds in which the functional group that bridges the two aromatic rings has been varied. Diuretic screening of these analogues in rats indicates that the keto group can be effectively replaced with an ether or thio ether function with a slight increase in potency, whereas the methylene and sulfoxide linking groups lead to diminished saluretic potency. Replacement with either -SO2-, -COCO-, -CH2O-, -CONH- or direct bond results in a loss of activity. Although the series was designed according to QSAR criteria, the traditional linear free-energy properties of these compounds do not correlate with diuretic potency. However, conformational analysis of the series by potential energy calculations indicates that all active compounds have an accessible conformation that matches the bridge atom-carboxylate distance of the very potent dihydrobenzofuran analogue 56. Conformational calculations of several compounds in which the aminomethyl group was varied suggests that the active conformation is probably a low-energy conformation. Consideration of rotation about the bridge could not distinguish between two possible orientations of the aminomethyl ring in the active conformation. However, there is a quantitative negative linear correlation between diuretic potency and the protrusion into space of the group that bridges the two aromatic rings.

Animals↗
PubMed1988

A quantitative method of evaluating the diuretic response to furosemide in rats.

Furosemide effects are usually evaluated by measuring the urinary excretion rate of Na+ (UVNa) in humans. In the present study, however, UVNa showed a nonlinear relationship with urine flow rate after intravenous injection of furosemide in rats. In contrast, when the urinary excretion rate of (Na+ + K+) (UVNa + K) was plotted against the urine flow rate, a linear regression line was observed, with small interindividual variations in normal rats and in rats with uranyl nitrate-induced acute renal failure (ARF). Piretanide, a loop diuretic, also showed a similar relationship, while other types of diuretics revealed different slope values for the relationship. Although the urinary excretion rate of Cl- (UVCl) vs UVNa + K is expected to show a linear relationship in normal rats, the correlation coefficient of the linear regression line was smaller than that of the urine flow rate vs UVNa + K. Further, the slope of UVCl vs UVNa + K was slightly different in ARF rats. Therefore, UVNa + K provides a better quantitative measure of diuretic response to loop diuretics than UVNa or UVCl.

Acute Kidney Injury↗
PubMed1996

Mode of interaction of loop diuretics with human serum albumin and characterization of binding site.

PURPOSE: The purpose of this study was to investigate the binding mechanism of loop diuretics with HSA and to characterize the binding site on HSA. METHODS: Quantitative analysis of potential interaction between ligands bound to HSA was performed by equilibrium dialysis and data for binding of the two ligands to HSA were analyzed on the basis of a theoretical model of simultaneous binding of two ligands. RESULTS: The binding of loop diuretics is dependent upon the N-B transition, conformational change of albumin. Furthermore, from the results of binding of the drugs to modified HSA, the lysine residue seems to be involved in the binding of loop diuretics to HSA. CONCLUSIONS: Analysis using models describing independent, competitive, cooperative and anti-cooperative binding led to the conclusion that loop diuretics bind to site I, particularly to the warfarin region on HSA.

Binding Sites↗
PubMed1982

Hemodynamic effects of diuretics in patients with marked peripheral edema and mild hypertension.

Hypertension develops in about 10% to 50% of patients with nephrosis or cirrhosis and peripheral edema, but the hemodynamic mechanism of the hypertension and its reversal by diuretic therapy has not been elucidated. In eight patients with marked edema and mild hypertension, diuretics (furosemide and spironolactone) decreased mean arterial pressure because of concurrent decrease in cardiac output and total peripheral resistance. Neither total blood volume nor plasma volume were decreased by the diuretics and the decrease in body weight was therefore attributed to the decrease in interstitial fluid volume. This, in turn, resulted in increased venous capacitance (as can be judged from the diuretic-induced decrease in the ratio of cardiopulmonary blood volume/total blood volume).

Adult↗
PubMed1987

Comparative effect of ANF and various diuretics on isolated nephron segments.

The effect of the synthetic form of ANF 0.1 to 10 microgram/ml (peptide 101-126), a diuretic and natriuretic peptide isolated from rat heart atria, on the metabolism of dog and rat kidney tubules was studied in vitro and compared to that of furosemide (0.1 to 1 mM), hydrochlorothiazide (0.5 mM) or amiloride (0.1 mM). In order to pinpoint eventual site(s) of ANF action along the nephron, proximal tubules, thick ascending limbs and papillary collecting ducts were isolated from dog kidneys as well as proximal tubules from rat kidneys. The substrate uptake (O2, lactate, glutamine, glucose) and production of metabolites (glutamate, ammonium, alanine, glucose) by these nephron segments were measured in absence or presence of the diuretic agents or the vehicle for ANF (acetate 1 mM). The total ATP turnover and the contribution of identified metabolic pathways for this turnover was calculated. It was expected that a molecule with diuretic properties reducing the permeability of cell membranes to NaCl would secondarily reduce the Na-K-ATPase activity, and therefore the oxygen and substrate utilization by affected cells. It was shown: that each nephron segment used presented the expected specific metabolic characteristics; that furosemide markedly inhibits the oxidative metabolism of thick ascending limbs; that acetate (the vehicle used for ANF) displaces the oxidation of glutamine and lactate in nephron segments with aerobic metabolism; that ANF had no effect on the metabolism of the studied segments despite the presence of specific c'GMP-generating receptors in the distal nephron. It is concluded that ANF must exert its natriuretic effect by a mechanism different from that of classical diuretics.

Adenosine Triphosphate↗
PubMed1999

Effectiveness and metabolic effects of perindopril and diuretics combination in primary hypertension.

The effectiveness as well as the metabolic effects of the combination of diuretics [hydrochlorothiazide (HCT) vs indapamide (IND)] and perindopril (P) in 14 patients (7 male, 7 female) aged 37-62 years with mild idiopathic hypertension were studied. Following a 4-week wash-out period and a 4-week period of monotherapy with P (4 mg/daily), IND (2.5 mg/daily) or HCT (25 mg/daily) was added for 4 weeks. Selection of the diuretic agent was random. Following a 4-week wash-out period from the diuretic, in which only P was given, the alternative diuretic was administered for another period of 4 weeks. P decreased blood pressure levels significantly. However, the drug was more efficacious in patients with higher plasma renin activity (PRA). Combination treatment induced an additional decrease in the blood pressure levels, mainly in patients with lower PRA. The combination of P + HCT was more effective than the combination P + IND. The addition of either HCT or IND evoked a small but statistically significant increase in serum glucose levels while fasting as well as during the 75 g oral glucose challenge. However, insulin levels did not change significantly during the study. Small but not statistically significant changes in serum electrolytes and lipid parameters were observed during the various phases of the study, while a statistically significant increase in the serum uric acid was noticed when the combination P + HCT was given. We conclude: (1) P in small doses is an effective and safe antihypertensive agent, (2) PRA has a predictive value in determining the effectiveness of P treatment, (3) the combination of P with small doses of HCT or IND is more efficacious than P alone, (4) the combination treatment has adverse effects in the carbohydrate tolerance, while there are not significant changes in serum electrolyte and lipid parameters.

Adult↗
PubMed2004

Reversal of diuretic-induced hepatic encephalopathy with infusion of albumin but not colloid.

In patients with cirrhosis, dehydration induced by diuretics is a common precipitant of hepatic encephalopathy (HE), which may respond to volume expansion. The mechanism of HE in this situation is not fully understood. The present study evaluates the effect of plasma volume expansion on the severity of HE, plasma and urinary ammonia in patients with diuretic-induced HE. Fifteen patients with alcoholic cirrhosis and diuretic-induced HE of Grade 2 or more were enrolled. In eight patients, 4.5% human albumin solution (HAS) was used for volume expansion and in seven patients colloid (Gelofusine) was used. Significant improvement of HE Grade was observed at 24 h and was sustained at 72 h ( P <0.05) only in the group treated with HAS. There were similar and statistically significant reductions in plasma ammonia concentration, plasma renin activity and angiotensin II and an increase in mean arterial pressure, renal plasma flow and urinary ammonia excretion in both groups. Plasma malondialdehyde was elevated in both groups, but was reduced significantly only in the group treated with HAS. The findings of the present study show that plasma volume expansion results in significant reduction in plasma ammonia concentration, possibly through an increase in urinary ammonia excretion. This reduction in ammonia concentration translates into an improvement in mental state only in those patients treated with HAS in whom concomitant reduction in oxidative stress was observed. These data support the notion that other factors, such as oxidative stress, act as adjuncts to ammonia in the pathogenesis of diuretic-induced HE and suggest a possible role for albumin infusion in its treatment.

Adult↗
PubMed2003

Dose-effect relations of loop- and thiazide-diuretics on calcium homeostasis: a randomized, double-blinded Latin-square multiple cross-over study in postmenopausal osteopenic women.

BACKGROUND: Thiazide diuretics (TDs) reduce whereas loop diuretics (LDs) increase urinary calcium. We studied the effects of different doses of a TD and LD on electrolytes, calcitropic hormones and biochemical bone markers. SUBJECTS AND METHODS: In a five-period crossover study, comparing four active doses with placebo, 40 postmenopausal women with osteopenia were treated with different doses of LD bumetanide (n = 20, 0.5-2.0 mg per day) or TD bendroflumethiazide (n = 20, 2.5-10 mg per day). Each treatment period lasted 1 week. RESULTS: Urinary calcium decreased dose-dependently in response to the bendroflumethiazide. The best hypocalciuric effect was achieved by 5 mg day-1 of bendroflumethiazide. Total plasma calcium levels increased, whereas ionised calcium at ambient pH-values decreased because of increased pH-values in response to the bendroflumethiazide. Plasma PTH levels did not change, whereas a slight dose-dependent increase occurred in plasma 1,25(OH)2D levels. As a marker of bone formation, plasma osteocalcin levels increased. Conversely, bumetanide dose-dependently increased renal calcium losses with a concomitant increase in plasma PTH and 1,25(OH)2D levels. Plasma osteocalcin levels increased and bone-specific alkaline phosphatase levels decreased dose-dependently. CONCLUSION: Whether a LD or TD is chosen as diuretic therapy affects calcium homeostasis. The effects of LDs are potentially harmful to bone. Further studies are needed to evaluate whether long-term treatment with LDs causes osteoporosis. Until then, we suggest using, if possible, a TD rather than a LD as diuretic therapy in order not to risk deleterious effects on bone metabolism.

Alkaline Phosphatase↗
PubMed2001

Diuretic renography in infants with prenatal unilateral hydronephrosis: an explanation for the controversy about poor drainage.

OBJECTIVE: To present an explanation for impaired drainage on diuretic renography in infants with a prenatal diagnosis of unilateral renal pelvic dilatation (RPD) who are stable both in terms of renal function and dilatation on follow-up investigations, despite undergoing no surgical intervention, and who undergo diuretic renography postnatally; this should provide some insight into whether impaired drainage is a sign of obstruction in these asymptomatic infants. MATERIALS AND METHODS: Using a combination of published studies on the technique of diuretic renography and an analysis of such studies, a theoretical model of the infant kidney was developed to assess the possibility of prolonged drainage. RESULTS: The results from the model showed prolonged drainage in many different situations, thus offering an explanation of expected impaired drainage even if there was no obstruction. CONCLUSION: Understanding the pathophysiology of prenatally diagnosed RPD allows different interpretations of the diuretic renogram and may affect the treatment of these children.

Child, Preschool↗
PubMed2002

Continuous haemodynamic monitoring during withdrawal of diuretics in patients with congestive heart failure.

AIMS: Right heart pressure parameters can be recorded continuously with the help of an implanted haemodynamic monitor. The aim of this study was to investigate the usefulness of the device in adjusting diuretic medication in patients with chronic congestive heart failure, and to evaluate the response of right ventricular pressure to increased volume load induced by diuretic withdrawal. METHODS AND RESULTS: Four patients with stable congestive heart failure were implanted with an implantable haemodynamic monitor. Furosemide, the only diuretic used, was reduced by 50% the first week, withdrawn completely for the second week and then reinstituted in the initial dose. Right ventricular systolic and diastolic pressure, pulse pressure, dP/dt, estimated diastolic pulmonary artery pressure and heart rate were sampled continuously. Patients were evaluated by body weight, NYHA class, serum creatinine, serum brain natriuretic peptide, the 6 min walk test, quality of life and echocardiography on days 0, 7, 14 and 21. We observed significant changes in right ventricular pressure parameters in parallel with clinical signs and symptoms of worsening heart failure, such as increased body weight, a shorter walking distance and impaired quality of life. Moreover elevated levels of brain natriuretic peptide and lower creatinine levels were observed. CONCLUSION: Haemodynamic changes due to increased volume load can be detected with an implantable haemodynamic monitor. Such data provide useful information for tailoring an optimal diuretic dose in patients with congestive heart failure.

Aged↗
PubMed1990

Thiazide diuretic agents and the incidence of hip fracture.

Thiazide diuretic agents lower the urinary excretion of calcium. Their use has been associated with increased bone density, but their role in preventing hip fracture has not been established. We prospectively studied the effect of thiazide diuretic agents on the incidence of hip fracture among 9518 men and women 65 years of age or older residing in three communities. At base line, 24 to 30 percent of the subjects were thiazide users. In the subsequent four years, 242 subjects had hip fractures. The incidence rates of hip fracture were lower among thiazide users than nonusers in each community; the Mantel-Haenszel relative risk of hip fracture, adjusted for community and age, was 0.63 (95 percent confidence interval, 0.46 to 0.86). The protective effect of the use of thiazides was independent of sex, age, impaired mobility, body-mass index, and current and former smoking status; the multivariate adjusted relative risk of hip fracture was 0.68 (95 percent confidence interval, 0.49 to 0.94). Furthermore, the protective effect was specific to thiazide diuretic agents, since there was no association between the use of antihypertensive medications other than thiazides and the risk of hip fracture. These prospective data suggest that in older men and women the use of thiazide diuretic agents is associated with a reduction of approximately one third in the risk of hip fracture.

Age Factors↗
PubMed2003

A comparison of outcomes with angiotensin-converting--enzyme inhibitors and diuretics for hypertension in the elderly.

BACKGROUND: Treatment of hypertension with diuretics, beta-blockers, or both leads to improved outcomes. It has been postulated that agents that inhibit the renin-angiotensin system confer benefit beyond the reduction of blood pressure alone. We compared the outcomes in older subjects with hypertension who were treated with angiotensin-converting-enzyme (ACE) inhibitors with the outcomes in those treated with diuretic agents. METHODS: We conducted a prospective, randomized, open-label study with blinded assessment of end points in 6083 subjects with hypertension who were 65 to 84 years of age and received health care at 1594 family practices. Subjects were followed for a median of 4.1 years, and the total numbers of cardiovascular events in the two treatment groups were compared with the use of multivariate proportional-hazards models. RESULTS: At base line, the treatment groups were well matched in terms of age, sex, and blood pressure. By the end of the study, blood pressure had decreased to a similar extent in both groups (a decrease of 26/12 mm Hg). There were 695 cardiovascular events or deaths from any cause in the ACE-inhibitor group (56.1 per 1000 patient-years) and 736 cardiovascular events or deaths from any cause in the diuretic group (59.8 per 1000 patient-years; the hazard ratio for a cardiovascular event or death with ACE-inhibitor treatment was 0.89 [95 percent confidence interval, 0.79 to 1.00]; P=0.05). Among male subjects, the hazard ratio was 0.83 (95 percent confidence interval, 0.71 to 0.97; P=0.02); among female subjects, the hazard ratio was 1.00 (95 percent confidence interval, 0.83 to 1.21; P=0.98); the P value for the interaction between sex and treatment-group assignment was 0.15. The rates of nonfatal cardiovascular events and myocardial infarctions decreased with ACE-inhibitor treatment, whereas a similar number of strokes occurred in each group (although there were more fatal strokes in the ACE-inhibitor group). CONCLUSIONS: Initiation of antihypertensive treatment involving ACE inhibitors in older subjects, particularly men, appears to lead to better outcomes than treatment with diuretic agents, despite similar reductions of blood pressure.

Aged↗
PubMed2004

Osmotic diuretics induce adenosine A1 receptor expression and protect renal proximal tubular epithelial cells against cisplatin-mediated apoptosis.

Osmotic diuretics are used successfully to alleviate acute tubular necrosis (ATN) produced by chemotherapeutic agents and aminoglycoside antibiotics. The beneficial action of these agents likely involves rapid elimination of the nephrotoxic agents from the kidney by promoting diuresis. Adenosine A1 receptor (A1AR) subtype present on renal proximal tubular epithelial and cortical collecting duct cells mediates the antidiuretic and cytoprotective actions of adenosine. These receptors are induced by activation of nuclear factor (NF)-kappaB, a transcription factor reported to mediate hyperosmotic stress-induced cytoprotection in renal medullary cells. In this study, we tested the hypothesis that induction of the A1AR in renal proximal tubular cells by NF-kappaB contributes to the cytoprotection afforded by osmotic diuretics. Exposure of porcine renal proximal tubular epithelial (LLC-PK1) cells to mannitol or NaCl produced a significant increase in A1AR. This increase was preceded by adenosine release and NF-kappaB activation. Expression of an IkappaB-alpha mutant, which acts as a superrepressor of NF-kappaB, abrogated the increase in A1AR. Cells exposed to mannitol demonstrated increased reactive oxygen species (ROS) generation, which was attenuated by inhibiting xanthine oxidase with allopurinol. Allopurinol attenuated both the increase in A1AR expression and NF-kappaB activation produced by osmotic diuretics, indicating a role of adenosine metabolites in these processes. Treatment of LLC-PK1 cells with cisplatin (8 microm) resulted in apoptosis, which was attenuated by mannitol but exacerbated by selective A1AR blockade. Administration of mannitol to mice increases A1AR expression and activation of NF-kappaB in renal cortical sections. Taken together, these data provide novel mechanisms of nephroprotection by osmotic diuretics, involving both activation and induction of the A1AR, the latter mediated through activation of a xanthine oxidase pathway leading to ROS generation and promoting activation of NF-kappaB.

Allopurinol↗
PubMed1982

Magnesium treatment of diuretic-induced hyponatremia with a preliminary report of a new aldosterone-antagonist.

Long-term diuretic treatment of patients with congestive heart failure is often complicated by hyponatremia and resistance to diuretic treatment, as well as by hypokalemia. Less widely recognized is the increase in intracellular sodium in the presence of hyponatremia, and loss of magnesium, caused by sustained diuretic therapy. Because the sodium pump, which maintains intracellular sodium and potassium against a concentration gradient, is dependent on optimal magnesium levels, we have investigated the influence of magnesium infusions on serum and skeletal muscle levels of sodium and potassium in congestive heart failure patients with electrolyte disturbances. Because aldosteronism, such as accompanies the disease and diuretic treatment, increases intracellular sodium, we have measured intracellular sodium and potassium in six patients given a new aldosterone antagonist (canrenone). It lowered the muscle sodium and raised the muscle potassium and magnesium, and slightly raised the serum sodium. The magnesium infusions, given to eight patients, significantly increased the serum sodium and lowered the muscle sodium levels, and normalized both serum and subnormal muscle potassium levels.

Aged↗
PubMed1989

Advantages and limitations of diuretic therapy in essential hypertension.

The diuretics previously considered the "cornerstone" of the antihypertensive treatment have recently undergone a reevaluation and have been considered as a potential cause of the lack of "cardioprotection" found in different epidemiological studies. The reduction in plasma potassium and the changes in lipoproteins should represent the mechanisms of the negative interference of diuretics at cardiac levels. In spite of this common opinion, there is no clinically consistent evidence that the lowering of serum potassium and the changes in lipoproteins are responsible for the lack of cardioprotection during antihypertensive therapy. It is possible that other causes, for instance the reflex activation of sympathetic nervous system and/or renin secretion, may play an important role in determining the cardiac effects of antihypertensive therapy. However, it is also true that diuretics have been used in the past at doses that were too high, and the changes in serum potassium and lipoproteins can be minimized by administering lower doses of diuretics without decreasing their antihypertensive efficacy.

Benzothiadiazines↗
PubMed1995

Torsemide: a new loop diuretic.

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage and administration of torsemide are reviewed. Torsemide belongs to the pyridine-sulfonylurea class of loop diuretics. Its primary site of activity is the thick ascending limb of the loop of Henle, where it blocks active reabsorption of sodium and chloride, resulting in diuresis, natriuresis, and other effects. Torsemide has high bioavailability, a relatively long half-life, and a prolonged duration of activity. It is highly protein bound. Clinical trials indicate that torsemide is effective in the treatment of hypertension and of edema and other symptoms in patients with chronic renal failure (CRF), hepatic dysfunction, or congestive heart failure (CHF). Torsemide has infrequent, mild, and transient adverse effects; among the most common are orthostatic hypotension, fatigue, dizziness, and nervousness. The recommended initial oral dosages of torsemide are 10-20 mg/day for CHF, 20 mg/day for CRF, 5 mg/day for hypertension, and 5-10 mg/day (in combination with a potassium-sparing diuretic or aldosterone antagonist) for hepatic cirrhosis. In most patients, the pharmacokinetic advantages of torsemide over other loop diuretics are unlikely to translate into a substantial edge in clinical outcomes, and in practice there may be no cost advantages. Although torsemide does not offer major advantages over other loop diuretics, it may be of benefit in patients who do not respond to or cannot tolerate other agents.

Antihypertensive Agents↗