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PubMed1988

Thiazide diuretic drug receptors in rat kidney: identification with [3H]metolazone.

Thiazides and related diuretics inhibit NaCl reabsorption in the distal tubule through an unknown mechanism. We report here that [3H]metolazone, a diuretic with a thiazide-like mechanism of action, labels a site in rat kidney membranes that has characteristics of the thiazide-sensitive ion transporter. [3H]Metolazone bound with high affinity (Kd = 4.27 nM) to a site with a density of 0.717 pmol/mg of protein in kidney membranes. The binding site was localized to the renal cortex, with little or no binding in other kidney regions and 11 other tissues. The affinities of thiazide-type diuretics for this binding site were significantly correlated with their clinical potency. Halide anions (Cl-, Br-, and I-) specifically inhibited high-affinity binding of [3H]metolazone to this site. [3H]Metolazone also bound with lower affinity (Kd = 289 nM) to sites present in kidney as well as in liver, testis, lung, brain, heart, and other tissues. Calcium antagonists and certain smooth muscle relaxants had Ki values of 0.6-10 microM for these low-affinity sites, which were not inhibited by most of the thiazide diuretics tested. Properties of the high-affinity [3H]metolazone binding site are consistent with its identity as the receptor for thiazide-type diuretics.

Animals↗
PubMed1991

Diuretics in the treatment of hypertension.

With 30 years of experience, it is possible to claim that diuretics are well tolerated antihypertensive drugs producing a significant decrease in systolic and diastolic blood pressure as good as obtained with beta-blockers, converting enzyme inhibitors, calcium antagonists and centrally acting drugs. Recently diuretics have been criticised because of a substantial number of important side-effects, and are disregarded by some authors as first-line agents for the treatment of mild hypertension. Diuretics seem however safe in the majority of hypertensive patients who do not present special problems. Using low doses, which are equally effective, most toxic properties can probably be avoided. Combination therapy, especially with ACE inhibitors, has not only additional effects, but lowers also the potential adverse effects, caused by diuretics. We are convinced that diuretics are still important as first-line agents for the treatment of arterial hypertension in the general population.

Arrhythmias, Cardiac↗
PubMed2000

Diuretic induced change in lung water assessed by electrical impedance tomography.

Monitoring patients with left ventricular failure can be difficult. Electrical impedance tomography (EIT) produces cross-sectional images of changes in the impedance of the thorax. We measured changes in the electrical impedance of the lung in nine volunteers following a diuretic challenge. The hypothesis was that lung impedance would increase with diuretic induced fluid loss. Heart rate, blood pressure and urine output were also recorded. After diuretic the mean urine output was 1220 ml compared with 187 ml after placebo. Following diuretic administration, mean thoracic impedance increased by 13.6% (p < 0.01) and lung impedance increased by 7.8% (p < 0.05). Taken as a group there was a correlation between overall impedance change and total urine output. However, for each individual, the time course of change in impedance and urine output did not correlate significantly. Our findings show that EIT may offer a better guide to the response of the lung to diuretic treatment than simply measuring urine output. The urine output is neither specific nor sensitive in the assessment of lung water. Mean lung impedance, however, is largely determined by lung water. The study showed that lung impedance can be recorded at supra-normal values. EIT may help in the management of patients with excess lung water.

Adolescent↗
PubMed1992

Where now the diuretics in antihypertensive treatment?

The ultimate aim in treating hypertension is to reduce cardiovascular mortality and morbidity, especially from coronary heart disease and strokes. In several long-term trials this goal has been achieved with antihypertensive therapy in the form of diuretics. Subsequently, diuretics and betablockers, compared as single agents or with the addition of other agents, did not appear to affect overall cardiovascular morbidity and mortality differentially. Therefore, recommended first-line therapy for hypertension was initially diuretics, followed later by beta blockers as alternatives. Recently, calcium antagonists and ACE inhibitors have been accepted as equally valuable in the treatment of hypertension because they similarly lower blood pressure, lack any adverse metabolic effects and may be more beneficial than diuretics or beta-blockers on the long-term prognosis of hypertensive patients. Such recommendations are, however, highly speculative and are not supported by trials using cardiovascular mortality and morbidity as endpoints. In order to solve the conflict between proven facts and sound theory, long-term trials comparing older (mainly diuretics) and newer (calcium antagonists, ACE inhibitors, alpha-adrenoceptor blockers) antihypertensive agents are needed. Until such trials are completed, the debate surrounding first-line drugs for antihypertensive treatment will not be resolved.

Adrenergic beta-Antagonists↗
PubMed1992

Comparative mechanisms of action of diuretic drugs in hypertension.

This review concerns the modes of action of thiazides, loop- and potassium-sparing diuretics, with particular emphasis on their antihypertensive activity. Thiazide diuretics inhibit an enzyme in the basolateral cell membrane in the distal tubule, thus bringing about an impaired absorption and enhanced excretion of both Na+ and Cl- ions. The loss of Na+ ions is countered by the exchange from Na+ against K+, hence causing a loss of K+ ions. The renal excretion of Ca++ ions is impaired, that of Mg++ ions enhanced. Loop diuretics inhibit a carrier mechanism that enhances the inward transport into the tubular cells of Na+, K+ and Cl- ions as well as water. This process, which occurs in the thick ascending limb of Henle's loop, enhances the urinary excretions of these ions together with water and Ca++ and Mg++ ions. Potassium-sparing diuretics comprise two different categories. Triamterene and amiloride inhibit a local transport mechanism in the distal tubular cells which allows the influx of Na+ and its exchange against K+ or H+ ions. Concomitantly, the excretion of Na+, but not that of K+, ions is enhanced. Aldosterone antagonists inhibit the renal effects of aldosterone at the receptor level and impair the reabsorption of Na+ ions and water and their exchange against K+ ions. Despite detailed knowledge of the renal mode of action of the diuretics, the mechanism whereby they exert their antihypertensive activity is still uncertain. The initial reduction in plasma volume is accompanied by reduction in cardiac output and increased systemic vascular resistance. Continued treatment leads to a return to normal in cardiac output and a reduction in systemic vascular resistance.(ABSTRACT TRUNCATED AT 250 WORDS)

Diuretics↗
PubMed1992

Neurohormonal consequences of diuretics in different cardiovascular syndromes.

Diuretics have long been used to lower blood pressure in hypertensive patients or to control body fluid and electrolyte homeostasis in diseases such as congestive heart failure, chronic renal failure or cirrhosis. The initial response to diuretics is a negative sodium and fluid balance. The diuretic-induced loss of salt and water activates several hormonal systems such as vasopressin, the renin-angiotensin-aldosterone system or the sympathetic nervous system which tend to compensate for the changes in sodium and water balance. This neurohormonal response may have important clinical implications. Thus, the activation of the renin-angiotensin-aldosterone cascade appears to be partially responsible for the flat dose-blood pressure response curve of thiazides in hypertensive patients. It may also be responsible for the difference between responders and non-responders to diuretic therapy and for the development of side-effects such as hypokalaemia, metabolic alkalosis or hyponatraemia. There are several ways to prevent the undesirable consequences of the neurohormonal responses to diuretics. The first is to use low doses of these agents. It is also possible to combine them with agents that block the activity of the renin-angiotensin-aldosterone system such as ACE inhibitors or in combination with drugs that reduce aldosterone secretion such as calcium antagonists. The development of drugs able to enhance urinary sodium excretion and to reduce simultaneously the activity of the renin-angiotensin-aldosterone system may offer a new interesting alternative. This might perhaps be achieved in the future with the administration of neutral endopeptidase inhibitors which interfere with the enzymatic degradation of atrial natriuretic peptide.

Animals↗
PubMed1992

Diuretics and cardiovascular risk factors.

Thiazide diuretics are efficacious, either as monotherapy or in combination with other antihypertensive drugs. They reduce blood pressure in a high percentage of hypertensive patients with minimal subjective side effects. There is increasing evidence that the use of diuretics, singly or in combination, will reduce morbidity and mortality associated with essential hypertension in both young and elderly subjects. Although diuretics may induce some changes in the plasma lipid profile, serum uric acid concentration and glucose metabolism, there is little evidence that these changes are of clinical significance. The increase in serum cholesterol concentration has rarely persisted in any trial beyond the first year of treatment. The incidence of diabetes mellitus in diuretic treated subjects is only about 1%, even when large doses are used. Gout may be precipitated in susceptible subjects, but is uncommon. For these reasons, diuretics should remain a preferred first-step drug of choice in the management of hypertension.

Blood Glucose↗
PubMed1995

Refocus on diuretics in the treatment of heart failure.

Diuretics have long been accepted as the traditional first-line treatment of the patient with symptomatic heart failure whatever its aetiology or dysfunctional stage. Their acceptance in this role is based on the rapid improvement in congestive symptoms experienced by most patients, which is arguably greater than that induced by any other currently available anti-heart failure drug. This symptomatic efficacy and their universal clinical acceptance as first-step treatment for the patient with symptoms of heart failure has precluded formal examination of their impact on prognosis. Evidence from indirect studies suggests that when used alone they may not be able to prevent clinical deterioration, possibly due to excitation of the renin-angiotensin-aldosterone system. When such excitation is suppressed by concomitant administration of angiotensin-converting enzyme inhibitors, relief of congestive symptoms is enhanced and the morbidity and mortality risk of heart failure significantly reduced. Studies on the mechanisms of diuretic resistance have demonstrated the synergy of diuretic activity when low doses of diuretics acting at different sites of the nephron are used in combination. Diuretics remain the cornerstone of treatment for symptoms in congestive heart failure but their overall efficacy is substantially improved when combined with ACE inhibitors.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2005

Diuretic usage in heart failure: a continuing conundrum in 2005.

Several large well-designed clinical trials have shown that the use of diuretics is beneficial in patients with hypertension. However, similarly robust data regarding their role in chronic heart failure are lacking. Historically, diuretics were developed for treatment of sodium and water retention in oedematous disorders and clinically, they remain the most potent drugs available to relieve symptoms and eliminate oedema in the congested patient with heart failure. In the non-congested patient, however, diuretics continue to be used on a purely clinical basis without sufficient characterization of benefits, adverse effects, and potential influence on mortality. There are also concerns that chronic diuretic usage can cause adverse vascular effects, unfavourable neuroendocrine activation, electrolyte imbalances, and life-threatening arrhythmias. In this article, we review the limited evidence available regarding the benefits and perils of using diuretics in heart failure.

Arrhythmias, Cardiac↗
PubMedDate not supplied

The effect of mannitol infusion on the response to diuretic therapy in cirrhotic patients with ascites.

GOALS: A good response to diuretics is obtained initially in the treatment of cirrhotic ascites. However, unresponsiveness to therapy and various complications may develop with disease progression. This makes obligatory the search for new treatment methods that may be alternative to standard diuretics. In our study, we investigated the effect of mannitol infusion on current therapies in patients with cirrhotic ascites who were using diuretic treatment. BACKGROUND: Thirty cirrhotic patients with ascites who were using diuretic treatment were included in the study. The patients were randomly divided into two groups; a dose of 100-mL 20% mannitol was administered to the first group, and 100-mL 5% dextrose solution was administered to the second group. The patients' urinary volumes and serum and urine electrolyte levels (sodium, potassium) were determined before and after the test. RESULTS: In the mannitol group, a significant increase in urinary volume was observed (p < 0.05). However, in the control group no significant differences in urinary sodium excretion were observed after the test (p > 0.05). In the mannitol group, a concomitant increase in urinary volume and sodium excretion was observed in eight cases (53%). The urinary sodium excretions and serum sodium levels before the test were significantly lower in patients who responded to mannitol than in patients who did not respond (p = 0.001 and p = 0.04, respectively). CONCLUSIONS: As a result, short-term mannitol therapy makes a significant contribution to diuretic therapy in approximately half of cases with cirrhotic ascites. The results we obtained suggest that mannitol may be a useful alternative in the treatment of ascites.

Ascites↗
PubMedDate not supplied

The effects of a sliding scale diuretic titration protocol in patients with heart failure.

Patients with heart failure (HF) are often instructed to temporarily adjust their diuretic dose. This approach has become routine in some HF management programs; however, no study has specifically examined the effects of a patient-directed flexible diuretic protocol. For the purposes of this study, patients were randomized into a usual care (UC) group (n = 31) or a flexible diuretic titration (DT) group (n = 35). The DT group completed a 6-item diuretic titration protocol once a day, for 3 months. The 6-minute walk distance, plasma B-type natriuretic peptide (NT-BNP), plasma norepinephrine (NE), and quality of life (QOL) were measured at baseline and at 3 months. Hospitalizations, emergency department (ED) visits, and mortality rates were measured at 3 months. Compared to baseline, at 3 months, there was a significant increase in the DT group's 6-minute walk distance (646 +/- 60 ft vs 761 +/- 61 ft, P = .01) and total QOL score (53 +/- 5 vs 38 +/- 5, P = .001), whereas these parameters remained unchanged within the UC group. There were significantly less ED visits in the DT group compared with those in the UC group (3% vs 23%, P = .015). No differences were found between the groups in HF-related hospitalizations or mortality. Within both groups, no differences were found between baseline and 3-month NE or NT-BNP plasma values. Patients with heart failure who used a sliding scale diuretic titration protocol had significant improvements in their exercise tolerance and QOL, had fewer ED visits, and had no change in plasma NE or NT-BNP levels.

Clinical Protocols↗
PubMed1989

Loop diuretics combined with an ACE inhibitor for treatment of hypertension: a study with furosemide, piretanide, and ramipril in spontaneously hypertensive rats.

Both angiotensin converting enzyme (ACE) inhibition and sodium-diuresis lower blood pressure in spontaneously hypertensive rats (SHR). The purpose of the present study was to examine whether long-term therapy with ramipril (RA, and ACE inhibitor) would lower blood pressure more effectively and without adverse reactions in combination with the loop diuretics piretanide (PI) or furosemide (FU). Groups of 15 SHR each were treated once daily for 3 weeks by gavage with 1 and 10 mg/kg RA, 2 and 4 mg/kg PI, and 8 and 16 mg/kg FU alone and with 1 mg/kg RA in combination with each of these diuretics at both the high and low doses. Sustained and marked ACE inhibition with 10 mg/kg RA normalized BP, but this was accompanied with slightly impaired kidney function as assessed by increases in both urea and creatinine. Low-dose diuretic therapy, producing little diuresis, or treatment with 1 mg/kg RA, producing less sustained ACE inhibition were less effective on blood pressure and scarcely altered serum solute levels, except 4 mg/kg PI, which produced slight reductions in Na+, K+, Mg2+, and PO4(3-). Combined treatment with the 1 mg/kg RA with either diuretic given at low or high dose was well tolerated at much improved reduction in blood pressure compared to their effects individually and without changes in serum solute concentrations and without hemoconcentration. Thus, combined treatment with low doses of loop diuretics and ACE inhibitors that permit partial recovery of serum ACE activity during the 24 h after dosing synergistically lowers blood pressure without adverse reactions associated with larger doses of either therapy alone.

Aldosterone↗
PubMed1993

Diuretics in heart failure: some knowns and unknowns.

There are many hemodynamic faces of heart failure, ranging from the subclinical to the terminal syndrome. The diuretics possess, with minor qualification, the pharmacotherapeutic attributes of the ideal first-line drug of choice. In heart failure, the loop diuretics have achieved eminence due to their improvement of the deranged hemodynamic profile without significant adverse pharmacologic effects. The new loop diuretics, including torasemide, have been shown to reduce the raised pulmonary vascular pressures without significant depression of the cardiac output in patients with chronic heart failure. This hemodynamic improvement has been paralleled by a significant improvement in clinical symptoms in the majority of patients. The undoubted and widely accepted efficacy of the loop diuretics in all the heart failure syndromes have presented a formidable ethical obstacle to their formal testing in terms of improvement in exercise capacity and reduction of mortality risk. There is still a paucity of information on their singular impact on the excited neuroendocrine reflexes in heart failure and their influence on the widespread metabolic disturbances occasioned by pumping failure of the heart. From the clinical standpoint, however, these deficiencies in information do nothing to reduce the importance of the loop diuretics in the treatment of acute and chronic heart failure.

Diuretics↗
PubMed2005

Screening procedure for detection of diuretics and uricosurics and/or their metabolites in human urine using gas chromatography-mass spectrometry after extractive methylation.

A gas chromatography-mass spectrometry (GC-MS)-based screening procedure was developed for the detection of diuretics, uricosurics, and/or their metabolites in human urine after extractive methylation. Phase-transfer catalyst remaining in the organic phase was removed by solid-phase extraction on a diol phase. The compounds were separated by GC and identified by MS in the full-scan mode. The possible presence of the following drugs and/or their metabolites could be indicated using mass chromatography with the given ions: m/z 267, 352, 353, 355, 386, and 392 for thiazide diuretics bemetizide, bendroflumethiazide, butizide, chlorothiazide, cyclopenthiazide, cyclothiazide, hydrochlorothiazide, metolazone, polythiazide, and for canrenoic acid and spironolactone; m/z 77, 81, 181, 261, 270, 295, 406, and 438 for loop diuretics bumetanide, ethacrynic acid, furosemide, piretanide, torasemide, as well as the uricosurics benzbromarone, probenecid, and sulfinpyrazone; m/z 84, 85, 111, 112, 135, 161, 249, 253, 289, and 363 for the other diuretics acetazolamide, carzenide, chlorthalidone, clopamide, diclofenamide, etozoline, indapamide, mefruside, tienilic acid, and xipamide. The identity of positive signals in such mass chromatograms was confirmed by comparison of the peaks underlying full mass spectra with reference spectra. This method allowed the detection of the abovementioned drugs and/or their metabolites in human urine samples, except torasemide. The limits of detection ranged from 0.001 to 5 mg/L in the full-scan mode. Recoveries of selected diuretics and uricosurics, representing the different chemical classes, ranged from 46% to 99% with coefficients of variation of less than 21%. After ingestion of the lowest therapeutic doses, furosemide was detectable in urine samples for 67 hours, hydrochlorothiazide for 48 hours, and spironolactone for 52 hours (via its target analyte canrenone). The procedure described here is part of a systematic toxicological analysis procedure for acidic drugs and poisons.

Diuretics↗
PubMed2006

Initial experience with fenoldopam after cardiac surgery in neonates with an insufficient response to conventional diuretics.

OBJECTIVE: Fenoldopam, a selective dopamine-1 receptor agonist, causes systemic vasodilation and increased renal blood flow and tubular sodium excretion. We hypothesized that urine output would improve when fenoldopam was added to conventional diuretic therapy after neonatal cardiopulmonary bypass. DESIGN: Retrospective cohort study using a time-series design. SETTING: Pediatric cardiac intensive care unit. PATIENTS: All neonates who received fenoldopam to promote diuresis after cardiac surgery requiring cardiopulmonary bypass from February 2002 through December 2004. INTERVENTIONS: Fenoldopam infusion for inadequate urine output despite conventional diuretics. MEASUREMENTS: Demographics, diagnostic information, and surgical procedures were recorded. Urine output, fluid balance, inotrope scores, diuretic doses, and other clinical variables that may influence diuresis were recorded for the 24-hr period immediately preceding fenoldopam initiation and during the initial 24 hrs of drug administration. MAIN RESULTS: A total of 25 neonates received fenoldopam to promote diuresis after the modified Norwood (n = 14), arterial switch (n = 4), or other operations (n = 7). Heart rate, conventional diuretic dosing, and fluid intake were similar during the 24-hr periods of conventional therapy and fenoldopam use (p = not significant for all), whereas inotrope scores decreased during the study (p = .021). There was a small but statistically significant increase in blood pressure during the 48-hr study period. Median urine output was 3.6 mL x kg(-1) x hr(-1) (range, 0.2-7.2 mL x kg(-1) x hr(-1)) during the 24-hr period of conventional therapy and 5.8 mL x kg(-1) x hr(-1) (range, 1.6-11.7 mL x kg(-1) x hr(-1)) during the initial 24 hrs of fenoldopam administration (Wilcoxon's signed-rank test, p = .001). CONCLUSIONS: Fenoldopam may improve urine output in neonates who are failing to achieve an adequate negative fluid balance despite conventional diuretic therapy after cardiac surgery and cardiopulmonary bypass. This study is limited by its retrospective design and the possibility that urine output improved spontaneously during the treatment period. A randomized, placebo-controlled clinical trial will be required to confirm these findings.

Cardiopulmonary Bypass↗
PubMed1980

Tissue zinc at autopsy--relation to medication with diuretics.

Diuretic treatment has been shown to cause a substantial increase in the urinary output of zinc. However, the serum zinc levels remain normal or even raised. In the present study, tissue zinc was studied in liver, kidney and skeletal muscle tissue from 147 consecutive autopsies. In 90 of the cases heart muscle and aortic tissue were also studied. The zinc values were correlated to previous treatment with diuretics. A lower liver zinc level was observed in the group of patients who had been on diuretic treatment for more than 6 months compared to the group without treatment, the difference being highly significant. The skeletal muscle zinc was also low in the patients who had been on diuretic treatment. With regard to the metabolic functions of zinc, the tissue depletion of this element after diuretic treatment may be of clinical importance.

Aorta↗
PubMed1993

Do diuretics cause magnesium deficiency?

1. Controlled trials, of which there are few, do not substantiate claims that diuretics play a role in causing magnesium deficiency. Consequently, the vast majority of patients taking conventional doses of thiazide diuretics (i.e. bendrofluazide 2.5 mg day-1 or equivalent) do not need magnesium supplements. On balance, potassium-sparing diuretics tend to increase serum and intracellular magnesium content; this should not be taken as evidence of prior magnesium deficiency. It remains theoretically possible that large doses of loop diuretics given more than once daily for long periods could induce negative magnesium balance and magnesium deficiency. However, it has been difficult to run appropriately controlled trials in conditions where such therapy is needed (i.e. heart failure) and until more reliable information becomes available no absolute recommendation can be made. 2. Methods for the measurement of intracellular free magnesium levels are now available and are more relevant to the assessment of magnesium deficiency than total intracellular magnesium content; the complex relationship between intracellular free and total magnesium content remains to be defined. Future work involving the effect of diuretics on intracellular free magnesium measurements should make every attempt to avoid the errors of trial design and multiple publication that litter current and past literature.

Animals↗
PubMed2005

Combination therapy in the management of hypertension: focus on angiotensin receptor blockers combined with diuretics.

There is increasing evidence that combination therapy should be emphasized more than it is at present for the initial treatment of hypertensive patients. Recent guidelines acknowledge the value of combination therapy, although some treatment algorithms fail to echo this message. Observations from major clinical trials in the elderly, diabetics, stroke patients, and African Americans all indicate that combination therapy is necessary to control blood pressure in the majority of these patients. Several combination therapies such as an angiotensin II receptor blocker and a diuretic, an angiotensin-converting enzyme inhibitor with a diuretic, a beta blocker with a diuretic, or an angiotensin-converting enzyme inhibitor with a calcium antagonist have been shown to be effective in patients who do not respond to monotherapy. The current review focuses on the newest such combination; an angiotensin II receptor blocker and a diuretic may have an added advantage of being well tolerated. Recent studies have shown that angiotensin II receptor blockers, given alone or combined with a diuretic, may prevent some cardiovascular outcomes independent of their blood pressure-lowering efficacy.

Angiotensin II Type 1 Receptor Blockers↗