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PubMed2005

Mechanism of enhanced bioavailability and diuretic effect of azosemide by ascorbic acid in rats.

To increase the extent of comparative oral bioavailability (F) value and the diuretic and natriuretic effects of orally administered azosemide, ascorbic acid was coadministered to rats. The rationales for this study are that ascorbic acid might inhibit intestinal first-pass effect of azosemide and might increase the unionized fraction of azosemide at the receptor sites. After oral administration of azosemide (20 mg/kg) with 100 mg of ascorbic acid, the F value (138% vs. 100%), 8-h urinary excretion of azosemide (5.18% vs. 1.32% of oral dose), 8-h urine output (41.3 vs. 23.0 ml), and 8-h urinary excretion of sodium (24.6 vs. 15.3 mmol/kg) were greater than controls (without ascorbic acid). The amount of spiked azosemide remaining after 30 min incubation of 50 mug of azosemide with the 9000 g supernatant fraction of rat small intestine was significantly greater by 100 microg of ascorbic acid (45.3 vs. 40.9 microg) than controls (without ascorbic acid). After oral administration of azosemide with NH4Cl, the urine pH decreased by 0.5 U, and 8-h urine output (25.8 vs. 11.0 ml) and 8-h urinary excretion of sodium (13.3 vs. 6.89 mmol/kg) were significantly greater than controls (without NH4Cl). The increase in F value and diuretic and natriuretic effects of azosemide with coadministration of ascorbic acid seemed to be due to reduced intestinal first-pass metabolism of azosemide, increased urinary excretion of azosemide, and increased unionized fraction of azosemide at the renal tubular receptor sites.

Ammonium Chloride↗

PubMed2005

Alteration of renal adrenomedullin and its receptor system in the severely hypertensive rat: effect of diuretic.

OBJECTIVE: We investigated the pathophysiological role of the renal adrenomedullin (AM) system, including the ligand, receptor, and amidating activity, in severe hypertensive rats. METHOD: We studied three groups: control Wistar Kyoto rats (WKY), spontaneously hypertensive stroke-prone rats (SHR-SP), and diuretic-treated SHR-SP. We measured AM-mature, active form, and AM-total (active form+inactive form) in plasma and renal tissues, and mRNA levels of AM and AM receptor system components such as calcitonin receptor-like receptor (CRLR), receptor activity-modifying protein (RAMP) 2, and RAMP3 in renal tissues. RESULTS: SHR-SP had higher blood pressure, plasma neurohumoral factors, and lower renal function than WKY. SHR-SP had higher AM-mature and AM-total levels in plasma and renal tissues than WKY. Although the plasma AM-mature/AM-total ratio was similar in the two groups, AM-mature/AM-total ratio in renal tissues was higher in SHR-SP than in WKY. In addition, mRNA levels of AM in the renal cortex and medulla and the mRNA levels of CRLR, RAMP2, and RAMP3 in the renal cortex were higher in SHR-SP than in WKY. Chronic diuretic treatment decreased blood pressure and improved kidney function and neurohumoral factors, with reductions in plasma and renal AM system. CONCLUSION: Upregulation of circulating and renal AM system may modulate pathophysiology in SHR-SP.

Adrenomedullin↗

PubMed2000

Diuretics and beta-blockers: is there a risk for dyslipidemia?

BACKGROUND: Hypertension is a major risk factor for cardiovascular disease, particularly in combination with other risk factors such as obesity, smoking, diabetes, and dyslipidemia. Effective management of hypertension, even a modest reduction in blood pressure, results in reduced mortality and morbidity from cerebrovascular and cardiovascular disease. METHODS: Data from clinical trials were examined to assess the effect of low-dose diuretics or beta-blockers on lipoprotein profile. RESULTS: Results of numerous clinical trials demonstrate that low doses of thiazides or cardioselective beta-blockers alone or in combination result in minimal changes in lipid profile. CONCLUSIONS: Low doses of thiazide diuretics or beta-blockers are a safe and effective approach to the management of uncomplicated essential hypertension and have the advantage of an association with an evidence-based reduction in morbidity and mortality in long-term clinical trials. There is little or no evidence that the minimal changes in serum lipid profile associated with use of these drugs have resulted in a negation of the beneficial effects of these agents on blood pressure.

Adrenergic beta-Antagonists↗

PubMed1996

Effectiveness of spironolactone added to an angiotensin-converting enzyme inhibitor and a loop diuretic for severe chronic congestive heart failure (the Randomized Aldactone Evaluation Study [RALES]).

The present study enrolled 214 patients, aged 26 to 83 years, with symptomatic New York Heart Association class II through IV congestive heart failure. Patients were continued on their previous therapeutic regimens, which included an angiotensin-converting enzyme (ACE) inhibitor and a loop diuretic with or without digitalis. Patients were randomized to 1 of 5 parallel treatment groups: placebo or spironolactone at a single daily dose of 12.5, 25, 50, or 75 mg for 12 weeks. Serum levels of creatinine, urea nitrogen, potassium, plasma renin activity, and N-terminal proatrial natriuretic factor (pro-ANF), as well as urinary aldosterone levels, were measured periodically. Measurements at 12 weeks versus baseline values indicated significant increases in plasma renin activity and aldosterone excretion and significant decreases in systolic and diastolic blood pressure and pro-ANF. Hypokalemia (serum potassium < 3.4 mmol/L) occurred in 10% of placebo-treated patients and in 0.5% of the spironolactone group. The incidence of hyperkalemia (serum potassium > or = 5.5 mmol/L) was 5% for the placebo group, whereas it was 5%, 13%, 20%, and 24% for the 12.5-, 25-, 50- and 75-mg spironolactone treatment groups, respectively. Predictors of hyperkalemia included the use of ACE inhibitors other than captopril, ACE inhibitor dose, and baseline elevation of serum creatinine or potassium levels. Thus, daily doses of 12.5 to 25 mg of spironolactone coadministered with conventional therapy of ACE inhibitors, loop diuretics, and digitalis are relatively safe (provided that serum potassium levels are monitored) and effective in blocking the effects of aldosterone, while reducing the potential for hypokalemia in patients with heart failure.

Adult↗

PubMed1996

Evidence for the efficacy of low-dose diuretic monotherapy.

Diuretic monotherapy has been recommended by the fifth report of the Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure (JNC-V) as a preferred initial treatment for hypertension. Thiazide diuretics are commonly used to treat hypertension because of their demonstrated efficacy, favorable safety profile, low acquisition cost, and their proven ability to reduce blood pressure-related morbidity and mortality. Once-daily low-dose hydrochlorothiazide (12.5 mg/ day) or chlorthalidone (15 mg/day) effectively reduces blood pressure in patients with stage 1 or stage 2 hypertension in comparison with placebo. Blood pressure reductions with low-dose hydrochlorothiazide and chlorthalidone are comparable to that achieved with higher doses (25 and 50 mg/day). Additional blood pressure reductions can be attained with concomitant use of once-daily low-dose hydrochlorothiazide or chlorthalidone with an angiotensin-converting enzyme (ACE) inhibitor, a beta blocker, or a calcium antagonist. Once-daily low-dose hydrochlorothiazide provides clinically meaningful blood pressure lowering while minimizing adverse effects, such as electrolyte disturbances, cholesterol elevations, and increases in serum uric acid levels.

Chlorthalidone↗

PubMed1998

The effects of diuresis on the pharmacokinetics of the loop diuretics furosemide and torsemide in patients with heart failure.

PURPOSE: To evaluate the pharmacokinetics of furosemide and torsemide before and after diuresis in patients presenting with marked fluid overload. SUBJECTS AND METHODS: We studied 44 patients with New York Heart Association class III or IV heart failure, ejection fraction < or =40%, and an estimated excess fluid body weight > or =6.8 kg. Oral furosemide or torsemide was administered before and after diuresis. Pharmacokinetic parameters were assessed before and after diuresis. RESULTS: Following diuresis, maximum plasma concentration increased from 11.0+/-5.0 microg/mL to 13.9+/-6.8 with torsemide (P <0.05) and from 3.1< or =1.5 to 3.9+/-1.9 with furosemide (P=0.16). Maximum concentration increased by more than 30% in only one third of the patients. Total absorption (by area under the curve method) increased 6% among patients on torsemide (P=0.38) and 7% among patients on furosemide (P=0.63) and increased >30% in only 1 torsemide and 2 furosemide patients. The time to maximum concentration decreased from 1.40+/-.82 h to 0.81+/-0.36 with torsemide (P <0.01). There were no differences between furosemide and torsemide in the effects of edema on absorption. CONCLUSION: Marked diuresis altered the pharmacokinetics of both furosemide and torsemide in only a small percentage of patients. The use of adequate doses of oral diuretics in edematous patients may be successful, thereby permitting home treatment with oral diuretics and avoiding the cost of hospitalizations or home intravenous administration services.

Aged↗

PubMed1985

Thiazide diuretics and bone mineral content in postmenopausal women.

This retrospective study of 54 postmenopausal women taking thiazide diuretics found that bone mineral measurements and bone fracture prevalence did not differ significantly from those of matched control subjects. Matching on the variables of type of menopause (surgical/nonsurgical), years postmenopausal, duration of estrogen therapy (if any), daily intake of dietary and supplemental calcium and vitamin D, and Quetelet index was done without knowledge of the bone mineral measurements. Bone mass was recorded as the bone mineral content and bone density of the distal and midshaft radius. Only fractures associated with osteoporosis (hip, rib, vertebrae, and wrist) were recorded. This study suggests that thiazide diuretics do not provide protection against osteoporosis.

Aged↗

PubMed1997

Role of duration of diuretic effect in preventing sodium retention.

OBJECTIVE: To determine whether the duration of diuretic effect at the active nephron site enhances ability to excrete an exogenous salt load. METHODS: We conducted a study that involved eight patients with New York Heart Association class II to III congestive heart failure. In a randomized, crossover manner, each patient received 3.25 mg intravenous bumetanide at 0 hours and again at 6 hours or a loading dose of 0.5 mg bumetanide at 0 hours followed by a continuous infusion of 0.5 mg/hr for 6 hours. Response was followed for 12 hours; a total of 6.5 mg of bumetanide was administered in each arm of the study. Eight hours after dosing began, we administered approximately 80 mEq sodium intravenously and examined its excretion over 4 hours. RESULTS: The percentage of the load excreted was 86% +/- 15% versus 29% +/- 30% for the infusion and bolus regimens, respectively (p = 0.0005). More bumetanide was excreted during the infusion (667 +/- 133 micrograms versus 240 +/- 121 micrograms; p = 0.0002). During the infusion, however, more sodium was excreted relative to amounts of bumetanide, indicating that the efficiency of response was greater during the infusion, 0.10 +/- 0.02 mEq sodium per microgram bumetanide versus 0.07 +/- 0.05 mEq for the bolus (p = 0.0145). CONCLUSIONS: These data support the notions that a long-acting loop diuretic maintains its efficacy and that a longer duration of action facilitates excretion of a sodium load, such as that which might occur during dietary indiscretion.

Adult↗

PubMed2000

Liquid chromatographic separation of the stereoisomers of thiazide diuretics.

A number of racemic thiazide diuretics and analogues were resolved on two diastereomeric chiral stationary phases (CSPs) prepared from (S)- or (R)-alpha-[1-(6,7-dimethyl)naphthyl]-10-dodecenylamine and (S)-2-phenylpropanoic acid. Of the two diastereomeric CSPs, the (S,S) and the (R,S), the former is found to be better than the latter in separating the enantiomers of the racemic thiazide diuretics and their analogues with complete separation being observed on the (S,S)-CSP. Chiral recognition is controlled principally by the (R)- or (S)-alpha-[1-(6,7-dimethyl)naphthyl]-10-dodecenylamine portion of the CSPs. The second stereogenic center of the CSP provides but secondary effects on the chiral recognition presumably involving, in the case of the (S,S)-CSP, face-to-edge pi-pi interaction between the aromatic ring of the analytes and the phenyl on the second stereogenic center.

Benzothiadiazines↗

PubMed2003

The effects of endogenous diuretic and antidiuretic peptides and their second messengers in the Malpighian tubules of Tenebrio molitor: an electrophysiological study.

The Malpighian tubules of Tenebrio molitor provide a model system for interpreting the actions of endogenous diuretic and antidiuretic peptides. The effects of diuretic (Tenmo-DH(37)) and antidiuretic (Tenmo-ADFa) peptides and their respective second messengers (cyclic AMP and cyclic GMP) on basolateral (V(bl)) and transepithelial (V(te)) potentials of Tenebrio Malpighian tubules were determined using conventional microelectrodes. In the presence of 6 mmol l(-1) Ba(2+), Tenmo-DH(37) (100 nmol l(-1)) reversibly hyperpolarized V(bl) and depolarized V(te). A similar response was seen with the addition of 1 mmol l(-1) cyclic AMP; however, the apical membrane potential (V(ap)) then showed a hyperpolarization, whereas a depolarization of V(ap) was observed with Tenmo-DH(37). Bafilomycin A(1) (5 micromol l(-1)) inhibited fluid secretion of stimulated tubules and reversed the hyperpolarization of V(bl) in response to Tenmo-DH(37). In response to 100 nmol l(-1) Tenmo-ADFa or 1 mmol l(-1) cyclic GMP, V(bl) and V(te) depolarized, although cyclic GMP affected membrane potentials somewhat differently by causing an initial hyperpolarization of V(bl) and V(te). In high [K(+)]-low [Na(+)] Ringer, 1 mmol l(-1) amiloride decreased fluid secretion rates, and depolarized both V(bl) and V(te). Amiloride significantly decreased luminal pH in paired experiments, indicating the presence of a K(+)/nH(+) exchanger in tubule cells of Tenebrio. The results suggest that the endogenous factors and their second messengers stimulate/inhibit fluid secretion by acting on the apical V-ATPase, basolateral K(+) transport, and possibly Cl(-) transport.

Amiloride↗

PubMed1977

Displacement of bilirubin from human albumin by three diuretics.

The interaction of three diuretics with bilirubin-albumin complexes was studied using the peroxidase assay, erythrocyte uptake, and sephadex gel filtration. On a molar basis, each diuretic was as potent or more potent than sulfisoxazole in displacing bilirubin from albumin. Furosemide and ethacrynic acid, when used at the recommended dosage (1 mg/kg), would probably not produce a significant increase in free bilirubin in most infants. Chlorothiazide could introduce a significant risk to jaundiced infants because of the higher dosage required.

Bilirubin↗

PubMed1998

Coadministration of theophylline enhances diuretic response to furosemide in infants during extracorporeal membrane oxygenation: a randomized controlled pilot study.

OBJECTIVE: This pilot study evaluates the efficacy of low-dose theophylline administered before furosemide to enhance diuresis in neonates recovering from fluid retention during extracorporeal membrane oxygenation (ECMO). STUDY DESIGN: Infants receiving ECMO (n = 24) were randomized (double blind, placebo-controlled) to receive either regimen A (placebo/furosemide day 1, theophylline/furosemide day 2, placebo/furosemide day 3) or regimen B (theophylline/furosemide day 1, placebo/furosemide day 2, theophylline/furosemide day 3). Urine flows and renal functions were compared. RESULTS: Urine flow rate before initiation of diuretic therapy was not significantly different between groups A and B (2.6 +/- 1.4 vs 3.5 +/- 1.3 ml/kg/hr, respectively, p = 0.12). Infants who received theophylline/furosemide had significantly higher urine flow rates than those who received placebo/furosemide on day 1 (11.8 +/- 4.6 vs 7.2 +/- 2.4 ml/kg/hr, p < 0.01). The 24-hour fluid volumes and balances became significantly more negative with theophylline enhancement of furosemide's effect. There were no significant differences in renal function between the two groups. CONCLUSION: Low doses of theophylline given before furosemide administration significantly enhance diuretic response in infants with fluid retention during ECMO.

Diuresis↗

PubMed1989

Diuretics.

Diuretics are a mainstay of modern medical therapy. Their effects on electrolyte excretion can largely be predicted from knowledge of their sites of action along the renal tubule. This article examines the role of diuretics in cardiac and noncardiac disease.

Diuretics↗

PubMed1990

The pharmacology and therapeutics of diuretics in the pediatric patient.

Selection of appropriate diuretic therapy in children is hampered by a lack of age-specific pharmacokinetic and pharmacodynamic data, especially in premature neonates. Well-designed clinical trials in neonates, infants, and younger children are necessary prerequisites to safer and more efficacious diuretic therapy.

Child↗

PubMed2001

Diuretic renography and angiotensin converting enzyme inhibitor renography.

Renovascular hypertension and renal outlet obstruction are two clinical conditions well evaluated by nuclear medicine techniques. They both require a specific intervention to challenge a specific aspect of renal functional reserve. Diuretic renography is the oldest common example in nuclear medicine where functional change in the kidney is provoked for diagnostic purposes. The kidney's tubular functional reserve, in this instance, is challenged to induce diuresis and increase urine flow. This intervention permits diuretic renography to retain an essential role in the evaluation of hydroureteronephrosis. Captopril renography is a more recent example of a similar principle and depends on a reactive renin-angiotensin system to identify a kidney responsible for RVH. In both renal outlet obstruction and RVH, an anatomic abnormality is also identified (hydronephrosis and RAS, respectively) at some point in the diagnostic workup. The final diagnosis in each instance, however, depends on evidence for a functional disorder, provoked and measured during the radionuclide interventional examination. These serve as excellent examples of the power of functional imaging to identify specific medical disorders.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1982

Reduction of the effects of diuretics or sodium chloride loading in the conscious rat by inhibitors of prostaglandin synthesis.

In conscious rats pretreatment with indomethacin or flurbiprofen, two chemically unrelated inhibitors of prostaglandin synthesis, reduced urine volume and sodium excretion induced by four diuretics, acetazolamide, amiloride, bendrofluazide and frusemide, or oral sodium chloride loads. The maximum reduction in sodium excretion was limited to approximately 2 mmol/kg Na+ even when sodium excretion was greatly increased. In contrast these inhibitors did not appreciably affect potassium excretion. These results indicate that part of the natriuretic response in the rat to highly and moderately efficacious diuretics and to sodium chloride loading is modified by prostaglandins. We suggest that the lack of effects on potassium excretion indicate that the collecting tubule is the probable site of action.

Acetazolamide↗

PubMed1998

Provocative imaging. Diuretic renography.

Diuretic renography remains the noninvasive functional study of choice in patients with hydronephrosis resulting from apparent UPJ obstruction. Meticulous attention to proper patient preparation, radiopharmaceutical selection, furosemide dosage and administration, and image interpretation and an awareness of potential pitfalls are essential for accurate diagnosis. For most patients, the F + 20 protocol is sufficient, however; the F-15 protocol allows clarification in cases of equivocal baseline F + 20 studies. Invasive antegrade techniques such as the Whitaker pressure/perfusion test are best reserved for patients in whom the diagnosis remains equivocal after diuretic renography, or in patients with massive hydronephrosis or renal insufficiency. New standardized protocol guidelines should help to ensure studies that are reproducible in different nuclear medicine laboratories.

Adult↗

PubMed2000

Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT).

BACKGROUND: The efficacy of antihypertensive drugs newer than diuretics and beta-blockers has not been established. We compared the effects of the calcium-channel blocker nifedipine once daily with the diuretic combination co-amilozide on cardiovascular mortality and morbidity in high-risk patients with hypertension. METHODS: We did a prospective, randomised, double-blind trial in Europe and Israel in 6321 patients aged 55-80 years with hypertension (blood pressure > or = 150/95 mm Hg, or > or = 160 mm Hg systolic). Patients had at least one additional cardiovascular risk factor. We randomly assigned patients nifedipine 30 mg in a long-acting gastrointestinal-transport-system (GITS) formulation (n=3157), or co-amilozide (hydrochlorothiazide 25 mg [corrected] plus amiloride 2.5 mg; n=3164). Dose titration was by dose doubling, and addition of atenolol 25-50 mg or enalapril 5-10 mg. The primary outcome was cardiovascular death, myocardial infarction, heart failure, or stroke. Analysis was done by intention to treat. FINDINGS: Primary outcomes occurred in 200 (6.3%) patients in the nifedipine group and in 182 (5.8%) in the co-amilozide group (18.2 vs 16.5 events per 1000 patient-years; relative risk 1.10 [95% CI 0.91-1.34], p=0.35). Overall mean blood pressure fell from 173/99 mm Hg (SD 14/8) to 138/82 mm Hg (12/7). There was an 8% excess of withdrawals from the nifedipine group because of peripheral oedema (725 vs 518, p<0.0001), but serious adverse events were more frequent in the co-amilozide group (880 vs 796, p=0.02). Deaths were mainly non-vascular (nifedipine 176 vs co-amilozide 172; p=0.81). 80% of the primary events occurred in patients receiving randomised treatment (157 nifedipine, 147 co-amilozide, difference 0.33% [-0.7 to 1.4]). INTERPRETATION: Nifedipine once daily and co-amilozide were equally effective in preventing overall cardiovascular or cerebrovascular complications. The choice of drug can be decided by tolerability and blood-pressure response rather than long-term safety or efficacy.

Aged↗