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PubMed1995

Determinants of furosemide delivery to its site of action.

We have investigated the pharmacokinetic determinants of delivery of furosemide to its site of action in the renal tubules in patients and healthy volunteers. The bioavailability of furosemide is low and variable. Patients with renal disease may also have a low renal extraction of furosemide. In clinically relevant concentrations the free fraction of furosemide is inversely proportional to the plasma albumin concentration. A change in the free fraction of furosemide will change Clr, Clnr, and Vd in the same direction and that will cause minimal changes in the excretion rate of furosemide and its t1/2. A change in RBF will change the secretory clearance of furosemide to the same proportion and consequently also the excretion rate and its t1/2.

Biological Availability↗

PubMed1976

Diuretic and clinical effects of low-dose furosemide in congestive heart failure patients.

A dose of 20 mg furosemide in congestive heart failure patients produces a significant diuretic and natriuretic effect. The peak effect was observed within 60-120 minutes in most patients. Twenty-four congestive heart failure patients were hospitalized for evaluation and management. Two withdrew from the study, and in three there was a prolonged (several months) remission of manifestations of congestive heart failure. The remaining 19 patients were treated with 40 mg furosemide per day for a four-week period. Six required 80 to 120 mg furosemide per day, and 13 were controlled on 40 mg per day. On 20 mg twice per day, one of the 13 patients dropped out voluntarily, two required a higher dose of furosemide, and 10 were controlled on this regimen for a four-week period. When dosage was reduced to 20 mg per day, five of the ten patients were controlled for an additional four weeks or longer, and five required higher doses of furosemide. Results of this study suggest that in congestive heart failure patients, 20 mg furosemide per day has significant diuretic and natriuretic properties. It also demonstrates that a number of patients with cardiac decompensation can be controlled on a relatively low dosage of furosemide and that periodic reevaluation of clinical status and diuretic requirements for maintenance therapy is of critical importance in management of patients with congestive heart failure.

Adult↗

PubMed1994

Furosemide enhances the release of endothelial kinins, nitric oxide and prostacyclin.

Despite a wealth of data, the mechanism of the direct dilator effect of furosemide on the systemic arterial and venous systems is far from being satisfactorily understood. Therefore, we investigated whether furosemide is capable of stimulating the production of the endogenous vasodilators nitric oxide and prostacyclin in primary cultured bovine aortic endothelial cells by an enhanced synthesis and release of endothelium-derived kinins. Nitric oxide production was assessed in terms of intracellular guanosine cyclic-3',5' monophosphate accumulation; kinin and prostacyclin release were determined by specific radioimmunoassays. Furosemide concentration- and time-dependently increased the formation of nitric oxide and prostacyclin. Maximal increases of both autacoids were already obtained after a 5-min incubation with 3 x 10(-7) to 10(-6) mol/l of furosemide. In the same concentration range, furosemide led to an enhanced release of kinins into the supernatant of the cells. This observation was supported by the inhibitory effect of the specific B2 kinin receptor antagonist icatibant (Hoe 140) on the furosemide-induced increase of nitric oxide and prostacyclin. Thus the hemodynamic effects, and in particular the direct early dilator effect, of furosemide may be explained in part by an enhanced endothelial synthesis and release of bradykinin and related kinins, which in turn stimulates endothelial autacoid formation via B2 kinin receptor activation.

Animals↗

PubMed1993

Effect of furosemide and weight carriage on energetic responses of horses to incremental exertion.

The effect of furosemide-induced weight loss on the energetic responses of horses to running was examined in a 3-way crossover study. Eight 2- to 3-year-old Standardbred mares received, in random order, 10 ml of saline solution 4 hours before running on a treadmill (control trial, C); or, during 2 trials, 1 mg of furosemide/kg of body weight, i.v., 4 hours before running. During one of the trials when the horses received furosemide, they carried weight equal to that lost over the 3.75 hours after furosemide administration while running (furosemide-loaded, FL), and during the other trial they did not carry weight equal to that lost after furosemide administration (furosemide-unloaded, FU). Horses performed an incremental exercise test on a treadmill during which rates of oxygen consumption (VO2) and carbon dioxide production (VCO2) were measured, respiratory exchange ratio was calculated, and blood samples were collected for determination of mixed venous plasma lactate concentration and arterial and mixed venous oxygen saturation. Furosemide treatment caused significantly (P < 0.001) greater weight loss than did saline administration; mean +/- SEM weight loss (exclusive of fecal loss) was 1.6, 8.8, and 10.2 kg (SEM = 2.0) for C, FL, and FU trials, respectively. The speed at which peak VO2 was achieved was 9.31, 9.56, and 9.50 (SEM = 0.16) m/s, respectively, time to fatigue was 547, 544, and 553 (SEM = 26) seconds, respectively, and the highest speed attained was 10.3, 10.2, and 10.2 (SEM = 0.2) m/s, respectively. Mean peak rate of oxygen consumption was 130.7, 129.6, and 129.6 (SEM = 1.9) ml/min/kg, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Effects of angiotensin-converting enzyme inhibition on renal adaptations to acute furosemide administration in conscious rats.

During administration of loop diuretics the initial volume depletion activates Na-conserving mechanisms, which reduces glomerular filtration rate (GFR) and stimulates renal tubular reabsorption of Na and water. By i.v. infusion of the angiotensin-converting enzyme inhibitor enalaprilat (100 micrograms bolus; 100 micrograms/h) we examined the role of angiotensin II for the compensatory renal responses occurring during furosemide administration in conscious rats. To evaluate the significance of hydration for the compensatory renal effects of angiotensin II, experiments were performed in groups of rats with or without i.v. replacement of urinary volume losses. Furosemide was administered i.v. (6 mg/kg/h) for 3 1/2 hr. Furosemide infusion produced a short-lasting increase in urine flow rate, Na, Li and K excretion after which the renal excretion rates returned toward pretreatment levels, along with significant reductions in effective renal plasma flow and GFR and increases in effective filtration fraction and effective renal vascular resistance. Sustained increases in urine flow and urinary excretion rates of Na, Li and K were observed in absence of changes in GFR in rats given furosemide with volume replacement. Enalaprilat did not alter the tubular response to furosemide during either euvolemia or volume depletion. However, enalaprilat attenuated the furosemide-induced increases in effective filtration fraction and effective renal vascular resistance. It is concluded that angiotensin II is not essential for the compensatory response of decreased GFR and increased tubular Na reabsorption. However, angiotensin II is an important mediator of renal vasoconstriction during furosemide infusion.

Absorption↗

PubMed1977

Stimulation of pancreatic secretion of water and electrolytes by furosemide.

The effect of furosemide on secretin-stimulated pancreatic secretion was examined in 12 normal subjects using a perfusion method to quantitate pancreatic output. During continuous secretin infusion (0.9 U per kg per hr), secretory volume rose to a steady state level of 32.5 +/- 10.2 ml per min. When a bolus injection of furosemide (20 mg) was given during continuous secretin infusion, mean secretory volume increased further to a maximum value of 110 +/- 14.7 ml per min. Similarly, the outputs of bicarbonate, sodium, and chloride increased significantly after furosemide, compared to values obtained with secretin infusion alone. Total bilirubin output fell after furosemide, suggesting that the effect of furosemide on secretory volume and electrolyte output was not due to a stimulatory effect on bile flow. Furosemide also had no effect on duodenal water transport. These observations demonstrate that furosemide stimulates pancreatic secretion of water and electrolytes, possibly via inhibition of pancreatic ductal absorption of sodium.

Adult↗

PubMedDate not supplied

Comparison of 6-hour infusion versus bolus furosemide in premature infants.

STUDY OBJECTIVE: To compare the renal, hemodynamic, and pulmonary effects of a 6-hour infusion of furosemide versus conventional bolus administration in premature infants. DESIGN: Prospective, blinded, placebo-controlled, randomized study. SETTING: Two level III, university-based neonatal intensive care units. PATIENTS: Thirty premature infants with significant lung disease, requiring furosemide after a red cell infusion. INTERVENTIONS: Infants received furosemide 1 mg/kg over 2 minutes, followed by a 6-hour placebo infusion, or a small loading dose of 0.1 mg/kg, followed by a slow infusion of 0.9 mg/kg over 6 hours. Serum and urine were collected to determine percentage fractional excretion of sodium (FENa). MEASUREMENTS AND MAIN RESULTS: Urine output and blood pressure were measured every 2 hours after furosemide administration. Percentage FENa was measured immediately before furosemide and compared with pooled urine from an 8-hour collection after furosemide administration. Serum sodium, creatinine, and calcium were measured before and 24 hours after drug administration. Mean airway pressure and percentage inspired oxygen were compared before, 1-4 hours after, and 4-12 hours after drug administration. No significant differences were detected between the two methods of drug administration. CONCLUSION: Our data suggest that a 6-hour infusion of furosemide does not offer substantial clinical advantage over conventional bolus administration in premature infants when focusing on urine output, blood pressure, FENa, or pulmonary effect.

Blood Pressure↗

PubMedDate not supplied

Assessment of the bronchodilator effect of inhaled furosemide compared to salbutamol in asthmatic patients.

To compare the bronchodilator effects of high-dose inhaled furosemide, we studied 80 patients who were nonsmokers presenting some degree of bronchial obstruction. Of these patients, 40 were given salbutamol (1%) aerosol and the remaining 40 were given furosemide aerosol (100 mg). Respiratory functional tests were conducted at 10 min and 30 min, as well as measurement of pulse and blood pressure. Patients in the salbutamol group showed an improvement in forced expiratory volume (FEV1) of 7.9% at 10 min and 30 min, and the group given furosemide improved 6.9% (p > 0.05). Systolic blood pressure showed a slight increase of 2 mmHg in the salbutamol group and a decrease of 6 mmHg in the furosemide group (p < 0.05). The same occurred for diastolic blood pressure (p < 0.05). Pulse increased from 73.7 to 75.2 beats per min in the salbutamol group; however, in the furosemide group, pulse declined from 73.7 to 71.8 beats per min (p < 0.05). We conclude that furosemide at a dose of 100 mg has the same bronchodilator effect as salbutamol, as measured by FEV1 and forced expiratory flow of 25% to 75%. Furosemide was also related with a mild hypotensive effect and drop in pulse.

Administration, Inhalation↗

PubMed2002

Furosemide for transient tachypnea of the newborn.

BACKGROUND: Transient tachypnea of the newborn results from delayed clearance of lung liquid and is a common cause of admission of full term infants to neonatal intensive care units. The condition is particularly common after elective Caesarean section. Conventional treatment involves appropriate oxygen administration and continuous positive airway pressure in some cases. Most infants receive antibiotic therapy. Hastening the clearance of lung liquid should shorten the duration of the symptoms and reduce complications. OBJECTIVES: To determine whether furosemide reduces the duration of oxygen therapy and respiratory symptoms and shortens hospital stay in term infants with transient tachypnea of the newborn. SEARCH STRATEGY: We searched the Cochrane Controlled Trials Register, PubMed and EMBASE. The primary author and experts in the field were contacted. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials. Infants of less than 7 days of age, born after 37 or more weeks of gestation with the clinical picture of transient tachypnea of the newborn. Intravenous, oral or nebulized furosemide compared to placebo or no diuretic in the first 7 days. DATA COLLECTION AND ANALYSIS: Two reviewers assessed trial quality in each potentially eligible manuscript and two reviewers extracted data. MAIN RESULTS: Searching revealed only one randomised trial which was methodologically sound. This recruited 50 infants with transient tachypnea. Infants were randomised to receive oral furosemide 2 mg/kg followed by 1 mg/kg 12 hours later, or placebo. Weight loss in the first 24 hours was greater in the furosemide treated group but there was no evidence of a difference between the groups in duration of tachypnea or severity of symptoms or length of hospitalization. The study was methodologically satisfactory. REVIEWER'S CONCLUSIONS: Oral furosemide cannot be recommended as treatment for transient tachypnea of the newborn and it should not be used unless additional data become available. The question remains as to whether intravenous furosemide given to the infant (or even to the mother before Caesarean section) might shorten the duration of the illness. As elective Caesarean section continues at a high level, these two interventions might be worthy of trials.

Administration, Oral↗

PubMed1979

Furosemide-induced adverse reactions in cirrhosis of the liver.

Furosemide is frequently used for ascites and causes adverse reactions (AR). In an intensive prospective drug monitoring study of 1,920 patients, 172 (8.9%) had cirrhosis of the liver and received furosemide. Mean age was 53 years, and 66.3% were male; and 87% had alcoholic cirrhosis. Eighty-eight (51.2%) had 221 events that by consensus of the monitoring team and attending physicians were either definitely of probably related to furosemide. No AR was fatal but 24% of patients had severe reactions. Almost all reactions were dose-related (96%). The most common were electrolyte disturbances (23.3% of patients) and volume depletion (14%). Furosemide-induced coma occurred in 20 (11.6%) patients and was more frequent in patients with prior hepatic encephalopathy (p less than 0.0005). Higher total doses (p less than 0.001), hyerbilirubinemia (p less than 0.05), prolonged prothrombin time (p less than 0.02), and longer hospital stay (p less than 0.001) were associated with higher frequencies of AR to furosemide. The frequency of hypokalemia did not decrease when potassium chloride or potassium-sparing diuretics were added to furosemide therapy. Frequdncy of AR did not correlate with age, sex, renal impairment, serum albumin, transaminase, or alkaline phosphatase.

Administration, Oral↗

PubMedDate not supplied

Diuretic and antihypertensive actions of furosemide.

Furosemide (4 - chloro - N - (2 - furyl - methyl) - 5 - sulfamoylanthranilic acid) caused a prompt increase in sodium, potassium, and chloride excretions in patients with chronic congestive heart failure. Doses of 50, 100, and 200 mg orally produced progressively increasing diuretic responses. When given over a period of one week to patients with essential hypertension, furosemide in doses of 100 to 200 mg orally per day caused a significant decrease in systolic and diastolic pressure. A significant lowering of blood pressure was also demonstrated in hypertensive patients treated with furosemide over a period of one year. Biochemical alterations during furosemide administration included elevation of fasting blood sugar levels in patients with diabetes mellitus, increased uric acid concentrations, and lowering of plasma potassium levels. All biochemical changes were reversible when the drug was discontinued. No evidence of hematologic or hepatic dysfunction was observed in 16 patients who received furosemide in a daily dose of 40 to 160 mg over a 52-week period. Although furosemide has been recommended primarily for the treatment of edema refractory to other forms of therapy, long-term studies indicate that the drug is also capable of maintaining patients with chronic congestive heart failure without producing serious systemic toxicity.

Aged↗

PubMed1980

Blunting of furosemide diuresis by aspirin in man.

Experiments were performed on humans to study the blunting on the diuretic action of furosemide by prostaglandin synthetase inhibitors. Maximal water diuresis was instituted. At the peak of urine flow, clearance periods were performed during baseline conditions and repeated after the injection of aspirin and, subsequently, of furosemide. Control subjects did not receive aspirin. Urine flow rate (V), Cosm, and Na excretion (UNa) . V were significantly lower when the administration of the diuretic had been preceded by that of aspirin. In the absence of furosemide, however, aspirin did not influence renal hemodynamics nor Na and water reabsorption. Therefore, the same experimental protocol was repeated in paired experiments where each normal subject served as his own control, being studied twice, in the presence and absence of aspirin, respectively. The average changes in water and Na excretion induced by furosemide were not different when the patients were pretreated with aspirin as compared with those measured in the absence of prostaglandin inhibition. Changes occurring in individual experiments were significantly correlated (r = 0.95, P less than 0.01) with those in calculated furosemide clearance. Since aspirin, indomethacin, and meclophenamate are secreted by the organic acid transport system of the proximal tubule, competition for a common secretory mechanism, rather than prostaglandin inhibition, could mediate the blunting of furosemide diuresis.

Aspirin↗

PubMedDate not supplied

Long-term bumetanide treatment of renal edema. Comparison with furosemide.

In an open, parallel, randomized study, bumetanide was compared with furosemide in the long-term management of patients with severe renal edema. The doses used were: bumetanide, 1 mg; furosemide, 40 mg. Graded increases were administered to daily maxima of 10 mg bumetanide and 400 mg furosemide. The efficacy of parameters measured were: weight, recumbent and standing pulse and blood pressure, abdominal girth, and estimated degree of malaise or fatigue when present. Safety parameters included: physical examination, CBC and platelets, blood chemistry, chemical and microscopic urinalysis, creatinine clearance, air audiometry, and ophthalmic examination. Weight loss and reduction of edema and of mean arterial pressure occurred in both groups of patients. In the bumetanide-treated group, weight loss was statistically significant at most observation times during the first eight weeks, and reduction in edema was significant throughout the trial (P less than 0.05). Reduction in these parameters in the furosemide-treated patients was not statistically significant. However, the differences between the diuresis and other changes produced by the two drugs were not significant. While reduction in the mean arterial pressure of patients on bumetanide was significant (P less than 0.05), the difference with that in the furosemide treatment group was not significant. Serum electrolyte abnormalities were infrequent. All patients tolerated the drug trial well. No deterioration in audiometry occurred in any patients, including 12 who entered the trial with abnormal air audiograms. Both drugs appear to be equally safe. While a daily dose of 4.2 mg bumetanide is highly effective in severe renal edema, the design of the study did not warrant definitive conclusion regarding comparative efficacy with furosemide.

Adult↗

PubMedDate not supplied

Protein binding and bilirubin displacing properties of bumetanide and furosemide.

We evaluated the protein binding and comparative bilirubin displacing properties of bumetanide and furosemide in pooled adult and cord serum by ultrafiltration (UF), difference spectra (DS), and Sephadex Gel-25 (SG-25) filtration. By UF, bumetanide was found to be highly protein bound (96.7 per cent), similar to published data on furosemide (97.2 per cent). SG-25 filtration and DS showed an equal shift to the left of the free bilirubin curve when bumetanide and furosemide were added to serum, in adult and cord, at equimolar concentrations and both shifted the free bilirubin curve equally. Bilirubin displacement was greater (P less than 0.001) in cord than in adult serum with both drugs. When "presumed therapeutic" plasma concentration of furosemide (1-2 mg/liter) and bumetanide (0.5 mg/liter) were compared, it was noted that bumetanide displaced significantly less (P less than 0.001) bilirubin from albumin in cord blood than furosemide. Hence, bumetanide displaces less bilirubin at "presumed therapeutic" plasma concentrations than furosemide, suggesting that it might be more prudent to use bumetanide in sick neonates with hyperbilirubinemia. Data also provide evidence that bilirubin displacement by both diuretics is greater in neonatal serum albumin than in the adult.

Adult↗

PubMed1992

Chronopharmacology of furosemide in the elderly.

The authors have previously reported the time-dependent change in the diuretic effects of furosemide, a loop diuretic agent, in young and middle-aged subjects. The current study was undertaken to examine an influence of aging on this chronopharmacologic phenomenon. Ten milligrams furosemide was given intravenously to 12 elderly subjects (greater than 70 years of age) at 9:00 AM (day trial) or at 9:00 PM (night trial) by a cross-over design. One-hour urine samples were collected for 3 hours after each administration, and urine volume and urinary excretions of sodium and furosemide were determined. Urine volume and urinary sodium excretion increased after furosemide administration. Contrary to the findings in the young and middle-aged subjects, no significant differences were observed in these parameters at any observation period between the day and night trials in the elderly subjects. Urinary furosemide excretion of the day and night trials did not significantly differ. These results suggest that the chronopharmacologic profiles of furosemide are altered in the elderly.

Aged↗

PubMed1990

Toxicology and carcinogenicity studies of diuretics in F344 rats and B6C3F1 mice. 2. Furosemide.

Toxicology and carcinogenesis studies of furosemide, a widely used diuretic, were conducted by administering diets containing the drug to both sexes of F344 rats and B6C3F1 mice in 14-day, 13-week and 2-year studies. Deaths occurred among rats and mice receiving diets containing 46,000 ppm furosemide in 14-day studies, and animals given diets containing lower concentrations lost weight. No deaths were seen in 13-week studies using top concentrations ranging from 10,000 to 20,000 ppm, but animals at higher concentrations had lower weight gains than controls. Nephrosis in rats and mice was the only significant compound-related lesion observed in the prechronic studies. In 2-year studies, rats received diets containing 0, 350 or 700 ppm furosemide and mice received diets containing 0, 700 or 1400 ppm furosemide. Survival of dosed and control rats of both sexes and male mice was similar; survival of high-dose female mice was lower than controls. Nephropathy was increased in male rats and in male and female mice. In female mice, increased malignant tumors of the mammary gland were associated with furosemide administration. In male rats, marginal increases in tubular cell neoplasms of the kidney and in meningiomas of the brain were observed in dosed animals, but these were not considered to be related clearly to exposure to furosemide.

Adenoma↗

PubMed1984

Comparative bioavailability of two furosemide formulations in humans.

Twelve healthy male volunteers participated in a balanced crossover comparison of a brand-name and generic furosemide formulations. Each treatment was given as a single 40-mg tablet following an overnight fast. Furosemide concentrations in plasma and urine were determined up to 24 h after treatment; urine output and urinary sodium excretion were also measured. In comparison with the brand-name tablets, generic furosemide was significantly less bioavailable. Using a 95% confidence interval approach, generic furosemide gave up to 66% lower maximum furosemide plasma levels, up to 52% less area under the plasma level curve to infinite time, and up to 37% less urinary recovery of furosemide. Comparison of the effect of the two treatments was a less sensitive measurement of bioequivalence. Confidence intervals for differences in urinary output and sodium excretion over the period of maximum effect (0-4 h) were, however, asymmetrical, and pharmacodynamic differences between treatments were significant at the 10% level.

Adolescent↗

PubMedDate not supplied

Effect of early furosemide administration in neonates with respiratory distress syndrome.

The effect of early furosemide-induced diuresis was prospectively evaluated in 39 neonates less than 24 hr of age with clinical respiratory distress syndrome (RDS) who received either four doses of furosemide (1 mg/kg) or no diuretic. Measurements of FiO2 alveolar-arterial oxygen gradient (P[A-a]O2), peak inspiratory pressure (PIP), and urine output as a fraction of intake (O/I) were averaged for every 8 hr. The furosemide group overall showed a significant decrease (P less than 0.01) in FiO2, P[A-a]O2, and PIP with an earlier (32 hr vs 52 hr) and more pronounced diuresis (35% greater O/I) when compared to the controls. This effect was accentuated in the subgroup with 1,000-1,500 g birth weight (significantly lower FiO2 and P(A-a)O2 from 16 to 48 hours), while no increase in urine output was observed for the infants weighing less than 1,000 g. A significant reduction in supplemental oxygen and need for ventilatory support at 96 hr of age was observed in the furosemide-treated, less than 1,500-g infants. The incidence of patent ductus arteriosus was not increased following furosemide therapy, and no significant difference in echocardiographic parameters was observed in 21 infants from both groups, who were followed daily during the first week of life. This study suggests that early furosemide-induced diuresis, particularly in infants weighing 1,000-1,500 g at birth, promotes improvement in pulmonary functions in RDS and leads to faster reduction in oxygen and ventilatory support.

Birth Weight↗