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PubMedDate not supplied

Furosemide: progress in understanding its diuretic, anti-inflammatory, and bronchodilating mechanism of action, and use in the treatment of respiratory tract diseases.

Accumulated experimental and clinical data suggest that adrenocorticosteroids and/or endogenous ouabain-like substances may play an important role in the mechanism of furosemide diuretic action. It was reported that the drug is highly bound in the adrenals, lungs, kidney, spleen, and liver. In patients with liver cirrhosis, furosemide exerted a markedly decreased natriuretic effect compared with normal subjects, and the plasma levels of circulating endothelin and atrial natriuretic factor (ANF) were significantly elevated. In neonates, after administration of furosemide, the urinary excretion of endothelin-1 and aldosterone increased markedly, and it is known that endothelin may release ANF and aldosterone in a dose-dependent manner. Furosemide was used to stimulate zona glomerulosa, whereas ANF decreased the production of steroids in zona glomerulosa and fasciculata cell culture owing to stimulation by various factors. Because the concomitant use of ANF and furosemide appeared to be diuretically effective in newborns after cardiac surgery, one may suggest that furosemide competes with ANF for its effects on the adrenals. Furosemide administered by inhalation exerted a protective effect on allergic and perennial nonallergic rhinitis and was effective in preventing the postsurgical recurrence of nasal polyposis. The drug can also be used as an antiasthmatic agent. In preterm ventilator-dependent infants with chronic lung disease, aerosolized furosemide improved pulmonary function with no marked effect on diuresis. In adults and children with asthma, furosemide exerted a protective effect against bronchoconstriction induced by several indirect stimuli similar to that of disodium cromoglycate or nedocromil. Aerosolized furosemide had a preventive effect also on bronchoconstriction induced by inhaled lysine acetylsalicylate in patients with aspirin-sensitive asthma. In high-dose beclomethasone-dependent asthma, inhaled lysine acetylsalicylate and furosemide exerted a mutually potentiating antiasthmatic activity, allowing considerable sparing of the inhaled steroid. It is proposed that this effect may be explained by the corticosteroid-sparing action of lysine released from the lysine acetylsalicylate molecule because similar beneficial effects were also obtained after the concomitant use of epsilon-aminocaproic acid (whose chemical structure is almost the same as that of lysine) and prednisone. Furosemide exhibited an anti-inflammatory effect through inhibition of production and release of cytokines interleukin (IL)-6, IL-8, and tumor necrosis factor-alpha from peripheral mononuclear cells, which may have a beneficial effect on local inflamed tissue imbalance in the ratio of different cytokines, thus improving the sensitivity of target cells to endogenous glucocorticosteroids.

Adult↗

PubMed2004

Furosemide responsiveness, non-adherence and resistance during the chronic treatment of heart failure: a longitudinal study.

BACKGROUND AND METHODS: Loop diuretic therapy is an essential part of chronic systolic heart failure (CH)F management, yet response to treatment can be variable. We analysed diuretic responsiveness in 39 stable patients with CHF in the community over 2 years. We measured serum ACE as a marker of adherence to ACE inhibitor therapy and urinary furosemide as a marker of diuretic adherence and action. Patients' clinical outcome was stable and not hospitalized (Group 0); alive but hospitalized (Group 1); or dead during follow up (Group 2). RESULTS: Prescribed furosemide dose was variable (range 20-370 mg generally once daily) and progressive dose increments were common. Failed furosemide adherence (defined as < 10% of a dose excreted in 24 h urine where normal average excretion = 50% of an oral dose) during static prescribed dosing was infrequent relative to all days of therapy; yet was equally common across all outcome groups. Furosemide non-adherence appeared to be independent of non-adherence with ACE inhibitor (as marked by serum ACE activity > 20 U l(-1)) treatment. Furosemide responsiveness (mm of sodium excreted per mg furosemide in urine) showed no relationship to prescribed dose and paradoxically tended to rise in patients with higher basal aldosterone concentrations. Furosemide responsiveness fell by outcome class despite increased dose. Within-patient responsiveness remained relatively constant although highly variable between individuals. CONCLUSIONS: Furosemide responsiveness varied greatly between individuals but was constant within an individual. Non-adherence with furosemide was less common among those who died and appeared to occur at different time points from non-adherence with ACE inhibitor treatment, which was slightly more common in all outcome groups. Patients who died were prescribed higher furosemide doses and had greater furosemide excretion yet had similar sodium excretion. The main factor in response to chronic furosemide therapy was intrarenal diuretic resistance. Gross non-adherence was less important.

Administration, Oral↗

PubMed1975

Renal secretion of [35-S]furosemide and depression by albumin binding.

It was determined by use of [35-S]furosemide and an ultrafiltration procedure that furosemide is bound extensively to bovine serum albumin. When 500 muM furosemide and albumin at a concentration of 2.5 g/100 ml were used, approximately 90% of the drug was bound. With this same amount of furosemide, but with 3 times as much albumin, binding was about 98%. Using a 25-fold lower concentration of furosemide, 20 muM, binding was nearly 98% with 2.5 g albumin/100 ml, and was over 98% with 7.5 g albumin/100 ml. These same concentrations of furosemide and albumin were used to investigate the excretory and secretory rates of [35-S]furosemide in the isolated perfused rat kidney. Tubular clearance (i.e., secretion) of [35-S]furosemide was inversely related to the concentration of albumin in the perfusate. In kidneys perfused without albumin, tubular clearance of the drug was 6-20 times that found when 2.5 or 7.5 g albumin/100 ml, respectively, was used. Probenecid, with or without albumin, reduced the clearance of furosemide to that of its filtration rate. It is concluded that at physiological albumin concentrations, a very small fraction of circulating furosemide will be available for filtration, and tubular-fluid and urinary furosemide will arise predominantly from secretion. Because of extensive binding of furosemide to albumin, the renal secretory process itself is depressed, and the rate of secretion will be dependent, in part, on the concentration of unbound drug.

Aminohippuric Acids↗

PubMed1986

Pharmacodynamic determinants of furosemide diuretic effect in children.

The pharmacodynamics of 1 or 2 mg/kg of furosemide administered as a single dose orally or intravenously were studied in 34 hospitalized children (ranging in age from 9 days to 16.5 years) with normal renal function. These patients were divided into 3 groups: infants (furosemide 1 mg/kg, intravenously); children with steroid-responsive nephrotic syndrome (furosemide 2 mg/kg, orally and intravenously); patients with urinary tract infections and mild hypertension (furosemide 2 mg/kg, orally). A statistically significant positive linear relationship was found in these groups between the furosemide urinary excretion rate and urine flow rate, but log dose-response curves to furosemide were found to vary between the groups of patients studied. This variability reflects differences in the relationship between the amounts of furosemide reaching active sites and the pharmacodynamic effect of the drug. No sigmoid-shaped log dose-response curve (i.e., one approaching a zero response at very low furosemide urinary excretion rates, and a maximum response at very high excretion rates) was attained in this study. This suggests that the capacity of the kidney tubules to respond diuretically to the administered doses of furosemide was not exceeded in the studied patients. However, in the infants, a very steep log dose-response curve to a 1 mg/kg intravenous dose of furosemide suggests that higher doses may not result in a significant increase in diuretic response in infants with reasonably normal renal function. The lowest mean furosemide urinary excretion rate associated with significant diuresis was 0.58 +/- 0.33 micrograms/kg/min. Also, a significant correlation was found between the amount (in milligrams), of furosemide excreted in the urine during the first 6 h after administration and the urine volume collected during that time (r = 0.71; p less than 0.001; number of measurements = 43).

Administration, Oral↗

PubMed1999

Clinical consequences of the biphasic elimination kinetics for the diuretic effect of furosemide and its acyl glucuronide in humans.

This review discusses the possibility of whether furosemide acyl glucuronide, a metabolite of furosemide, contributes to the clinical effect of diuresis. First an analytical method (e.g. HPLC) must be available to measure both parent drug and furosemide acyl glucuronide. Then, with correctly treated plasma and urine samples (light protected, pH 5) from volunteers and furosemide-treated patients, the kinetic curves of both furosemide as well as its acyl glucuronide can be measured. The acyl glucuronide is formed in part by the kidney tubules and it is possible that the compound is pharmacologically active through inhibition of the Na+/2Cl-/K+ co-transport system; up to now the mechanism of action has been solely attributed to furosemide. The total body clearance of furosemide occurs by hepatic and renal glucuronidation (50%) and by renal excretion (50%). Enterohepatic cycling of furosemide acyl glucuronide, followed by hydrolysis, results in a second and slow elimination phase with a half-life of 20-30 h. This slow elimination phase coincides with a pharmacodynamic rebound phase of urine retention. After each dosage of furosemide, there is first a short stimulation of urine flow (4 h), which is followed by a 3-day recovery period of the body. The following clinical implications arise from study of the elimination kinetics of furosemide. Repetitive dosing must result in accumulation of the recovery period. Accumulation of furosemide and its acyl glucuronide in patients with end-stage renal failure results from infinite hepatic cycling. Impaired kidney function may result in impaired glucuronidation and diuresis. While kidney impairment normally requires a dose reduction for those compounds which are mainly eliminated by renal excretion, for diuretics, a dose increment is required in order to maintain a required level of diuresis. The full clinical impact of the accumulation of furosemide and its acyl glucuronide in patients with end-stage renal failure has to be determined.

Chromatography, High Pressure Liquid↗

PubMed1997

Pulmonary effect of inhaled furosemide in ventilated infants with severe bronchopulmonary dysplasia.

BACKGROUND: When administered parenterally, furosemide, a loop diuretic, results in improved lung compliance and decreased airway resistance in infants with bronchopulmonary dysplasia (BPD). However, furosemide-induced diuresis results in hypokalemia, chloride deficiency, hypercalciuria, nephrocalcinosis, and rickets. In patients with asthma, inhaled furosemide has recently been demonstrated to inhibit the bronchoconstrictive effects of exercise, cold air hyperventilation, and antigen challenge. We hypothesized that inhaled furosemide will result in improved pulmonary mechanics in ventilated infants with BPD and will prevent the systemic complications of parenteral furosemide. OBJECTIVE: To determine the efficacy and safety of a single dose of inhaled furosemide on pulmonary mechanics in infants with severe BPD who are ventilator dependent at 21 days of age. DESIGN AND METHODS: A randomized, double-blind, crossover study was performed on 9 infants with BPD, each serving as his own control. Each patient was randomized to receive an aerosol dose of furosemide (1 mg/kg in 2 mL of saline) or placebo (2 mL of saline) on the first day of the study and the other agent the following day of the study. Pulmonary mechanics were measured before and 1 and 2 hours after the inhalation using the Pulmonary Evaluation and Diagnostics System. RESULTS: Gestational age (mean +/- SEM) was 29 +/- 1 weeks; birth weight was 1.1 +/- 0.1 kg; age at study was 47 +/- 6 days; and weight at study was 1.8 +/- 0.2 kg. There was no significant change in the pulmonary function measurements before treatment and 1 or 2 hours after treatment with either placebo or furosemide. Baseline and 2-hour values were: dynamic compliance (mL/ cm H2O per kilogram): 0.46 +/- .03 to 0.50 +/- .03 (placebo) and 0.50 +/- 0.02 to 0.51 +/- 0.02 (furosemide); dynamic resistance (cm H2O/L per second): 118 +/- 9 to 106 +/- 7 (placebo) and 111 +/- 8 to 105 +/- 7 (furosemide); and tidal volume (mL/kg): 8.6 +/- 0.5 to 8.9 +/- 0.5 (placebo) and 8.9 +/- 0.2 to 9.4 +/- 0.3 (furosemide). CONCLUSION: We conclude that, under the conditions of our study, a single dose of 1 mg/kg inhaled furosemide does not improve the pulmonary mechanics in ventilator-dependent infants with severe BPD.

Administration, Inhalation↗

PubMedDate not supplied

Pharmacokinetics and pharmacodynamics of furosemide after oral administration to horses.

Furosemide is the most common diuretic drug used in horses. Furosemide is routinely administered as IV or IM bolus doses 3-4 times a day. Administration PO is often suggested as an alternative, even though documentation of absorption and efficacy in horses is lacking. This study was carried out in a randomized, crossover design and compared 8-hour urine volume among control horses that received placebo, horses that received furosemide at 1 mg/kg PO, and horses that received furosemide at 1 mg/kg IV. Blood samples for analysis of plasma furosemide concentrations, PCV, and total solids were obtained at specific time points from treated horses. Furosemide concentrations were determined by reversed-phase high-performance liquid chromatography with fluorescent detection. Systemic availability of furosemide PO was poor, erratic, and variable among horses. Median systemic bioavailability was 5.4% (25th percentile, 75th percentile: 3.5, 9.6). Horses that received furosemide IV produced 7.4 L (7.1, 7.7) of urine over the 8-hour period. The maximum plasma concentration of 0.03 microg/mL after administration PO was not sufficient to increase urine volume compared with control horses (1.2 L [1.0, 1.4] PO versus 1.2 L [1.0, 1.4] control). There was a mild decrease in urine specific gravity within 1-2 hours after administration of furosemide PO, and urine specific gravity was significantly lower in horses treated with furosemide PO compared with control horses at the 2-hour time point. Systemic availability of furosemide PO was poor and variable. Furosemide at 1 mg/kg PO did not induce diuresis in horses.

Administration, Oral↗

PubMed1987

Indomethacin antagonizes furosemide's intratubular effects during loop segment microperfusion.

To determine if indomethacin antagonizes the effect of intraluminal furosemide, superficial loop segments were microperfused from latest proximal to earliest distal tubules at 20 nl/min with 10(-5) M furosemide in rats treated with indomethacin or vehicle. Base-line loop chloride reabsorption was determined in the presence and absence of indomethacin in a third and fourth group perfused with a similar solution with furosemide omitted. Arterial pressure, whole kidney inulin clearance and urinary chloride excretion were not different among groups. Fractional loop chloride reabsorption was less (P less than .05) in vehicle-treated rats perfused with furosemide than in time control rats perfused without furosemide (30.8 +/- 2.8 vs. 50.3 +/- 2.8%). Fractional chloride reabsorption was greater (P less than .05) in furosemide-perfused loops of indomethacin-treated rats than furosemide-perfused loops of vehicle-treated rats (44.2 +/- 1.9 vs. 30.8 +/- 2.8%). Addition of 10(-4) M prostaglandin E2 to perfusate did not potentiate furosemide's effect in vehicle-treated rats but restored furosemide's potency in indomethacin-treated rats. Thus, indomethacin had no effect on base-line loop chloride uptake but attenuated furosemide's luminal effect. This response could be reversed by luminal prostaglandin E2. This study demonstrates that indomethacin antagonizes furosemide's tubular effects in the absence of furosemide-induced vasodilatation.

Absorption↗

PubMed1985

Influence of heart failure and sodium content in the diet on the natriuretic response to furosemide in hamsters.

The aims of this study were to investigate the influence of heart failure and dietary sodium content on the natriuretic effect of furosemide. Ten healthy Golden Syrian hamsters (HH) and 10 hamsters with a cardiomyopathy (CMH) were maintained on a normal sodium diet (NSD) and an equal number of animals on sodium deficient diet (SDD) for a minimum of 40 days. Three experiments were conducted on days 1, 20 and 40. Each experiment started with a 24-hour urine collection (control), followed by the administration of 5 mg/kg of furosemide i.p. and a second 24-hour urine collection and finally, the administration of 2 mg/kg of indomethacin i.p. followed 30 minutes later by 5 mg/kg of furosemide and a 24-hour urine collection as well as blood sampling. Sodium, creatinine, furosemide and arginine vasopressin (AVP) were measured in the urine and sodium, creatinine and AVP in plasma. After 134 days on a SDD, four HH resumed a NSD and the response to furosemide was again assessed after 12 days. Our results indicate that the natriuretic response to furosemide is higher in CMH than in HH. The SDD tended to increase the response to furosemide in HH as well as in CMH. Indomethacin did not influence the response to furosemide under any experimental condition. In four HH the increment in the fractional excretion of sodium in response to furosemide was 0.88 +/- 0.21% after 134 days on SDD and decreased to 0.35 +/- 0.12 (p less than 0.05) after 12 days on NSD. In all cases urinary excretion of furosemide was similar. Plasma AVP was higher in CMH and was not influenced by the SDD. In conclusion, SDD as well as cardiomyopathy with congestive heart failure do not decrease the natriuretic effect of furosemide and may not be a cause in the variability of the natriuretic response to furosemide.

Animals↗

PubMed1999

Role of plasma protein binding on renal metabolism and dynamics of furosemide in the rabbit.

To investigate the influence of furosemide plasma protein binding on its kinetics and dynamics, the kinetics of furosemide was studied in the presence of a protein binding displacer, warfarin, and in hypoalbuminemic rabbits. Compared with controls, in anesthetized rabbits pretreated with warfarin, the unbound fraction of furosemide increased from 1.8 +/- 0.4% to 7.0 +/- 0.4% (p <.001), and its metabolic clearance increased by 30%, whereas furosemide urinary excretion decreased by 48% (p <.05). Experiments in nephrectomized rabbits showed that the increase in metabolic clearance was secondary to an increase in its renal metabolic clearance (p <.05). Compared with controls, in warfarin pretreated rabbits, sodium excretion and diuresis were decreased by 30% (p <.05). However, when furosemide was injected mixed with albumin, warfarin-induced kinetic and dynamic alterations of furosemide were reversed. Compared with control rabbits, in conscious hypoalbuminemic rabbits, furosemide unbound fraction was enhanced from 1.2 +/- 0.1% to 5.5 +/- 0.5% (p <. 001), and its urinary excretion, diuresis, and sodium excretion were reduced by 22% (p <.05). The administration of warfarin to hypoalbuminemic rabbits further increased the fraction of unbound furosemide, and diminished its urinary excretion and diuretic effect. In conclusion, 1) binding of furosemide to plasma proteins, and not albumin per se, facilitates its renal secretion and pharmacological response; 2) the decrease in furosemide binding, secondary to drug displacement and/or hypoalbuminemia, can be a cause of resistance to the diuretic; and 3) when furosemide binding is decreased, the administration of furosemide mixed with albumin enhances its renal secretion and diuretic effect.

Animals↗

PubMed1997

Pharmacokinetics and pharmacodynamics of furosemide after direct administration into the stomach or duodenum.

The pharmacokinetics and pharmacodynamics of furosemide were compared after an oral administration or a direct administration of Lasix into the duodenum in humans (40 mg). Furosemide was absorbed quickly after a direct administration of Lasix into the duodenum; the peak plasma concentration of furosemide was reached within 1 h in both routes of administration, and the peak concentration was higher in all four subjects after a direct administration into the duodenum than after an oral administration. Furosemide was absorbed considerably after a direct administration of Lasix into the duodenum; the values of the area under the plasma concentration-time curves of furosemide from time zero to 4 h (AUC0-4 h, 93.6 versus 122 micrograms min mL-1, p < 0.123) and the cumulative amounts of the dose excreted in 8 h (10,600 versus 15,000 micrograms, p < 0.0185) and 24 h (11,300 versus 15,400 micrograms, p < 0.0192) urine as unchanged furosemide were significantly higher after a direct administration into the duodenum than after an oral administration. However, the amounts excreted in urine as glucuronide conjugates, a metabolite of furosemide, tended to increase after an oral administration (4030 versus 1670 micrograms as expressed in terms of furosemide, p < 0.0858) when compared to a direct administration into the duodenum, possibly due to the increased gastric first-pass metabolism of furosemide. The 8 h urine output and 8 h urinary excretion of sodium did not increase significantly after a direct administration of Lasix into the duodenum, despite the significantly greater amount of the drug delivered to the active site after a direct administration into the duodenum. This could be explained by the fact that the urinary excretion rates of furosemide after a direct administration into the stomach were closer to the values of maximally efficient urinary excretion rate of furosemide during the 8 h experimental period than after a direct administration into the duodenum.

Administration, Oral↗

PubMed1994

Pharmacokinetics and pharmacodynamics of furosemide after intravenous and oral administration to spontaneously hypertensive rats and DOCA-salt-induced hypertensive rats.

The pharmacokinetics and pharmacodynamics of furosemide were investigated after intravenous (i.v.), 1 mg/100 g body weight, and oral administration, 2 mg per 100 g body weight, to spontaneously hypertensive rats (SHRs) and deoxycorticosterone acetate-salt-induced hypertensive rats (DOCA-salt rats). After i.v. administration, the 8 h urinary excretion of furosemide/g kidney (397 versus 572 micrograms) was significantly lower and the non-renal clearance (5.78 versus 3.94 ml min-1 kg-1) was significantly faster in SHRs of 16 weeks of age than in age-matched control Wistar rats. This suggested that the non-renal metabolism of furosemide could be faster in SHRs of 16 weeks of age than in age-matched control Wistar rats, and this could be supported by the significantly greater amount of 4-chloro-5-sulphamoyl anthranilic acid, a metabolite of furosemide, excreted in 8 h urine as expressed in terms of furosemide (11.1 versus 4.79% of the i.v. dose) in SHRs. It could also be supported at least in part by a study of liver homogenate; the amount of furosemide remaining per gram of liver after 30 min incubation of 50 micrograms of furosemide with the 9000g supernatant fraction of liver homogenate was significantly smaller (40.4 versus 43.7 micrograms) in SHRs of 16 weeks of age than in age-matched Wistar rats. The greater metabolic activity of furosemide in liver may also be supported by the result that the amount of hepatic cytochrome P-450 (0.7013 versus 0.5186 nmol/mg protein) and the weights of liver (3.52 versus 2.93% of body weight) were significantly greater in SHRs of 16 weeks of age than in age-matched Wistar rats. After i.v. administration of furosemide, the 8 h urine output (9.93 versus 16.5 ml) and 8 h urinary excretion of sodium (1.21 versus 2.05 mmol) and chloride (1.37 versus 2.17 mmol) per gram of kidney in SHRs of 16 weeks of age were lower than those in age-matched Wistar rats, this could be due to the significantly smaller amount of furosemide excreted in 8 h urine per gram of kidney. After oral administration, the pharmacokinetics and pharmacodynamics of furosemide were not significantly different between SHRs and the control Wistar rats of 16 weeks of age. After i.v. and oral administration of furosemide, there were no significant differences in the pharmacokinetics and pharmacodynamics between DOCA-salt rats and control SD rats of 16 weeks of age except for the significantly lower urinary excretion of potassium per gram of kidney in DOCA-salt rats.(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Oral↗

PubMed1983

Effects of furosemide on biliary secretion, pancreatic blood flow, and pancreatic exocrine secretion.

The effects of furosemide on biliary secretion and on pancreatic hemodynamics and exocrine function were studied by quantitative flowmetry and timed collections of biliary and pancreatic exocrine secretion in the anesthetized dog. Biliary flow and the output of its components (Na+, K+, Ca, Mg, 3-OH bile salts, and bilirubin) increased significantly following a furosemide injection of 0.6 mg/kg and rose progressively to 75-150 per cent above basal levels as the furosemide dose was increased to 9.6 mg/kg. Pretreatment with secretin had no influence on furosemide-induced biliary secretion. Furosemide doses of 4.8 and 9.6 mg/kg increased blood flow in the superior pancreaticoduodenal arterial bed by 30-60 per cent but did not alter flow in the inferior pancreaticoduodenal arterial bed or the pancreatic branch of the splenic artery. However, small increases were seen in flow in the latter two arterial beds after furosemide when secretin administration preceded furosemide. Basal pancreatic secretion was not affected by furosemide, but pretreatment with a submaximal sustaining infusion of secretin uncovered a furosemide action to increase pancreatic exocrine flow and the outputs of Na+, K+, Ca, Mg, and enzymes by 25-35 per cent. These data extend previous studies of the gastrointestinal vasodilator effects of furosemide to the pancreatic circulation and previous data demonstrating furosemide-induced ionic transport in nonrenal systems to biliary, pancreatic acinar, and ductular transport in both organs. Whether the augmentation of pancreatic blood flow is secondary to enhanced ion transport in the exocrine pancreas or to an effect on ionic cotransport in vascular smooth muscle is unknown.

Animals↗

PubMed1989

Interference of different ACE-inhibitors with the diuretic action of furosemide and hydrochlorothiazide.

In healthy volunteers the acute effect of furosemide (40 mg i.v.) and hydrochlorothiazide (100 mg p.o.) on diuresis, natriuresis and renal kallikrein and kinin excretion was investigated. Furosemide stimulated markedly diuresis and natriuresis as well as urinary kallikrein and kinin excretion. Pretreatment by captopril (C) reduced the diuretic and natriuretic effect of furosemide significantly probably due to a diminished (about 50%) proximal-tubular secretion of furosemide. Captopril did not alter significantly the furosemide induced changes in urinary kallikrein and kinin excretion. After captopril there was a clear dissociation between aldosterone, which was diminished by captopril continuously, and renal kallikrein and kinins, which were still stimulated by furosemide. These results suggest that renal kallikrein-kinin system is stimulated by furosemide directly and independently of aldosterone secretion. Other ACE-inhibitors like ramipril (5 mg) or enalapril (20 mg) did not influence the stimulatory effects of furosemide on diuresis or kallikrein-kinin excretion. Ramipril at a dose of 10 mg, however, enhanced the initial diuretic effect of furosemide by increased furosemide secretion and increased relative sodium excretion. Hydrochlorothiazide induced a prolonged diuresis which was not changed by either captopril or ramipril. Urinary kallikrein excretion was not stimulated by hydrochlorothiazide. Our results show an important drug interference between captopril and furosemide, which is independent of ACE-inhibition and probably only due to an interference in proximal-tubular secretion of both drugs. Between captopril and hydrochlorothiazide no such interaction could be observed.

Adult↗

PubMedDate not supplied

Bioavailability and elimination kinetics of the combination furosemide-retard/triamterene.

In a pharmacokinetic study on 18 healthy male volunteers the bioavailability and elimination kinetics of furosemide-retard and the combination furosemide-retard/triamterene were investigated and compared with the non-retarded form and another retard form of furosemide. The relative bioavailability of the non-retarded form of furosemide was distinctly reduced by the retardation in the substances investigated. It varied between 42-66% in the plasma and between 37-73% in the urine. In the combination with triamterene the serum concentration time curve of furosemide was only slightly modified but the renal excretion of furosemide was more influenced (36% for furosemide-retard and 25% for furosemide-retard/triamterene). In comparison, the values for the renal excretion of triamterene and OH-TA sulfate were distinctly greater than those obtained after administration of triamterene alone. A renewed increase of the plasma concentration and renal excretion of furosemide were observed between 9 and 10.5 h after administration of furosemide-retard/triamterene. This observation suggests that a further absorption of furosemide occurs as a consequence of the delayed release from distal parts of the small intestine or from the large intestine.

Absorption↗

PubMed2001

Continuous intravenous furosemide in haemodynamically unstable children after cardiac surgery.

OBJECTIVE: The commonly used continuous intravenous (i.v.) furosemide dosing schedule after cardiac surgery in children is largely empirical and may not be optimal. This may even be more marked in children after cardiac surgery who are haemodynamically unstable, and in whom transient renal insufficiency may occur. A study was performed to obtain an impression regarding which clinically applicable measures may be used to design a rational scheme for continuous i.v. furosemide therapy in children after cardiac surgery. SUBJECTS AND METHODS: Twelve paediatric patients (5F/7 M, age 0-33 weeks) post-cardiac surgery, who were to receive 3 days of continuous i.v. furosemide treatment, were included in an open study. Blood and urine samples were taken for furosemide, creatinine, and electrolyte levels, and fractionated urinary output was measured. Furosemide in blood and urine was measured using high performance liquid chromatography (HPLC). RESULTS: The mean starting dose of continuous i.v. furosemide was 0.093 (+/- 0.016) mg/kg per hour. The mean dose was increased to 0.175 (+/- 0.045) mg/kg per hour per hour on day 2, and changed to 0.150 (+/- 0.052) mg/kg per hour on day 3. Infusion rates were increased from day 1 to day 2 in ten cases, and decreased from day 2 to day 3 in three cases. Serum furosemide levels never exceeded ototoxic levels. The urinary furosemide excretion rate was inversely related to serum creatinine levels. CONCLUSIONS: This study extends the observation of the beneficial effects of continuous i.v. furosemide also to those children who are haemodynamically unstable after cardiac surgery. However, as the effects of furosemide are dependent on renal function, it can be hypothesised that the dosing schedule may be optimised. Contrary to the currently used dosage schedule in which the dose of furosemide is gradually increased over time, it may be more rational to start with a higher dose and adapt this dose (downward) guided by the observed effect (urine output). Because the infusion rate was increased to 0.2 mg/kg per hour in nine out of 12 patients on day 2 and was never increased further, this suggests that a starting rate of 0.2 mg/kg per hour may be optimal.

Cardiac Surgical Procedures↗

PubMed1993

Acute effects of captopril on the renal actions of furosemide in patients with chronic heart failure.

This study examined the effects of conventional doses of oral captopril on the renal responses to oral furosemide in ambulant patients with stable chronic heart failure. Twenty-five men (mean age 63 years) were randomized to one of two groups. Group 1 received placebo on days 1 and 2 before furosemide. Group 2 received placebo on day 1 before furosemide and captopril thereafter (i.e., captopril before furosemide on day 2). Urine was collected after either placebo or captopril and after furosemide (taken after placebo or captopril pretreatment). Captopril by itself did not affect renal function. Captopril did, however, significantly affect the renal response to furosemide. The increase in urine flow rate after furosemide in group 2 was decreased from 225% with placebo to 128% with captopril (p < 0.02). The increase in sodium excretion after furosemide was decreased from 623% with placebo to 242% with captopril (p < 0.001). Pretreatment with captopril abolished the increase in creatine clearance after furosemide. The increase in urinary albumin excretion (used as a marker of glomerular function) after furosemide was also significantly blunted by captopril. Conventional doses of captopril acutely inhibit the natriuretic and diuretic responses to furosemide at the glomerular level in ambulant patients with stable chronic heart failure.

Administration, Oral↗

PubMed1987

Altered furosemide pharmacokinetics in chronic alcoholic liver disease with ascites contributes to diuretic resistance.

Some patients with chronic alcoholic liver disease and ascites have an impaired natriuretic response to furosemide. To elucidate the mechanism of this diuretic resistance, we measured para-aminohippurate and inulin clearances and urinary excretion of electrolytes, prostaglandin E2, and furosemide after intravenous administration of 80 mg of furosemide in 26 patients. The natriuretic response was variable (3.3-172 mEq/h) and was unrelated to basal sodium excretion, renal clearances, or urinary prostaglandin E2. Natriuresis correlated negatively with plasma aldosterone (r = -0.54, p less than 0.01), and strongly with urinary furosemide (range 5.5-76 mg/h, r = 0.71, p less than 0.001). As urinary furosemide excretion reflects the amount of furosemide reaching the active site on the luminal side of the tubule, the data demonstrate markedly reduced amounts of furosemide at its primary site of action in patients with diuretic resistance. Plasma furosemide was higher in patients with reduced furosemide excretion and impaired natriuresis, suggesting that the defect was an impairment of furosemide transport into the tubule. Thus, a major factor in diuretic resistance is altered furosemide pharmacokinetics.

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