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PubMed1990

[Renal effects of ibopamine in comparison with furosemide in patients with mild heart failure].

Ibopamine is a novel oral dopamine analogue with positive inotropy and diuretic effects. In a double-blind, randomized study, the drug was investigated in 10 patients (mean age 49 +/- 10 years, six male, four female) with mild heart failure (NYHA classes II: six patients, III: four patients). Effects of single oral doses of 200 mg ibopamine, of 40 mg furosemide, and of 200 mg ibopamine plus 40 mg furosemide were compared in each patient at 3-day-intervals. One h after application, systolic and diastolic blood pressure increased from 119 +/- 11 to 124 +/- 8, and from 75 +/- 4 to 80 +/- 6 mm Hg (p less than 0.01) in the ibopamine group, while changes in both other groups and changes of the heart rate were insignificant. During 2 h after drug ingestion urinary flow was raised from 124 +/- 81 to 227 +/- 166 ml/2 h in the ibopamine group (p less than 0.05), while the application of furosemide (with or without ibopamine) resulted in several fold increases of urinary flow. After ibopamine, the 2-h-creatinine-clearance rose from 123 +/- 73 to 130 +/- 85 ml/min (not significant). Sodium excretion remained unchanged by ibopamine, potassium excretion was increased from 2.9 +/- 1.7 to 4.0 +/- 3.3 mmol/h (p less than 0.05), while effects of furosemide were several fold of those of ibopamine. Atrial natriuretic factor concentrations in plasma increased significantly after ibopamine and after ibopamine plus furosemide (p less than 0.01), but remained constant after furosemide alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Atrial Natriuretic Factor↗
PubMed1990

Pharmacokinetics and dynamics of furosemide in the newborn piglet.

Furosemide was administered as either an i.v. bolus (6 mg/kg) or primed continuous infusion (4 mg/kg/hr) with quantitative fluid replacement to 10 3-day-old and 9 18-day old piglets. Total and unbound plasma as well as urinary furosemide concentrations were measured for up to 6 hr and drug disposition and renal sodium excretory dynamics were compared at the two ages. The plasma clearance of furosemide was concentration-independent over the range studied (0.1-10 mg/l). Steady-state volume of distribution and unbound fraction of furosemide in plasma were both considerably higher in the younger piglets (618 +/- 320 vs. 201 +/- 71 ml/kg, p less than .01 and 0.22 +/- 0.08 vs. 0.06 +/- 0.02 ml/kg, p less than .001, respectively) while unbound secretory clearance was several-fold lower in this age group (49.2 +/- 23 vs. 107 +/- 55 ml/min/kg, P less than .01). A log-logistic equation was fitted to sigmoidal plots of sodium excretion rate vs. log furosemide excretion rate. While basal response and slope parameters did not differ significantly, maximal response and stimulus required for half-maximal response were both reduced in the younger piglets (0.70 +/- 0.24 vs. 1.18 +/- 0.30 mmol/min and 0.06 +/- 0.04 vs. 0.14 +/- 0.06 mumol/min, respectively, P less than 0.05). Thus, younger piglets were more sensitive to the natriuretic effects of the drug. While term piglets were useful for studying the maturation of protein binding and renal drug excretory processes for furosemide, drug disposition was not comparable to that in human premature infants because of the higher secretory capability of the piglet.

Aging↗
PubMed1990

Bioavailability and pharmacokinetics of furosemide marketed in Thailand.

Thirteen different brands of 40 mg furosemide tablets available in Thailand were evaluated. In vitro studies revealed that all products met the requirement of United States Pharmacopoeia XX for weight variation, per cent labeled amount, and disintegration time. However, there were only 4 brands that passed the dissolution test specification. The original brand (brand A) and the three local brands (brand B, C and D) with differences in dissolution characteristics were selected for bioavailability study. Relative bioavailability of 40 mg furosemide tablets were performed on eight healthy Thai males using a crossover design. Plasma furosemide concentrations were determined by high-performance liquid chromatographic method. Clinical response to these tablets were also studied by determination of urine output and electrolyte excretion. Individual plasma data was analyzed according to one-compartment open model using the PCNONLIN computer program. The elimination half-life of furosemide was 1.27 hours. The mean individual peak plasma levels ranged from 0.61-1.12 micrograms/ml and the time required to reach the peak ranged from 1.63-2.00 hours. There were no statistically significant differences in parameters studied between the original and the local brands (p greater than 0.05). The relative bioavailability of furosemide with respect to brand A were 70.29, 113.41, and 94.93 per cent for brand B, C and D, respectively. There was no relationship between in vitro and in vivo characteristics. Clinical response, in terms of diuresis and electrolyte excretion, e.g., sodium, chloride and potassium, between four brands of furosemide tablets were also not significantly different (p greater than 0.05), indicating that the four brands are clinically equivalent.

Adult↗
PubMed1989

Furosemide directly stimulates prostaglandin E2 production in the thick ascending limb of Henle's loop.

Studies were conducted to investigate direct effects of loop diuretics on prostaglandin E2 (PGE2) production using microdissected nephron segments. At first, the effect of indomethacin on the diuretic response to furosemide was re-evaluated in anesthetized rats. Indomethacin significantly attenuated the diuretic, natriuretic and chloruretic effects of furosemide without significantly affecting inulin and p-aminohippurate clearance or filtration fraction. But, in nondiuretic states, indomethacin had no significant effects on these parameters. Furosemide, ethacrynic acid and bumetanide significantly increased PGE2 production in cortical and medullary thick ascending limbs of Henle's loop (P less than .001), but not PGE2 production in the cortical and outer medullary collecting tubules. The effect of furosemide on PGE2 production in CTAL was dose-dependent, and higher concentrations of of furosemide than 10(-6) M significantly increased PGE2 production. On the other hand, chlorothiazide showed no PGE2 productive stimulation in these four nephron segments. This study demonstrates that the enhanced PGE2 production in the thick ascending limb of Henle's loop by furosemide and other loop diuretics is one possible mechanism of these drugs.

Animals↗
PubMed1989

Caffeine potentiates the renin response to furosemide in rats. Evidence for a regulatory role of endogenous adenosine.

Adenosine is a potent inhibitor of renin release. It has therefore been suggested that endogenous adenosine may play a role in the regulation of renin release. Sodium-chloride transport at the level of the macula densa has been proposed as the primary source of endogenous adenosine. Evidence to support a modulatory role of adenosine on renin release in vivo is, however, limited. We therefore wanted to determine if: 1) adenosine modulates furosemide-induced renin release and 2) sodium-chloride reabsorption at the macula densa is essential for adenosine actions. To test these hypotheses, three groups of rats were pretreated either with saline or the adenosine receptor antagonists caffeine or 1,3-dipropyl-8-(p-sulfophenyl)xanthine (both at a dose of 30 mg/kg followed by 450 micrograms/kg/min). Rats then received furosemide (50 mg/kg i.v.). In the vehicle group, furosemide increased urinary volume, sodium and potassium excretion and increased plasma renin activity from 6 +/- 1 to 45 +/- 11 ngAl/ml/hr. Caffeine and 1,3-dipropyl-8-(p-sulfophenyl)xanthine potentiated the increase in plasma renin activity produced by furosemide (to 120 +/- 15 and 147 +/- 21 ng Al/ml/hr, respectively), whereas having no significant effects on urinary volume, sodium excretion or blood pressure. These results suggest that furosemide-induced renin release in vivo is restrained by endogenous adenosine. In as much as furosemide blocks sodium-chloride transport in the thick ascending limb of Henle's loop and the macula densa cells, it appears that under the conditions of this study sodium transport across these segments is not essential to initiate adenosine-mediated mechanisms.

Adenosine↗
PubMed1989

Potentiation of the diuretic and natriuretic effect of furosemide by the calcium antagonist nifedipine.

The renal excretory function was studied in rats under control conditions, after treatment with nifedipine, with furosemide and combined treatment with nifedipine and furosemide. The experimental animals were investigated in metabolic cages. Spontaneously excreted urine was collected for 6 h (under control conditions and when nifedipine was applied) and for two hours in the experiments with furosemide treatment. The diuresis, the excretion of sodium, potassium, chlorine, creatinine and the total amount of osmotically active substances were studied. Blood samples were taken from the heart under nembutal anaesthesia. The clearances and the excretory fractions of the substances tested were determined. The glomerular filtration was determined by the clearance of the endogenous creatinine. The blood pressure in the tail artery was measured in control experiments. Increased diuresis was observed after treatment with nifedipine, without substantial changes in the sodium, chlorine, potassium and total osmotic excretion. When furosemide was applied after pretreatment with nifedipine, the diuresis was by 33 per cent higher than when only furosemide was applied (p less than 0.01), sodium excretion was by 40% higher (p less than 0.01) and that of chlorine--by 16.9% (p less than 0.01). Potassium excretion remained unchanged. The results of the excretory fractions and of the clearances of the substances studied support the evidence about potentiation of the natriuretic and chlorouretic effect of furosemide under the effect of nifedipine. The concentrating function of the kidney, determined through the clearance parameter Cosm/TcH2O manifested an additional limitation under the effect of nifedipine.

Animals↗
PubMed1988

Comparison of efficacy and tolerance of different oral doses of torasemide and furosemide in patients with advanced chronic renal failure.

In a double-blind, randomised group comparative study the efficacy of daily oral administration of 100 mg and 200 mg torasemide (1-isopropyl-3-([4-(3-methyl-phenylamino)pyridine]-3-sulfonyl)urea) were compared with that of 250 mg furosemide over 2 weeks in patients with advanced chronic renal failure, who had been pretreated with a maintenance therapy of 500 mg furosemide per day. Of the 19 patients 7 had been allocated strictly at random to 100 mg torasemide, 6 to 200 mg torasemide and 6 patients to 250 mg furosemide. The volume excretion after administration of 200 mg torasemide was significantly higher than after administration of 250 mg furosemide and non-significantly higher than after 100 mg torasemide. In comparison with baseline values under pretreatment with 500 mg furosemide there was a slight reduction of fluid and sodium excretion in the 100 mg torasemide group and a clear reduction in the 250 mg furosemide group. In contrast, in the 200 mg torasemide group excretion of fluid and sodium increased. The tolerance was good in all 3 groups.

Adult↗
PubMed1988

A comparative study of the diuretic, natriuretic, and kaluretic effects of furosemide when administered at 07:00 h and at 19:00 h.

Furosemide (0.5 mg/kg, i.v.) was administered to 31 healthy, day-active adults (Group 1) at 07:00 h (study 1) and urine output during the next 2 h was collected. Urine volume, urinary sodium, potassium and creatinine were determined. After 60 h, furosemide (0.5 mg/kg, i.v.) was administered at 19:00 h (study 2) and urine output during the subsequent 2 h (19:00 h to 21:00 h) was collected for estimation of urine volume, sodium, potassium and creatinine. Twenty-two healthy, day-active adults (Group 2) who constituted the control group underwent study 1 and study 2 and received 2 ml of normal saline instead of furosemide. There was no significant difference in urinary volume, urinary sodium, potassium and creatinine excretion between study 1 and study 2 in the control subjects (Group 2). In contrast, administration of furosemide at 07:00 h (study 1) resulted in greater diuresis (247.1 +/- 202.07 ml), more marked sodium excretion (42.66 +/- 29.06 mmol), increased potassium excretion (5.14 +/- 4.014 mmol), and greater creatinine excretion (0.415 +/- 0.414 mmol) as compared to study 2. In conclusion, the diuretic, natriuretic and kaluretic effects of furosemide are greater when administered at 07:00 h than at 19:00 h. Therefore, in clinical practice, the time of administration of furosemide can be so chosen as to achieve a greater diuresis or to prevent a marked loss of sodium.

Adult↗
PubMed1987

Steady state absorption kinetics and pharmacodynamics of furosemide in congestive heart failure.

Furosemide, a potent loop diuretic, is commonly used in the treatment of congestive heart failure (CHF). Unpredictability in the diuretic effect following oral doses has been attributed to variable and incomplete absorption and to variability in the pharmacodynamic response to furosemide. The present study is undertaken to investigate the absorption kinetics and pharmacodynamics of furosemide in patients with CHF during chronic medication. Ten patients with congestive heart failure were maintained on 40 to 160 mg furosemide for a month. The final dose at the end of this period was administered on an empty stomach. Plasma and urine were collected and assayed for furosemide, potassium, chloride, sodium and creatinine. Urine flow was also measured as a function of time. Plasma furosemide concentration-time data were fit to a two-compartment model with either two consecutive, discontinuous first order absorption rate constants or with a single monoexponential input; the former absorption model describing the data better than the latter. Average values of the half-life (205 +/- 28 min) and renal clearance (0.8 +/- 0.09 ml/min/kg) were similar to those reported by previous investigators. Drug excretion-response curves were lower and shifted to the right compared to data reported for normal subjects. Furthermore, a clockwise hysteresis was evident indicating acute within-dose tolerance.

Aged↗
PubMed1987

Dose dependence of proximal and distal tubular effects of furosemide in conscious rats.

The dose-response relationship for the diuretic effect of furosemide, given as i.v. bolus injections (0.1-480 mg/kg) was investigated by clearance technique in conscious rats. By measuring the renal Li clearance, the effects on proximal and distal nephron segments were separated, and peak responses were correlated to the maximal excretion rate of furosemide in the urine. At the highest dose of furosemide, fractional Na excretion was increased from 1 to 19%, due to inhibition of fractional proximal Na reabsorption from 65 to 40% and fractional distal Na reabsorption from 97 to 57%. Furosemide inhibition of fractional proximal Na reabsorption showed a maximum at intermediate doses (7.5 mg/kg), whereas there was no maximum for the inhibition of distal fractional Na reabsorption. The natriuretic response was shorter than expected from the decline in furosemide excretion due to an abrupt fall in glomerular filtration rate and a rapid normalization of proximal fractional Na reabsorption. It is suggested that the maintenance of a normal delivery of tubular fluid to the distal nephron during furosemide-induced volume contraction may be due to inhibition of proximal tubular reabsorption.

Animals↗
PubMed1985

Acute tolerance to furosemide diuresis in humans. Pharmacokinetic-pharmacodynamic modeling.

Furosemide, 40 mg, was given to eight healthy volunteers as an i.v. dose and as oral doses (tablet and solution) with and without food intake. The urine and plasma were sampled frequently and analyzed on their content of furosemide (high-performance liquid chromatography). The urine flow and chloride excretion rate were used as measures of the effect. In spite of a 3-fold difference (28 vs. 9 mg/8 hr, P less than .001) in the cumulative urinary excretion of furosemide between i.v. and postprandial oral administration, no significant difference in the diuretic effect was found (2-2.2 liters/8 hr). The drug excretion-response curves showed parallel shifts depending on mode of administration of furosemide. Clockwise hysteresis, indicating acute tolerance development to the diuretic effect, was seen after the oral doses after food intake. This within-dose development of tolerance was modeled with an extended Hill equation. The tolerance development seems to have a near relationship to acute volume depletion (inadequate substitution of urine losses), probably activating some intrarenal mechanism for extracellular fluid volume preservation. Thus, the time course of furosemide excretion, as well as the degree of renal compensation, determine the renal sensitivity to furosemide. This has important implications for the proper design and interpretation of studies of the excretion-response relationship of diuretics.

Adult↗
PubMed1985

[Furosemide-sensitive transport of chloride through the apical membrane of cells of the proximal tubule of the triton kidney].

The effect of furosemide on transtubular electrical potential (Vt) as well as on the potentials of apical (Va) and basolateral (Vb) membranes of the Triturus vulgaris proximal nephron cells was studied in alteration of the electrochemical potential gradient Na+ and Cl- through the apical membrane. Furosemide did not change the Va and Vb provided the concentration of NaCl in the lumen of proximal canal was the same as in the blood plasma. When the NaCl concentration diminished in the lumen furosemide increased Va and Vb, the Vt remaining unchanged. The effect of furosemide is considerably lesser when the Cl- concentration alone diminishes in the lumen. The data obtained suggest presence of furosemide-sensitive transport of Cl- in the apical membrane of proximal canal cells in the Triturus kidney. This membrane seems to have systems of electrogenic transport of Cl- insensitive to furosemide but depending on the Na+ electrochemical potential gradient.

Animals↗
PubMedDate not supplied

Biotransformation of furosemide in patients with acute pulmonary edema.

Furosemide (20-80 mg) was administered iv over 5 min to 16 patients with the diagnosis of acute pulmonary edema due to left heart failure. Serum and urine samples collected during the 24 hr after administration were assayed for furosemide and its biotransformation products by gas-liquid chromatography. A biexponential decay of serum furosemide concentrations vs. time was observed. Recovery of furosemide and its metabolites from urine in 24 hr varied between 30 and 98% of the administered dose. The excretion of unchanged drug accounted for 22.6-73.4% of the dose. The excretion of the glucuronide metabolite and 2-amino-4-chloro-5-sulfamoylanthranilic acid accounted for 3.3-40.4% and from 0.13-3.92% of the dose, respectively. Urinary excretion of furosemide was less in patients with, than in those without, myocardial infarction. Urinary excretion of the oxidative acidic metabolite was increased in patients with reduced creatinine clearance. The glucuronide metabolite of furosemide was the major biotransformation product in these patients with acute pulmonary edema.

Acute Disease↗
PubMed1981

Effects of prostaglandin and kinin synthesis inhibitors on renal responses to furosemide in normal and low-sodium rats.

The role of renal prostaglandin (PG) and kallikrein-kinin systems in the renal effects of furosemide was assessed indirectly by using known inhibitors of synthetic pathways in conscious rats supplemented with physiological saline (2.0% body wt.). In normal rats oral pretreatment of indomethacin or meclofenamic acid (cyclooxygenase inhibitors) each at 10 mg/kg failed to alter the diuretic and natriuretic responses to furosemide (10 and 30/kg, p.o.). In contrast, the natriuretic and diuretic actions of furosemide in sodium-deficient rats were greatly inhibited by indomethacin and by meclofenamic acid independent of changes in endogenous creatinine excretion. Aprotinin (2..0 x 10(5) KIU/kg, s. c.), an inhibitor of kallikrein formation, did not impair the natriuretic and diuretic responses to furosemide in either normal or low-sodium rats. Additionally aprotonin did not influence the antagonistic effects of indomethacin against furosemide in low-sodium rats. These results suggest that the renal PG system but not the kallikreinkinin system is necessary for furosemide to produce optimal diuretic and natriuretic effects during sodium restriction.

Animals↗
PubMed1983

Effect of furosemide on mitochondrial electron transport system and oxidative phosphorylation.

The effects of furosemide on the mitochondrial electron transport system and on oxidative phosphorylation were explored. Furosemide above the concentration of 2 X 10(-3) mol/l was found to inhibit state 3 (ADP-dependent) respiration of the rat liver, renal cortex, renal medulla mitochondria. State 4 (resting) respiration was not affected by furosemide. Furosemide above the concentration of 7.5 X 10(-6) mol/l (substrate: glutamate-malate), and above 5 X 10(-6) mol/l (substrate: succinate) inhibited the respiration of rat liver mitochondria released by 3,5-di-tert-butyl-4-hydroxybenzylidenemalononitrile (SF 6847). This fact exactly indicates that furosemide inhibits the electron transport system in mitochondria. Furosemide at the concentration of 4 X 10(-3) mol/l inhibited the activities of NADH cytochrome c reductase and succinate cytochrome c reductase in sonicated mitochondrial subparticles of beef heart by 78.2% and 79.2% of control, respectively.

Animals↗
PubMedDate not supplied

[Furosemide--pharmacokinetics in geriatric patients with multimorbidity].

20 geriatric patients with multiple diseases were administered a single intravenous dose of 40 mg furosemide. Furosemide plasma and urine concentrations were measured using a thin-layer chromatography method (25) and were fitted to an open 2-compartment model. Furosemide half-life was prolonged twofold in the elderly patients compared with a control group of younger adults. In the same way renal clearance and total clearance were markedly reduced in the geriatric group. The nonrenal clearance and the volume of distribution (beta) were not significantly altered. There were many significant correlations between clinical and biochemical data and pharmacokinetic parameters, especially between blood pressure and the area under the curve (AUC 0-infinity), total clearance and nonrenal clearance of furosemide. Our data suggest a special function of alpha-2-globulins in binding of furosemide. Renal function (i.e. creatinine clearance) was shown to be an important parameter for estimating the elimination rate of furosemide.

Aged↗
PubMed1978

Adverse biochemical and clinical consequences of furosemide administration.

Nurse monitors collected clinical and laboratory data from 204 hospitalized patients receiving furosemide (122 men and 82 women; mean age 69.6 years). Biochemical abnormalities and clinical problems definitely or probably induced by any drug occurred in 70.6% and 49.0% respectively of the patients, and were attributed to furosemide in 81.3% and 13.0% respectively of these patients. The most important clinical events were dehydration and hypotension. Furosemide-induced hypochloremia, hypokalemia and hyponatremia occurred in 35.8%, 25.0% and 24.5% of the patients respectively. Most of the biochemical changes were slight, and only 3.9% of the patients had a furosemide-induced decrease in the serum potassium concentration to less than 3.0 mmol/L. Surprisingly, 24.5% of the patients also manifested drug-induced hyperkalemia. Administration potassium supplements or spironolactone, or both, concurrently with furosemide was responsible in most cases for the development of hyperkalemia. The occurrence of drug-induced adverse effects after 2 weeks of hospitalization was significantly associated (P less than 0.05) with subsequent prolongation of hospitalization. The high frequency of drug-induced events warrants careful monitoring of all patients receiving furosemide in spite of the low frequency of serious toxic effects produced by the drug.

Adult↗
PubMed1983

[Clinical comparative trial of piretanide and furosemide in patients with advanced renal insufficiency. Drug levels and diuretic potency of single oral doses].

Piretanide is a new diuretic agent that is structurally related to bumetanide and furosemide. The effect of a single oral dose of piretanide 12 mg on the serum agent levels and diuretic activity was compared with that of Furosemide 80 mg p.o. in 12 patients with advanced renal insufficiency using a balanced randomized design. Piretanide was seen to have its most pronounced activity in the 1st h, while the effect of furosemide was more prolonged without abrupt peaks. There was a tendency of water conservation following the diuresis with piretanide, which produced a lesser response in volume and sodium excretion than furosemide when analysed as cumulative excretion at 24 h. The sodium-potassium ratio of the total urinary volume increased slightly by the same amount. Piretanide was approximately 5 times more potent on a weight basis than furosemide. Piretanide appeared to be effective in advanced renal insufficiency. Due to its rapid elimination effect piretanide as well as furosemide is also indicated for the treatment of renal edema in emergency situations.

Aged↗