Dependence of urinary prostaglandin E2 excretion on urinary volume rather than solute handling or segmental nephron function in man.

Eight normal subjects underwent water loading alone and water loading plus 40 mg of frusemide IV, fluid intake ad libitum alone and fluid intake ad libitum plus frusemide, plus each of the preceding after pretreatment with indomethacin. After frusemide administration, increases in urinary sodium excretion paralleled increases in urinary volume, and urinary prostaglandin E2 (PGE2) excretion correlated closely with sodium excretion (y = 1.03x - 0.28; r = 0.940; P less than 0.0001). In the absence of the diuretic, urinary volume varied over a wide range with little change in sodium excretion. Again, urinary PGE2 excretion correlated with urinary sodium excretion (y = 0.12x + 0.05; r = 0.789; P less than 0.002). However, the correlation differed markedly from that observed in the studies with frusemide. Expressing urinary PGE2 excretion as a function of urinary volume for all of the studies resulted in a highly significant correlation (y = 10.7x - 0.70; r = 0.975; P less than 0.0001). Multiple and stepwise regression analyses assessing the correlation of urinary PGE2 excretion with urinary flow rate and with indices of function of various nephron segments indicate that the correlation with urinary PGE2 could be predominantly accounted for by urinary volume. We conclude that in the condition of this study in man, urinary PGE2 excretion is a correlate of urinary volume.

Pharmacodynamics of the diuretic effects of aminophylline and acetazolamide alone and combined with furosemide in normal subjects.

The current study was performed in normal subjects to assess the mechanism of the natriuretic effects of aminophylline, to confirm the effect of acetazolamide on the proximal tubule and to assess the pharmacodynamics of the combination of aminophylline and of acetazolamide with furosemide. None of these agents or their combination affected renal hemodynamics. Aminophylline inhibited solute reabsorption at the diluting segment manifested by a 15% decrease in free water clearance relative to solute delivery (P less than .001). In addition, it decreased solute reabsorption in the proximal nephron. Acetazolamide affected only the proximal tubule. The combination of either aminophylline or of acetazolamide with furosemide was little different from furosemide alone. Analysis of dose-response curves to furosemide revealed a minor additive, i.e., parallel upward shift, of the dose-response curves with both combinations.

Bumetanide and furosemide.

We assessed the response to and handling of furosemide and bumetanide in 30 experiments with the former and 46 with the latter in normal subjects. Oral doses of furosemide (20, 40, and 80 mg) were used, and subjects received oral doses of 0.5, 1, and 2 mg bumetanide and intravenous doses of 0.5 and 1 mg bumetanide. both drugs were quickly absorbed and peak urinary amounts were reached at 75 min (median). Approximately 30% of an oral dose of each drug was excreted unchanged in the urine with no evidence of dose-dependent elimination. After intravenous injection, 36% of the bumetanide was excreted unchanged. Consequently, bumetanide has an estimated bioavailability of 80% (approximately 40% for furosemide). The relationship between the logarithm of the urinary bumetanide excretion rate and the logarithm of the sodium excretion rate was described by a sigmoid-shaped dose-response curve, with a dose inducing half-maximal response of 1 +/- 0.04 micrograms/min; it was 69.8 micrograms/min for furosemide. Overall, the distinguishing features between the two drugs are the 200% greater bioavailability and the much greater potency of bumetanide.

Nephron site of effect of nonsteroidal anti-inflammatory drugs on solute excretion in humans.

Indomethacin and other nonsteroidal anti-inflammatory drugs (NSAIDs) decrease solute excretion when administered acutely to normal subjects. We performed clearance studies during water loading of 10 normal volunteers and during hydropenia in eight additional subjects to determine the nephron site of this effect using indomethacin and carprofen as inhibitors of prostaglandin (PG) synthesis. Their administration decreased fractional excretion of sodium, chloride, and volume. During water loading, fractional clearance of free water decreased from 0.13 +/- 0.04 during the control study to 0.09 +/- 0.03 and 0.06 +/- 0.02 with indomethacin and carprofen, respectively. However, fractional delivery of solute to the dilution segment decreased in parallel such that free water clearance corrected for delivery did not change with either drug. In humans, therefore, the decrement in solute excretion that occurs with administration of NSAIDs occurs prior to the diluting segment. During hydropenia, free water reabsorption relative to osmolar clearance increased (P less than 0.01). In both studies, neither the marker of renal perfusion or of proximal nephron function changed with inhibition of PG synthesis. The data indicate that at the tubular level, NSAIDs increase solute reabsorption at the medullary segment of the thick ascending limb of the loop of Henle. Therefore, a physiologic role of renal prostaglandins at this nephron site is implied.

Absorption and disposition of furosemide in congestive heart failure.

Changes in response to furosemide and other diuretics in patients with congestive heart failure (CHF) could occur because of disease-induced changes in absorption of the drug or changes in disposition which affect its access to its site of action. A difference was not found in the bioavailability of forosemide in patients with CHF compared to normal volunteers, 31 +/- 12 vs. 38 +/- 20% (mean +/- sd), respectively. Both groups showed considerable interindividual variability, though serial analyses within individuals revealed consistency. Amounts of furosemide delivered into the urine after an intravenous dose correlated significantly to that after an oral dose implying that the interindividual variability is not caused primarily by variability in absorption in either group. Overall, disposition kinetics of furosemide did not differ between groups. Because of heterogeneity of renal and cardiac function among the patients, we were able to demonstrate correlations of plasma and renal clearance of furosemide with renal function; in turn, renal function correlated with left ventricular ejection fraction. Consequently, some patients had changes in furosemide disposition, but, for the most part, differences in response to furosemide were caused by abnormal responses to, rather than changed handling of the diuretic.

Aminoglycoside dosage adjustment in renal failure: a hand-held calculator program.

Several problems occur when devising dosage guidelines for aminoglycoside antibiotics in patients with renal failure. To rationally address these problems, dosage guidelines require several steps involving complex calculations, use of graphic charts and/or use of sophisticated computer systems. We describe a practical program for modifying doses of aminoglycosides using a programmable hand-held calculator; this program is based both on pharmacokinetic theory and on applicability to varied clinical settings. The program compiles a series of equations to provide recommended doses, dosing intervals and predictions of serum concentrations of aminoglycosides at various times after a dose. It is hoped that patient care can be improved by using this simple, convenient and low-cost approach which retains efficiency and accuracy as a bed side method of dosage adjustment for aminoglycosides.

Interaction studies with bumetanide and furosemide. Effects of probenecid and of indomethacin on response to bumetanide in man.

Bumetanide was administered intravenously in doses of 0.5 and 1.0 mg to eight normal subjects with and without pretreatment with probenecid or indomethacin. Probenecid did not affect either the cumulative response or the time course of response to bumetanide. This may mean that probenecid and potentially other exogenous or endogenous organic acids do not affect the renal handling of bumetanide in normal man. Indomethacin pretreatment decreased the cumulative 4-hour excretion of sodium caused by 1.0 mg bumetanide from 276 +/- 22.9 to 202 +/- 20.9 mEq (P less than 0.003). Effects on volume and chloride paralleled those of sodium, while potassium excretion was not affected. When the response was analyzed as increment in fractional excretion over basal solute excretion, determined from separate control studies, indomethacin still decreased the response, possibly indicating that endogenous prostaglandins may play a role in determining the overall response to bumetanide.

Electrolyte excretion patterns. Intravenous and oral doses of bumetanide compared to furosemide.

The response to bumetanide and furosemide administered orally and intravenously was compared in normal subjects. Doses of bumetanide were 0.5 and 1 mg intravenously and 0.5, 1 and 2 mg orally. Doses of furosemide were 20 and 40 mg intravenously and 20, 40, and 80 mg orally. After intravenous doses of both drugs, peak natriuresis occurred during the first collection period of 30 minutes and the response returned to baseline by 3.5 hours. After oral dosing, peak effect occurred at 75 minutes and returned to baseline within 4 hours. Cumulative response was assessed for volume, sodium, potassium, and chloride excretion. The response did not differ substantially between drugs. On a milligram basis, bumetanide was approximately 50 times as potent as furosemide. For both drugs, the intravenous dose was approximately three times as potent as the oral preparation. The time course of response shows that the curves are virtually superimposable. The diuretic effect was short-lived for both diuretics. The urine volume and sodium and chloride excretion were parallel. The sodium/potassium ratio was calculated as follows: for every 200 mEq sodium excreted in 4 hours, bumetanide caused about 35 mEq and furosemide caused about 50 mEq potassium to be eliminated. Even if statistically significant, this difference does not appear to be clinically remarkable. If bumetanide offers therapeutic advantages in this regard, studies in patients with various disease states would have to be performed.

Variability in derived parameters of furosemide pharmacokinetics.

The pharmacokinetics of furosemide in normal man reported from a number of investigators show great discrepancies. We have evaluated the effect on derived pharmacokinetic parameters of furosemide of using different weighting factors or fewer data points to fit the same set of data to an exponential equation, or using noncompartmental analysis. Terminal half-lives of furosemide differed vastly, as did the volume of distribution, but to a lesser extent. The plasma clearance was rather consistent with the different methods used. Thus the discrepancies of the pharmacokinetics of furosemide may, in large part, be due to different methods of analysis of the data. The terminal half-life was most subject to errors of method and the plasma clearance the least.

Effect of probenecid on response to bumetanide in man.

We administered 0.5-and 1.0-mg doses of bumetanide intravenously to eight normal subjects with and without pretreatment with probenecid. Probenecid did not effect either the cumulative response or the time course of response of bumetanide. These results are in contrast to results reported in dogs but consistent with similar studies in cats. The data imply that probenecid and potentially other exogenous or endogenous organic acids do not affect the renal handling of bumetanide in normal man.

Nomograms for drug use in renal disease.

The medical literature is replete with dosing guidelines for patients with renal dysfunction. Altering dosing regimens in such patients is particularly important with drugs with a narrow therapeutic index, such as digoxin and the aminoglycoside antibiotics. A variety of methods have been used to devise dosing nomograms. This article reviews the salient features of different methods, and addresses the issues of predictability or unpredictability in attaining desired plasma concentrations of drug. It is suggested that therapy must be individualised, and that the clinician can best plan his therapy by understanding the principles on which dose adjustment is based, rather than using the same nomogram or guideline for each and every patient.

Pharmacokinetic-dynamic analysis of the indomethacin-furosemide interaction in man.

Indomethacin decreased the natriuretic response to furosemide. A possible mechanism of this effect of indomethacin, independent of prostaglandin synthetase inhibition, is a pharmacokinetic drug interaction in which indomethacin affects access of furosemide to its intratubular site of action. We administered 40 and 20 mg of furosemide to eight normal volunteers with and without pretreatment to eight normal volunteers with and without pretreatment with indomethacin. Furosemide concentration in serum and urine samples was measured by high performance liquid chromatography. Indomethacin significantly decreased plasma clearance of furosemide from 1.84 +/- 0.36 to 1.10 +/- 0.08 ml/kg/min (P < 0.2) and renal clearance of furosemide from 1.05 +/- 0.23 to 0.60 +/- 0.06 ml/kg/min (P < 0.05). The nonrenal clearance of furosemide decreased, but not significantly, from 0.80 +/- 0.17 to 0.50 +/- 0.10 ml/kg/min. Neither the total amount of furosemide delivered into the urine, nor the time course of furosemide delivery after the 40 or 20 mg doses changed with indomethacin pretreatment. Indomethacin significantly altered dose-response curves of furosemide. While the serum concentration-response curves of furosemide significantly shifted to the right, the urinary furosemide-response curve did not shift after indomethacin pretreatment. However, with both analyses, maximal response decreased. Indomethacin altered furosemide disposition and delivery into the urine. Nevertheless, this pharmacokinetic drug interaction did not account for the inhibitory effect of indomethacin on the response of furosemide.

Furosemide in patients with heart failure: shift in dose-response curves.

We studied 10 patients with congestive heart failure to assess the dynamics of their response to 40 mg of furosemide. Patients excreted less sodium than normal controls: 142 +/- 36 and 245 +/- 16 mEq/4 hr (p < 0.05). Patients delivered the same amount of furosemide into the urine--14.9 +/- 2.0 and 18.7 +/- 2.1 mg/4 hr (p < 0.20)--but the time course of delivery differed. Normal subjects had a sigmoid-shaped curve when furosemide excretion rate was related to response. All patients but one had shifts in this curve and for a number of patients the configuration differed substantially from a sigmoid curve.

Indomethacin and the response to bumetanide.

Pretreatment of 8 normal subjects with 100 mg indomethacin decreased the response to bumetanide; cumulative 4-hr excretion of sodium due to 1.0 mg of bumetanide was reduced from 276 +/- 22.9 to 202 +/- 20.9 mEq (p less than 0.003). Effects on volume and Cl paralleled those on Na while K excretion was not affected. When response was analyzed as increment in fractional excretion over basal solute excretion determined from separate control studies, indomethacin decreased response, an effect differing from that of indomethacin on the response to furosemide. The importance and mechanism of the difference in the effect of indomethacin on bumetanide and furosemide is not known.