Correspondence
Dosage regimen
and natriuretic response to furosemide
To the Editor: The article, "Effect of dosage regimen on natriuretic response to furosemide," which appeared in the August, 1975, issue of the JOURNAL, presents a seemingly paradoxical approach to the use of a drug felt to act on a "threshold" rather than on a cumulated basis. That an additional dose of 20 mg of furosemide-given at a 6-hr interval after the first-could cause almost twice the natriuretic response of a single 40-mg dose is indeed an unexpected finding. More surprising yet is the explanation offered by Wilson and co-authors! We contend that the greater 24-hr cumulative effect is NOT AT ALL "predictable from pharmacokinetic considerations."1 Assuming a one-compartment open model (as done by Cutler and colleagues 2), assuming that equilibration at the steady state occurred (which we admit is probably not correct but, if anything, will yield higher calculated plasma levels), and finally assuming that the effect of the drug is proportional to the plasma concentration (CpSS), then: C
ss P
= F· Do . tl/2 Vd' 0.693 .
T
and
CSS-~ P
-
CI B
• T
where F is the fraction of the dose absorbed (and hence assumed to be bioavailable), Do is the dose, CI B is the body clearance, and T is the dosing interval. Using Cutler's values ,2 F = 0.6, mean CI B = 150 ml/min and a dosing interval of 360 min, then: C p ss
598
0.6 x 20 mg 150 ml/min x 360 min =0.002 ILg/ml
Although the minimal effective plasma concentration of furosemide is unknown, Cutler's group2 has pointed out that following an 80-mg oral dose, serum concentration peaked between 60 and 70 min (mean, 2.2 ILg/ml) and decreased to nearly undetectable levels after 4 hr. Clinical experience also points to a threshold effect of furosemide, especially in patients with renal disease. 3 , 4 Successful diureses in patients with markedly diminished GFR depends on the amount of drug reaching the ascending limb of the loop of Henle. 5 Equivalent dosage intravenously may be more effective than an oral dose, but a single high dose by either route often results in a diuretic response while equal but divided doses are inadequate for natriuresis. From the renal and pharmacologic standpoints, the second dose of furosemide administered by Wilson l had interesting results. It should be emphasized that all 12 subjects in the Wilson paper had normal renal function. We propose (1) that any enhanced effect of such a split-dose regimen relates to the disturbances of the cortico-medullary-transtubular electrolyte gradient induced by the initial dose and not to higher blood levels achieved with the second dose, and (2) we suggest that, at least for the present, single, large-dose furosemide therapy be used in the azotemic, salt-retaining patient. leffrey David Lazar, M.D. Paul Z. Kissner, M.D. Department of Internal Medicine The University of Michigan Medical Center Ann Arbor, Mich. References 1. Wilson, T. W., Falk, K. J., Labell, J. L., and Nguyen, K. B.: Effect of dosage regimen on natriuretic response to furosemide, CUN. PHARMACOL. THER. 18:165-169, 1975. 2. Kelly, M. R., Cutler, R. E., Forrey, A. W., and
Correspondence
Volume 19 Number 5, Part 1
Kimpel, B. M.: Pharmacokinetics of orally administered furosemide, CUN. PHARMACOL. THER. 15:178-186, 1974. 3. Huang, C. K., Atkinson, A. J., Jr., Levin, M., Levin, N. W., and Quintanilla, A.: Pharmacokinetics of furosemide in advanced renal failure, CUN. PHARMACOL. THER. 16:659-666, 1974. 4. Lead article, High-dose frusemide in renal failure, Br. Med. J. 2:278-279, 1974. 5. Ferguson, D. R., and Twite, B. R.: Furosemide-pharmacology and cellular mode of action. Naunyn Schmiedebergs Arch. Pharmacol. 281:295-300, 1974.
Reply
To the Editor: Drs. Lazar and Kissner appear to have misinterpreted both our data and our interpretation of the data. Firstly, the second 20 mg of furosemide did not cause almost twice the natriuretic response of a single 40-mg dose. Taken over a 24-hr period, the mean urinary sodium excretion was 137 mEq with 20 mg, 194 mEq with 2-20 mg tablets, and 160 mEq with 1-40 mg tablet. We did show that in the period from 6 to 12 hr the natriuretic response to a single 40-mg dose at time 0 is minimal. In fact, our Fig. 2,B shows that less sodium is excreted at this time with 40 mg at time 0 than with 20 mg alone at time O. If a second 20-mg dose is given at time = 6 hr, natriuresis continues in the 6 to 12 hr intervals. In the total 24-hr period the response to the 2 x 20 mg regimen is significantly greater than the response to the 1 x 40 mg regimen. Secondly, we stated that the response to a second 20-mg dose given 6 hr after the first is greater than the response to the first 20-mg dose. This is "predictable from pharmacokinetic considerations" and is discussed in perhaps more detail in a previous publication by Levy, "Kinetics of pharmacologic effects," which appeared in the May-June, 1966 issue of the JOURNAL on page 362. Thirdly, the 24-hr sodium excretion is the integrated response to the drug and cannot be related to the C pss level of furosemide. Perhaps it should be related to the area under the plasma concentration-time curve. As we did not measure plasma furosemide levels, we cannot comment further.
599
It should be noted that C pss works out to 0.22
p..g/ml for 20 mg given at 6 hourly intervals and not 0.002 as stated by Drs. Lazar and Kissner. Fourthly, Hunter and Underwood 1 confirmed the increased natriuresis on splitting the dose of butmetanide, another short-acting diuretic. Finally, we would agree that the enhanced natriuretic effect of divided-dose furosemide has not been shown in sodium-retaining states, in hypertensive individuals, and in patients with reduced renal function. We also agree that azote mic patients often require large doses to realize an acceptable natriuretic effect. T. W. Wilson, M.D. Assistant Professor Departments of Pharmacology and Medicine University of Saskatchewan Saskatoon, Canada Reference 1. Hunter, K. R., and Underwood, P. N.: Evaluation of once daily versus twice daily bumetanide in heart failure, Postgrad. Med. J. 51(Suppl. 6):91-95, 1975.
Digoxin concentrations
To the Editor: Dr. Hartel and colleagues, in their article, "Human serum and myocardial digoxin," which appeared on page 153 of the February, 1976, issue of the JOURNAL, have confirmed our previous finding of a constant ratio between digoxin concentrations in myocardial tissue and serum at a given interval after the last dose of the drug. They have found higher mean ratios for papillary muscle compared to atrial tissue samples and suggest that this may be due to fibrous tissue present in atrial tissue. The obvious explanation for this observation, however, is that samples in our study were taken 48 hr after the last dose and 5.5 to 6 hr in Dr. Hfutel's study. In addition, it has been known for some time that digoxin concentrations are higher in the ventricle than in the atrium. We have investigated the relation between time after last digoxin dose and myocardial concentrations of the drug in some detail in dogs by using a sequential sampling technique.
600
Clinical Pharmacology and Therapeutics
Correspondence
The half-life of disappearance of digoxin is shortest in ventricle and longest in skeletal muscle (ventricle < atrium < skeletal muscle < serum). These data may further explain some of the contradictory results of heart/serum correlations. Hans-Georg Giillner, M.D. Department of Pharmacology The University of Texas Health Sciences Center Dallas, Texas
Reference 1. Gullner, H.-G., Stinson, E. B., Harrison, D. C.,
and Kalman, S. M.: Correlation of serum concentrations with heart concentrations of digoxin in human subjects, Circulation 50:653-655 1974.
Dosage regimen
and natriuretic response to furosemide
To the Editor: The article, "Effect of dosage regimen on natriuretic response to furosemide," which appeared in the August, 1975, issue of the JOURNAL, presents a seemingly paradoxical approach to the use of a drug felt to act on a "threshold" rather than on a cumulated basis. That an additional dose of 20 mg of furosemide-given at a 6-hr interval after the first-could cause almost twice the natriuretic response of a single 40-mg dose is indeed an unexpected finding. More surprising yet is the explanation offered by Wilson and co-authors! We contend that the greater 24-hr cumulative effect is NOT AT ALL "predictable from pharmacokinetic considerations."1 Assuming a one-compartment open model (as done by Cutler and colleagues 2), assuming that equilibration at the steady state occurred (which we admit is probably not correct but, if anything, will yield higher calculated plasma levels), and finally assuming that the effect of the drug is proportional to the plasma concentration (CpSS), then: C
ss P
= F· Do . tl/2 Vd' 0.693 .
T
and
CSS-~ P
-
CI B
• T
where F is the fraction of the dose absorbed (and hence assumed to be bioavailable), Do is the dose, CI B is the body clearance, and T is the dosing interval. Using Cutler's values ,2 F = 0.6, mean CI B = 150 ml/min and a dosing interval of 360 min, then: C p ss
598
0.6 x 20 mg 150 ml/min x 360 min =0.002 ILg/ml
Although the minimal effective plasma concentration of furosemide is unknown, Cutler's group2 has pointed out that following an 80-mg oral dose, serum concentration peaked between 60 and 70 min (mean, 2.2 ILg/ml) and decreased to nearly undetectable levels after 4 hr. Clinical experience also points to a threshold effect of furosemide, especially in patients with renal disease. 3 , 4 Successful diureses in patients with markedly diminished GFR depends on the amount of drug reaching the ascending limb of the loop of Henle. 5 Equivalent dosage intravenously may be more effective than an oral dose, but a single high dose by either route often results in a diuretic response while equal but divided doses are inadequate for natriuresis. From the renal and pharmacologic standpoints, the second dose of furosemide administered by Wilson l had interesting results. It should be emphasized that all 12 subjects in the Wilson paper had normal renal function. We propose (1) that any enhanced effect of such a split-dose regimen relates to the disturbances of the cortico-medullary-transtubular electrolyte gradient induced by the initial dose and not to higher blood levels achieved with the second dose, and (2) we suggest that, at least for the present, single, large-dose furosemide therapy be used in the azotemic, salt-retaining patient. leffrey David Lazar, M.D. Paul Z. Kissner, M.D. Department of Internal Medicine The University of Michigan Medical Center Ann Arbor, Mich. References 1. Wilson, T. W., Falk, K. J., Labell, J. L., and Nguyen, K. B.: Effect of dosage regimen on natriuretic response to furosemide, CUN. PHARMACOL. THER. 18:165-169, 1975. 2. Kelly, M. R., Cutler, R. E., Forrey, A. W., and
Correspondence
Volume 19 Number 5, Part 1
Kimpel, B. M.: Pharmacokinetics of orally administered furosemide, CUN. PHARMACOL. THER. 15:178-186, 1974. 3. Huang, C. K., Atkinson, A. J., Jr., Levin, M., Levin, N. W., and Quintanilla, A.: Pharmacokinetics of furosemide in advanced renal failure, CUN. PHARMACOL. THER. 16:659-666, 1974. 4. Lead article, High-dose frusemide in renal failure, Br. Med. J. 2:278-279, 1974. 5. Ferguson, D. R., and Twite, B. R.: Furosemide-pharmacology and cellular mode of action. Naunyn Schmiedebergs Arch. Pharmacol. 281:295-300, 1974.
Reply
To the Editor: Drs. Lazar and Kissner appear to have misinterpreted both our data and our interpretation of the data. Firstly, the second 20 mg of furosemide did not cause almost twice the natriuretic response of a single 40-mg dose. Taken over a 24-hr period, the mean urinary sodium excretion was 137 mEq with 20 mg, 194 mEq with 2-20 mg tablets, and 160 mEq with 1-40 mg tablet. We did show that in the period from 6 to 12 hr the natriuretic response to a single 40-mg dose at time 0 is minimal. In fact, our Fig. 2,B shows that less sodium is excreted at this time with 40 mg at time 0 than with 20 mg alone at time O. If a second 20-mg dose is given at time = 6 hr, natriuresis continues in the 6 to 12 hr intervals. In the total 24-hr period the response to the 2 x 20 mg regimen is significantly greater than the response to the 1 x 40 mg regimen. Secondly, we stated that the response to a second 20-mg dose given 6 hr after the first is greater than the response to the first 20-mg dose. This is "predictable from pharmacokinetic considerations" and is discussed in perhaps more detail in a previous publication by Levy, "Kinetics of pharmacologic effects," which appeared in the May-June, 1966 issue of the JOURNAL on page 362. Thirdly, the 24-hr sodium excretion is the integrated response to the drug and cannot be related to the C pss level of furosemide. Perhaps it should be related to the area under the plasma concentration-time curve. As we did not measure plasma furosemide levels, we cannot comment further.
599
It should be noted that C pss works out to 0.22
p..g/ml for 20 mg given at 6 hourly intervals and not 0.002 as stated by Drs. Lazar and Kissner. Fourthly, Hunter and Underwood 1 confirmed the increased natriuresis on splitting the dose of butmetanide, another short-acting diuretic. Finally, we would agree that the enhanced natriuretic effect of divided-dose furosemide has not been shown in sodium-retaining states, in hypertensive individuals, and in patients with reduced renal function. We also agree that azote mic patients often require large doses to realize an acceptable natriuretic effect. T. W. Wilson, M.D. Assistant Professor Departments of Pharmacology and Medicine University of Saskatchewan Saskatoon, Canada Reference 1. Hunter, K. R., and Underwood, P. N.: Evaluation of once daily versus twice daily bumetanide in heart failure, Postgrad. Med. J. 51(Suppl. 6):91-95, 1975.
Digoxin concentrations
To the Editor: Dr. Hartel and colleagues, in their article, "Human serum and myocardial digoxin," which appeared on page 153 of the February, 1976, issue of the JOURNAL, have confirmed our previous finding of a constant ratio between digoxin concentrations in myocardial tissue and serum at a given interval after the last dose of the drug. They have found higher mean ratios for papillary muscle compared to atrial tissue samples and suggest that this may be due to fibrous tissue present in atrial tissue. The obvious explanation for this observation, however, is that samples in our study were taken 48 hr after the last dose and 5.5 to 6 hr in Dr. Hfutel's study. In addition, it has been known for some time that digoxin concentrations are higher in the ventricle than in the atrium. We have investigated the relation between time after last digoxin dose and myocardial concentrations of the drug in some detail in dogs by using a sequential sampling technique.
600
Clinical Pharmacology and Therapeutics
Correspondence
The half-life of disappearance of digoxin is shortest in ventricle and longest in skeletal muscle (ventricle < atrium < skeletal muscle < serum). These data may further explain some of the contradictory results of heart/serum correlations. Hans-Georg Giillner, M.D. Department of Pharmacology The University of Texas Health Sciences Center Dallas, Texas
Reference 1. Gullner, H.-G., Stinson, E. B., Harrison, D. C.,
and Kalman, S. M.: Correlation of serum concentrations with heart concentrations of digoxin in human subjects, Circulation 50:653-655 1974.
