Drugs 41 (Suppl. 3): 35-59, 1991 0012-6667/ 91 /0300-0035/ $12.50/0 © Adis International Limited All rights reserved. DRSUP1800a

Effects of Diuretics on Outputs and Flows of Urine and Urinary Solutes in Healthy Subjects Ariel J. Reyes Institute of Cardiovascular Theory, Sotelo, Montevideo, Uruguay

Summary

The effects of single oral doses of common formulations of diuretics (i.e. formulations on the market or designed to be marketed) on 24-hour diuresis and natriuresis in healthy subjects are considered as a measure of the renal excretory potency of diuretics. Common formulations of distal tubular diure;ics (e.g. hydrochlorothiazide 25mg, xipamide IOmg and 20mg) are more potent diuretics' andnatriuretics th'an common formulations ofioop diuretics [e.g. furosemide (frusemide) 40mg, torasemid~ 2.5, 5 and IOmgj. Indeed, some common formulations of loop diuretics, such as toraseinide 2.5, do not increase 24-hour diuresis or natriuresis in healthy subjects. 24-hour kaliuresis and magnesiuresis are elevated by .common formulations of distal tubular diuretics, but they are only slightly increased or (more usually) not affected by common formulations of loop diuretids, f when single doses are administered to healthy individuals. Common formulations of loop diuretics have lower diuretic and natriuretic potency and lower kaliuretic and magnesiuretic effects than common formulations of distal tubular diuretics, because the pronounced elevations in urinary excretions caused by loop diuretics during the first 6 hours after dosing are follo{ved by rebounds, with respect to post-placebo excretions, between 6 and !24hours after dosing. These rebounds, which affect the urinary flows of fluid, chlo~d:e, ~odium, po:tassium and magnesium, do not occur after administration of com mod forrrlulations of distal tubular diuretics, at least during the first 24 hours after admihi~tr~tio'n of single!~oses to healthy subjects. The time courses of urinary excretion~ after loop diuretics are dose dependent. Higher doses produce more rapid changes in !the urinary flo~s: of fluid, chloride, sodium, potassium and magnesium than lower do~es, to th~ ext~~t that single administration of torasemide 2.5 or 5mg to healthy subj~cl s is followed by urinary fluid and solute flows whose time courses resemble those aft~r adfuihisttatioh of hydrochlorothiazide 25mg.

I :

The evaluation of the actions of a diuretic .on the urinary excretions of fluid and solutes in healthy subjects constitutes a logical and obligatory step in the course of the study of any new drug of this class. Such evaluation identifies pharmacodynamic characteristics (e.g. diuretic potency, time course of the renal excretory effects, etc.), which must be de-

I

'

~

fined in normal individuals for reasons of biological homogeneity. Furthermore, results obtained in normal 'volunteers in this respect can be extrapolated :to patients wiih uncomplicated essential hypertension, who do .not present a distinctive respons~ to diuretics in terms of drug-induced changes in urirlary excretions. Information about the most

Drugs 41 (Suppi. 3) 1991

36

appropriate dosages for certain therapeutic indications is also derived from such studies. In addition to the applied or practical knowledge afforded by studies on the renal excretory effects of diuretics in normal volunteers, findings which open new investigative avenues with respect to the mechanisms of action of these drugs in health and disease may also emerge from this . type of investigation (Reyes 1985, 1987a,b, 1988, 1989). Specific clinical interrogations usually make it necessary to reappraise the urinary excretory effects of older diuretics in normal individuals, even by the conventional experimental techniques reviewed by Roberts and Daneshmend (1981). New research techniques (Reyes & Leary 1981 a, 1984c; Reyes et al. 1990a,b) have produced data conducive to new definitions and interpretations and even to new therapeutic criteria, as the effects of well established diuretics are reassessed (Leary & Reyes 1987, 1988; Reyes 1985, 1987a, 1988, 1989; Reyes & Leary 1987; Reyes et al. 1988a, 1990c). This review will summarise a selection ·of representative studies (Leary et al. 1983, 1984, 1985a,b, 1990; Leary, Reyes & van der Byl, unpublished data; Reyes & Leary 1984d; Reyes et al. 1985, 1988a, 1990c; Reyes, Leary & van der Byl, unpublished data), which are part of an ongoing research series.

1. Nomenclature and Definitions 1.1 Nomenclature of Diuretic Classes The 3 most frequently used classes of diuretics are considered in this review. These are drugs whose principal renal site of action is in the straight distal tubule or thick ascending limb ofthe loop of Henle [i.e. 'loop' diuretics such as furosemide (frusemide), muzolimine (Hanisch 1983) and torasemide (Cuvelier et al. 1986; Delarge et al. 1981 )]; drugs whose principal renal site of action is in the early distal convoluted tubule [i.e. 'distal tubular' diuretics such as hydrochlorothiazide and xipamide (Prichard & Brogden 1985)], and drugs whose principal renal site of action lies in the late distal tubule, the connecting tubule and the early collecting

duct (i.e. potassium-retammg diuretics such as amiloride). The loop diuretic muzolimine has been withdrawn from the market because it caused central nervous system damage in some patients with chronic renal insufficiency who received high doses. However, muzolimine will be considered in this review because of its clinicopharmacological interest. 1.2 Nomenclature of Diuretic Formulations for Oral Use Diuretic formulations which are currently marketed, or which are intended for marketing, are referred to as 'common' formulations. Doses of diuretics outside those available in common formulations are termed either 'low' or 'high' doses. In some cases common formulations are produced in a range of dose strengths, as occurs for hydrochlorothiazide, which is currently marketed in 25, 50 and 100mg formulations. In these cases, the expressions 'low dose common' and 'high dose common' diuretic formulation are used to differentiate within the dose range of common formulations. Muzolimine 20 and 30mg are considered common formulations in this review. 1.3 Use of Variables Describing Urinary Excretion of Fluid and Solutes 1.3.1 Urinary Outputs The expression 'output' is used to describe the volume of urine or the amount of urinary solute which is excreted during a certain period. 1.3.2 Transfer Rates: Flows of Urine and Urinary Solutes The variable 'urine flow' stands for the rate at which urine is excreted, i.e. it bears the physical dimensions of a flow (volume' time-I). By extension, the rate at which urinary solutes are excreted is termed the 'urinary solute flow'; this latter variable is really a rate of transfer of substance mass, with dimensions of mass' time-I, which should therefore be referred to as a 'transfer rate'. However, the expression 'urinary solute flow'is used,

37

Effects of Diuretics on Urinary Outputs

since the transfer rates of urine and its solutes are physiologically interrelated parallel phenomena. The word 'excretion' has never been defined unequivocally; its use in the present review refers to its common signification, i.e. removal of waste material from the body.

2. Methodology of the Experimental Series The studies which form the basis of this review followed the same experimental design. 2.1 Subjects and Experimental Design Subjects were healthy male Caucasian volunteers (university students) aged between 18 and 30 who were not obese, smokers, alcoholics or drug abusers, and who had not received any active medication during the 2 weeks preceding the initiation of each study. No individual had any history of renal, hepatic, cardiovascular or metabolic disorders. No medication other than the trial formulations was taken by participants during the course of each study. Only a very few subjects participated in more than 1 study. Study subjects followed a diet controlled for fluid and sodium chloride during a period adequate to ensure the attainment of steady-state turnovers of water and these 2 electrolytes before the medications were given. fluid was taken ad libitum during the 24-hour periods after drug administration. The 24-hour urinary volume and urinary sodium excretions after treatment with placebo, quoted as part of the results presented, allow estimation of the fluid and sodium content of the diet in each study. Single oral doses of placebo and of diuretic formulations were given separately in double-blind fashion, following a randomised crossover design. Treatment days were separated by at least 7 days. Subjects stayed in a metabolic unit during treatment days and medications were given at 8am (hour oof the experiments). Urine passed during defined intervals after dosing was collected, measured and analysed for various solutes. Fractional urine collection intervals extended from 0 to 1.5, 1.5 to 3, 3 to 6, 6 to 9, 9 to 12, and 12 to 24 hours after

dosing when a loop diuretic was included in the study; in all other studies the collection periods of o to 1.5 and 1.5 to 3 hours after dosing were combined. In addition, the collection periods of 6 to 9 and 9 to 12 hours after study treatment were combined in 2 studies (Leary et al. 1983; Reyes & Leary 1984d). Venous blood was drawn at experimental hours 0, 1.5 (not in all studies), 6 and 24, and serum analysed for the same solutes as urine, In a methodologically different study, parts of whose results are also considered, daily doses of each trial preparation (placebo and hydrochlorothiazide 25mg) were administered to volunteers during 4 days (Leary, Reyes & van der Byl, unpublished data). The metabolic sampling was carried out on the first and fourth day of each treatment period, the procedure being otherwise similar to that of the single-dose studies. Standard techniques were used for laboratory analyses. All laboratory measurements were carried out more than once (3 times in most studies), and averages of the assay results were considered final measurements. 2.2 Mathematical Methods 2.2.1 Description of Experimental Urine and Urinary Solute Cumulative Outputs and of Derived Flows as Continuous Functions of Time The time courses of the outputs of urine, and/ or of naturally occurring urinary solutes, and/or of diuretics or their metabolites in urine, accumulated after the administration of placebo or of a diuretic, are usually presented as sigmoid-shaped discrete functions of time in studies similar to those described here. This treatment of results is tenable, since the flows of urine and of naturally or artificially occurring urinary solutes have a maximum value after placebo or a diuretic is administered; this maximum becomes evident when urine is collected sufficiently frequently after drug administration and outputs of urine and urinary solutes over each urine collection period are divided by the duration of the period. In this way, discrete estimates of the mean urine and urinary solute flows for each

Drugs 41 (Suppl. 3) 1991

38

a 300

.-.-.- .-._.-.

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'c"

"§ ~

200

alE

.s

~ 100 E~ ::::l

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.~

8.2

4;

fj

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.. ' ~

.;:~-r~

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. /.~.. ..•. ... ....... " ~

...

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_.-----------

.

b 'i

.c

40

8 '

(5

E

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---

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12

24

Hours after dosing Fig. 1. (a) Example of the fit of the UY function (curves) to the cumulative urinary excretion data for chloride in I subject after separate randomised, double-blind, crossover oral administration of placebo (e---e), furosemide 40mg (...... ) and hydrochlorothiazide 25mg (.-.-.) at 0800h. For the linear transformation of each fitted function, r (the correlation coefficient) is > 0.9999 and p (the 2-sided probability that the corresponding correlation coefficient does not differ from 0) is < 0.0000 I. The function parameter T is 0.1973 hours for placebo, 0.0483 hours for furosemide 40mg, and 0.0853 hours for hydrochlorothiazide 25mg; the function parameter k is 0.1328, 0.1218 and 0.1152, respectively. (b) Urinary chloride flows evaluated as the first derivatives of the curves shown in a. The maximal urinary chloride flow value is 5.93 mmol· h- i after placebo (---). 40.09 mmol· h- i after furosemide 40mg (••.. ). and 32.22 mmol· h- i after hydrochlorothiazide 25mg (_._); the times to maximal urinary chloride flows are 4.08. 1.22 and 2.43 hours. respectively (from Reyes. Leary & van der Byl. unpublished data).

period are obtained; these adopt an asymmetrical 'staircase' shape with an ascending phase, a ceiling, and a descending phase during the 24 hours after

dosing. Thus, cumulative outputs after dosing must be measured as sigmoid-shaped functions of time, in order for a maximum to appear in their timederivatives, i.e. flows. An established asymmetrical bell-shaped function which upon integration produces a sigmoid function (Davis 1965) was postulated as a continuous description of urinary flows of fluid and solutes (Reyes & Leary 198Ia). Since the primitive sigmoid function fitted cumulative excretions satisfactorily, it was designed to stand as a mathematical model of the outputs of urine and of naturally, or artificially, occurring urinary solutes as continuous functions of time, when urine is collected during different periods throughout 24 hours (Reyes & Leary 1981a). This mathematical model holds during control urine excretion or during or after dietary manipulation, and after the administration of placebo, a diuretic or of any other medicament, in health and disease. The derivative of this function with respect to time represents the flow of urine or of any urinary solute as a continuous function of time. The primitive function in question fitted experimental data of the type presented in this review with a great degree of accuracy (Reyes et al. 1988a). A better sigmoid-shaped function than that initially propounded (Reyes & Leary 1981 a), named the Urinary Yield (UY) function, was elaborated recently by this author (Reyes et al. I 990c); this departed from the previously used function. The UY function describes the individual or mean cumulative excretion of urine or of any urinary solute (A) as a function of time (t) throughout the 24-hour period after administration of placebo, a diuretic, or any other type of drug (Reyes et al. 1988b, I 990b,c). In the analytical expression of the UY function In([(7a+ 7eeA)/a]{l/ln[(ae LA)/aJl) = 1/(T+kt), where a = an A-dimensioned constant which equals one A unit (litre for urine, mmol or /.Lmol for solutes), T = a time-dimensioned parameter, and k = a dimensionless parameter. T and k have no direct physiological correlates. At t = 0, A = O. This implicit function may be readily linearised to evalu-

Effects of Diuretics on Urinary Outputs

a

39

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150

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ate the linear correlation coefficient (r) and the original-ordinate intercept (T) and slope (k) parameters by linear regression using individual or mean A values and clinicoexperimental t values. The linearised version is as follows:

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.+ ,/ ... "

100

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t/ln([(7a+7e eA)ja]{ l/ln[(ae L A)/alJ) = T+kt.

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Fig. 2. (a) Example of the fit of the UY function (curves) to the cumulative urinary excretion data for chloride in 1 subject after separate, randomised, double-blind, crossover oral administration of placebo (e-e), torasemide 5mg (.---.) and torasemide 10mg (+-+) at 0800h. As in fig. I, r = 0.9999, p < 0.00001 for each linearised curve fitting. The function parameter T is 0.1973 hours for placebo, 0.0534 hours for torasemide 5mg, and 0.0330 hours for torasemide 10mg; the function parameter k is 0.1328, 0.1227 and 0.1223, respectively. (b) Urinary chloride flows evaluated as the first derivatives of the curves shown in a. The maximal urinary chloride flow value is 5.93 mmol· h- i after placebo (-),34.64 mmol· h- i after torasemide 5mg (---), and 57.06 mmol· h- i after torasemide IOmg (....); the times to maximal urinary chloride flow are 4.08 hours, 1.33 hours and 0.82 hours, respectively (from Reyes, Leary & van der Byl, unpublished data).

For optimal fittings, data are expressed in the following units when correlation and regression are evaluated: urine in L x 10- 2 , urinary chloride, sodium, potassium and urea nitrogen in mmol, urinary calcium, magnesium, inorganic phosphate, urate and creatinine in mmol x 10- 1, and urinary zinc in ,umol x 10- 1• Figures 1 and 2 exemplify fittings of the UY function to individual experimental. data, and table I shows the outstanding degree of accuracy with which the UY function fits such a datum type. The precision with which the UY function fits mean cumulative urinary outputs from various subjects as functions of time is even higher than that quoted in table I for individualised data (Reyes, Leary & van der Byl, unpublished data). All variables derived from the UY function (maximal urine and urinary solute flows after dosing, times from dosing to maximal flow and instantaneous renal clearances) quoted in this review originated in fittings of the UY function to individual (not mean) data. Each of these fittings had an r value which differed from 0 at least at the 5% 2-tailed p level; however, the p "" 0.00001 level was met by the majority of the fittings (see table I).

2.2.2 Flows of Urine and Urinary Solutes as Continuous Functions of Time The flow of urine or of any urinary solute as a continuous function of time during the 24-hour period after administration of placebo, a diuretic or any other drug is given by the first derivative of the UY function: dA/dt = T/[(T+kt)2(ee/(a+eeA)+ 1/ {(ae 7 -A)ln[(ae 7 -A)/a] l )]. The dA/dt function exhibits an increasing interval, a maximum value and a decreasing interval thereafter (figs I and 2).

40

Drugs 41 (Suppl. 3) 1991

Table I. Goodness of fit of the UY function to individual urinalysis data obtained after randomised, double-blind, crossover singledose administration of placebo, diuretics and other drug forml,llations to healthy volunteers a Study and no. of subjects

Number of evaluated correlation coefficients, with p values vs 0 as indicated, divided by the number of evaluated correlation coefficients (0.001 < P < 0.05 not quoted)

Treatment

fluid, chloride, sodium and potassium

calcium, magnesium, inorganic phosphate, zinc, urate, urea nitrogen and creatinine

p < 10-3 A (n = 14)b

B (n

C (n

= 14)b

= 14)b

Placebo Torasemide 2.5mg Torasemide 20mg Placebo Furosemide 40mg and amiloride 5mg Captopril 25mg Furosemide 40mg and captopril 25mg Placebo c

1/56

1/56

Furosemide 40mg

o (n

= 12)d

E (n = 12)d

HCTZ 25mg Torasemide 5mg Torasemide 10mg Placebo e

12/48

HCTZ 25mg HCTZ 25mg and spironolactone 100mg Placebo HCTZ 25mg Rilmenidine 1mg HCTZ 5mg and rilmenidine 1mg

1148

p ~ 10-5

P < 10-3

p ~

56/56 56/56 56/56 55/56 56/56

7198 6198 7198 13/98 7198

90/98 92/98 91/98 85/98 91/98

55/56 56/56

14/98 7198

84/98 91/98

56/56 56/56 56/56 56/56 56/56 36/48 48/48 47/48

13/98 9198 6198 8198 10/98 54/84 31/84 38/84

83/98 89/98 92/98 90/98 88/98 29/84 52/84 46/84

10-5

15/48

33/48

41/84

42/84

4148

44/48

32/84

11/48

37/48

46/84

52/84 37/84

2148

46/48

42/84

42/84

In studies A, Band C urine was collected between 0 and 1.5, 1.5 and 3, 3 and 6, 6 and 9, 9 and 12, and 12 and 24 hours after dosing; in studies 0 and E urine was collected between 0 and 3, 3 and 6, 6 and 9, 9 and 12, and 12 and 24 hours after dosing. b From Reyes, Leary & van der Byl, unpublished data. 0.12248. c In 1 subject, calcium gave an r value with p a

=

d From Leary, Reyes & van der Byl, unpublished data. e In 1 subject, inorganic phosphate gave an r value with p = 0.24952. Abbreviation: HCTZ = hydrochlorothiazide.

The maximal flow of urine or of any urinary solute after dosing is given by the maximal value of the dA/dt function. The time from dosing to the maximal flow of urine or of any urinary solute is defined and evaluated accordingly. Since the maximal urine or urinary solute flow after dosing occurs at a time when d 2A/dt 2 = 0, both maximal flow and time to maximal flow have clear mathematical purport and include the information

conveyed by T and k; maximal flow and time to maximal flow also bear unequivocal physiological meanings. 2.2.3 Instantaneous Renal Clearances of Urinary Solutes The renal clearance of a substance is defined as the amount of plasma from which the substance is removed during the passage of blood through the

Effects of Diuretics on Urinary Outputs

kidneys in a given period of time. To assess the renal clearance of a substance, urine passed during a certain period (usually 15 minutes) is collected and analysed for the substance. Blood is withdrawn in the midpoint of the period, and the plasma concentration of the substance is measured; the product of the urinary concentration of the substance (mass· volume-I) and the mean urine flow (volume • time-I) during the period gives the mean urinary flow (mass· time-I), and the ratio between the mean urinary flow of the substance and its plasma concentration (mass· volume-I) gives the conventional renal clearance (volume· time-I). When the flow of urine is rapidly changing, as after administration of a loop diuretic (figs 1 and 2), the standard method for the assessment of the renal clearance of a substance results in a mean value which differs markedly from its constituent elements when the period considered approaches zero. To gain sensitivity under these circumstances, the variable 'instantaneous renal clearance' was propounded, and defined as the ratio between the value of the urinary flow of the substance at a definite time and the simultaneous plasma concentration of the substance (Reyes & Leary 1984c). To calculate the instantaneous renal clearance of a substance, it is necessary to know the urinary flow of the substance when blood is withdrawn. The urinary-solute-flow function of time, derived from the corresponding UY cumulative urinary-soluteoutput function of time, provides a continuous set of instantaneous urinary solute flow values, which have been used for computing the values of instantaneous renal clearances at the definite times after dosing (Reyes et al. 1990a) quoted in this reVIew. 2.2.4 Central Tendencies of Derived Variables When the UY function is fitted to mean cumulative outputs, the T and k values obtained differ slightly from the mean T and k values which are calculated from individual T and k values. This difference, which stems from the fact that T and k are evaluated by linear regression on linearised (and not plainly linear) experimental data, results in differences of minor importance between the values

41

of variables derived from the dA/dt function (maximal urine or urinary solute flows, times to maximal flows, and instantaneous renal clearances), representing the central tendency of a set of excretions, when they are evaluated by the 2 different procedures. Central-tendency estimations of maximal flows, times to maximal flows and instantaneous renal clearances quoted in this review were all evaluated as the means of individual values, because of the goodness of fit and to allow the drawing of statistical inferences. 2.3 Statistical Methods 2.3.1 Presentation of Data Large numbers of individual data were produced in each study, and these results are partially quoted and discussed in this review. Data are measurements of continuous variables which have been assumed to satisfy the requisites for parametric descriptive and inferential techniques; accordingly, results are expressed as means or as means and SEMs. The text refers to changes in the mean values of variables. 2.3.2 The Issue of Multiple Comparisons The nature of the studies described required that various multiple comparisons between mean values were carried out. Multiple 2-tailed paired t-tests were used for this purpose, and the null hypothesis was rejected when p was lower than 0.05. In as much as this technique is not ideal for multiple contrasts (Godfrey 1985; Louis et al. 1984; Smith et al. 1987), various reasons which grounded its use should be considered carefully . • The renal excretions of fluid and the electrolytes examined here are interdependent, and the variables aimed at describing each such excretion (urinary output and flow, and derived variables such as maximal urinary flow after dosing, time to maximal urinary flow and instantaneous renal clearances) are also interdependent; these interdependencies attenuate the impact of multiple univariate comparisons on the possibility of rejecting the null hypothesis unduly (Ottenbacher 1988). • The 2-sided t-test for dependent samples was

42

Drugs 41 (Suppl. 3) 1991

used throughout, despite the fact that monodirectional changes could be expected in many cases. This procedure is in such cases equivalent to having the a-level (p value beyond which the null hypothesis about the difference between 2 means is rejected), i.e. it provides a conservative margin of safety against undue rejection of the null hypothesis. • The results oft-tests are always cited as p > 0.05, p < 0.05, p < 0.01 or p < 0.001, thus leaving no doubt as to the probability range within which each of them falls, and allowing independent reassessment of multiple contrasts through (exaggeratedly stringent for these cases) criteria such as the Bonferroni method (Ottenbacher 1988; Smith et al. 1987). The expressions 'significant' and 'not significant' are avoided, since exact p values or p values defined within known ranges are more precise, efficient and unbiased, and allow further conceptual elaborations (Romano 1988). • The main objective of the statistical analyses performed is to identify clear trends, whereas any attempt to determine terminal points is out of the question. • Extant methods for multiple comparisons of de-

pendent interrelated variables as well as methods for correcting the a-level upon quantitative criteria are far from ideal for the type of data under analysis, since all such methods invariably increase the possibility of undue acceptance of the null hypothesis when the conventional criterion of decision (p = 0.05) is applied.

3. Renal Excretory Potency of Diuretics 3.1 Definition The renal excretory potency of diuretics may be defined in terms of the actions of these drugs on the urinary excretions of water, sodium and chloride. Diuresis and natriuresis have been selected as the reference variables for defining diuretic and natriuretic potency in this uptake; these variables are considered together, because there is no need to discriminate between them for the present purpose, although diuresis and natriuresis are not comparably affected by different classes of diuretics. The time during which the effects of diuretics on urinary water and sodium excretions should be considered for defining diuretic potency must be

Table II. Urinary solute outputs after randomised, double-blind, crossover single doses of placebo and xipamide, in 13 healthy subjectsa (hour 0800) [adapted from Reyes & Leary 1984d with permission from the Brazilian Journal of Medical and Biological

Research] Urinary variable

Sodium

Potassium

Magnesium

Time after administration (h)

Mean excretion after placebo (mmol)

0-6 6-24 0-24 0-6 6-24 0-24 0-6 6-24 0-24

43 108 151 17 25 42 1.0 3.0 4.0

Change after xipamide 5mg

Change after xipamide 10mg

Change after xi pam ide 20mg

(%)

(%)

(%)

192 92 120***tt 91 31 55*' 47 51 50**'

142 99

97 26 47" 68 22 41** 21 30 28**

111***ttt 74 83 79***tt 22 47 40***

a 12 subjects for xipamide 20mg. Comparisons between the mean 24-hour outputs of each urinary solute after the different treatments (xipamide 5mg vs placebo, xipamide 10mg vs placebo, and xipamide 10mg vs xipamide 5mg) were made using the 2-tailed paired t-test; only p values lower than 0.05 are quoted: '* and "* indicate differences from placebo (p < 0.01 and p < 0.001, respectively), and tt and ttt indicate differences from xipamide 5mg (p < 0.01 and p < 0.001, respectively).

Effects of Diuretics on Urinary Outputs

43

Comparisons with PLA

Urine output (L)

o

2

4

3

o to 6h

6 to 24h

o to 24h

NS NS

NS NS

* *** *** **

*** **

NS NS NS

PLA A PLA B TOR 2.5 TOR 5

TOR 10 TOR 20 FUR 40 HCTZ 25

*** NS

NS

**

Fig. 3. Mean urine output (0 = 0 to 6 hours, • = 6 to 24 hours) after randomised, double-blind, crossover oral administration of single doses of various formulations to the same number of healthy subjects (14) in 2 different studies; PLA A, TOR 5, TOR 10, FUR 40 and HCTZ 25 were given in study A, and PLA B, TOR 2.5 and TOR 20 in study B. Comparisons with corresponding means after placebo were made using the 2-tailed paired t-test. Abbreviations: FUR 40 = furosemide 40mg; HCTZ 25 = hydrochlorothiazide 25mg; PLA = placebo; TOR 2.5 = torasemide 2.5mg; TOR 5 = torasemide 5mg; TOR 10 = torasemide 10mg; TOR 20 = torasemide 20mg; NS = p > 0.05; * = p < 0.05; ** = p < 0.01; *** = p < 0.001 (adapted from Reyes et al. 1988a, with permission from Progress in Pharmacology, and from Reyes, Leary & van der Byl, unpublished data).

established exactly (Hamdy et al. 1984a,b; Leary & Reyes 1988; Reyes 1987b; Reyes & Leary 1987). It

daily. A general definition of the renal excretory

appears that the 24 hours following diuretic admin-

carried out in healthy subjects with a steady-state water and sodium balance, since patients with oedema or subjects on diets which interfere with this

istration is an appropriate evaluative lapse, because diuretics are most frequently prescribed once

potency of diuretics must be based upon studies

Urinary sodium output (mmol)

o

Comparisons with PLA

o to 6h

6 to 24h

o to 24h

*** *** *** ***

NS NS

NS NS NS

FUR 40

***

***

NS

HCTZ 25

***

100

200

300

PLA A PLA B TOR 2.5 TOR 5 ' TOR 10 TOR 20

**

*** *** ***

Fig. 4. Mean urinary sodium excretions (0 = 0 to 6 hours, • = 6 to 24 hours) after randomised, double-blind, crossover oral administration of single doses of various formulations to the same number of healthy subjects (14) in 2 different studies; PLA A, TOR 5, TOR 10, FUR 40 and HCTZ 25 were given in study A, and PLA B, TOR 2.5 and TOR 20 III study B. Comparisons with corresponding means after placebo were made using the 2-tailed paired t-test. Abbreviations: FUR 40 = furosemide 40mg; HCTZ 25 = hydrochlorothiazide 25mg; PLA = placebo; TOR 2.5 = torasemide 2.5mg; TOR 5 = torasemide 5mg; TOR 10 = torasemide 10mg; TOR 20 = torasemide 20mg; NS = P > 0.05; * = p < 0.05; ** = p < 0.01; *** = P < 0.001 (adapted from Reyes et al. 1988a, with permission from Progress in Pharmacology, and from Reyes, Leary & van der Byl, unpublished data).

44

Drugs 41 (Suppl. 3) 1991

"able III. Urinary solute outputs after randomised, double-blind, crossover single doses of placebo and muzolimine, in 10 healthy subjects (hour 0800) [adapted from Leary et al. 1985a, with permission from Zeitschrift fur Kardiologiej Urinary variable

Sodium

Potassium

Magnesium

Time after administration (h)

Mean excretion after placebo a (mmol)

Change after muzolimine 20mg (%)

Change after muzolimine 30mg (%)

Mean excretion after place bob (mmol)

0-6 6-24 0-24 0-6 6-24 0-24 0-6 6-24 0-24

57 129 186 22 32 54 1.3 3.4 4.7

79 -25 7 24 -16

154 -20

60 165 225 17 32 49 1.2 3.6 4.8

0 34 -21 -6

33** 60 -5 21t 52 -8 9

Change after muzolimine 40mg (%)

163 -36 17* 106 -22 24* 84 -14 11

a Applies to muzolimine 20 and 30mg. b Applies to muzolimine 40mg. Comparisons between the mean 24-hour outputs of each urinary solute after the different treatments (muzolimine 20mg vs placebo, muzolimine 30mg vs placebo, muzolimine 30mg vs muzolimine 20mg, and muzolimine 40mg vs placebo) were made using the 2tailed paired t-test; only p values lower than 0.05 are quoted: • and ** indicate differences from placebo (p < 0.05 and p < 0.01, respectively), and t indicates a difference from muzolimine 20mg (p < 0.05).

balance show a high level of intra- and intersubject variability in urinary outputs of fluid and sodium. The renal excretory potency of diuretics should be defined after a single dose of diuretic formulations, given that the initial increases in the renal excretions of water, sodium and other urinary solutes caused by diuretics fade after a few days during repeated once-daily administration to healthy subjects (Lameire & Dodion 1988; Leary, Reyes & van der Byl, unpublished data). Since the intakes of sodium and fluid determine the functional status of processes which regulate the renal handling of sodium and water, the diuretic and natriuretic potency of diuretics must be defined in subjects receiving a sodium diet which does not shift the activity of regulatory processes, such as the reninangiotensin-aldosterone system, from what is usual in the majority of the healthy population. The renal excretory potency of diuretics is thus defined by the changes in 24-hour diuresis and natriuresis, witlt!. respect to post-placebo excretions of fluid and sodium, when single doses of diuretics are orally administered to healthy subjects who are in habitual steady-state sodium and water balance.

3.2 Potency of Common Diuretic Formulations 3.2.1 Distal Tubular Diuretics Formulations of distal tubular diuretics, such as xipamide 5 (low dose), 10 and 20mg (common formulations) and hydrochlorothiazide 25mg (low dose common formulation), increase 24-hour diuresis and natriuresis markedly (table II, figs 3 and 4). These medications augment the urinary output of sodium over the 24 hours which follow drug administration, and they do not decrease diuresis or natriuresis between 6 and 24 hours after dosing (table II, figs 3 and 4). 3.2.2 Loop Diuretics Common formulations of loop diuretics do not increase 24-hour diuresis and natriuresis or increase them moderately (e.g. muzolimine 20 and 30mg, table III, and torasemide 2.5 and 5mg, figs 3 and 4). With respect to renal excretions after placebo, the striking renal excretory action induced by loop diuretics shortly after dosing is followed by directionally opposing rebounds in the urinary outputs of water and sodium, which usually extend

Effects of Diuretics on Urinary Outputs

45

between 6 and 24 hours after dosing (table III, figs 3 and 4). These rebounds account for the fact that common formulations of loop diuretics are not effective or are poorly effective as 24-hour diuretics and natriuretics in healthy subjects. The mechanism(s) of the rebounds is unknown. It may be primarily postulated that the rapid haemodynamic consequences of the renal excretory effect of loop diuretics, principally through the hypovolaemia that they cause, result in increases in reabsorptive processes from the preurine, mediated by local renal and/or indirect systemic processes (e.g. increases in sympathetic outflow, antidiuretic hormone and the activity of the renin-angiotensin-aldosterone system, and a decrease in atrial natriuretic factor). 3.2.3 Potassium-Retaining Diuretics A' common and a high dose (5 and lOmg) of the potassium-retaining diuretic, amiloride, were fo und to increase 24-hour natriuresis moderately (table IV).

potent (high potency) diuretics and natriuretics, loop diuretics as ineffectual or relatively low potency drugs, and potassium-retaining substances appear as low potency diuretics and natriuretics. This reclassification of diuretic formulations by their urinary excretory potency rectifies the mistaken concept that common formulations of loop substances are the most potent diuretics available. Table V shows that hydrochlorothiazide 25mg (usually and erroneously regarded as a weak formulation of this diuretic) exerts chloruretic, natriuretic and diuretic actions similar to those of furosemide 80mg (usually regarded as a strong formulation of this diuretic). The excretions of chloride, sodium and fluid after furosemide 80mg were higher than after hydrochlorothiazide 25mg during the first 6 hours after dosing, but they were lower during the 6- to 24-hour period after dosing, when rebounds with respect to post-placebo excretions occurred (table V). This accounts for the similar 24-hour excretions with both formulations.

3.3 New Classification of Common Formulations of Diuretics by Their Renal Excretory Potency When common formulations of diuretics are considered, distal tubular drugs appear as the most

3.4 Origin of the Erroneous Standard Classification of Diuretics When furosemide became the first loop diuretic to gain widespread clinical use, it was considered

Table IV. Urinary solute outputs after randomised, double-blind, crossover single doses of placebo and amiloride in 13 healthy SUbjects (hour 0800) [adapted from Leary et al. 1983, with permission from Current Therapeutic Research] Urinary variable

Sodium

Potassium

Magnesium

Time after administration (h)

Mean excretion after placebo (mmol)

Change after amiloride 5mg

Change after amiloride 10mg

(%)

(%)

0-6 6-24 0-24 0-6 6-24 0-24 0-6 6-24 0-24

37 85 122 20 25 46 1.0 3.1 4.1

54 31 38* -26 -32 -29** -14 2 -5

83 58 66***tt -29 -34 -32** -14 -5 -7

Comparisons between the mean 24-hour outputs of each urinary solute after the different treatments (amiloride 5mg vs placebo, amiloride 10mg vs placebo, and amiloride 10mg vs amiloride 5mg) were made using the 2-tailed paired t-test; only p values loWer than 0.05 are quoted: *, ** and *** indicate differences from placebo (p < 0.05, p < 0.01 and p < 0.001, respectively), and tt indicates a difference from amiloride 5mg(p < 0.01).

Drugs 41 (Suppl. 3) 1991

46

Table V. Urinary solute outputs (mean ± SEM) after randomised, double-blind, crossover single doses of placebo and diuretics in

14 healthy subjects (hour 0800) [Leary et al. 1990, with permission from the Journal of International Medical Research] Urinary variable a

Fluid

Chloride

Sodium

Potassium

Calcium

Magnesium

Time after administration (h)

Treatment

0-6 6-24 0-24 0-6 6-24 0-24 0-6 6-24 0-24 0-6 6-24 0-24 0-6 6-24 0-24 0-6 6-24 0-24

0.64 1.99 2.63 36 116 155 35 111 147 18 33 50 1.3 4.3 5.6 1.2 4.1 5.4

hydrochlorothiazide 25mg

placebo

± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±

0.06 0.15 0.17 5 10 13 4 9 13 2 2 3 0.1 0.3 0.5 0.2 0.3 0.4

1.25 2.04 3.29 132 151 283 116 141 257 26 34 59 1.9 3.4 5.3 1.9 4.1 6.5

± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±

0.12*** 0.14 0.18* 10*** 10* 16*** 7*** 10* 15*** 4 3 4* 0.2** 0.3* 0.5 0.2* 0.3 0.7*

furosemide 80mg 2.11 1.32 3.43 243 45 288 225 49 273 34 32 66 3.8 2.5 6.4 3.0 3.3 6.3

± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±

0.09***ttt 0.11***tt 0.13*** 13***ttt 6***ttt 15*** 14***ttt 6***ttt 17*** 2*** 3 5** 0.2***ttt 0.4***tt 0.5t 0.2***t tt 0.4* 0.5**

a Fluid in htres, solutes in mmol. Comparisons between the mean outputs of each urinary solute during each excretion period after the different treatments (hydrochlorothiazide 25mg vs placebo, furosemide 80mg vs placebo and furosemide 80mg vs hydrochlorothiazide 25mg) were made using the 2-tailed paired t-test; only p values lower than 0.05 are quoted: *, ** and *** indicate differences from placebo (p < 0.05, P < 0.01 and p < 0.001, respectively), and t , t t and ttt indicate differences from hydrochlorothiazide 25mg (p < 0.05, p < 0.01 and p < 0.001, respectively).

a high potency diuretic by comparison with extant thiazides. In addition, furosemide became referred to as a 'high-ceiling' diuretic because the doseresponse curves of its renal excretory effects are steep over a wide dose range, a novel feature amongst diuretics. The extreme epithets applied to furosemide were later extended to all loop diuretics, a practice which involves the following errors: firstly, overtly or implicitly considering loop diuretics as the most potent diuretics available (Hanisch 1983; Lant 1985a,b; Leary & Reyes 1981 ; Puschett 1981, 1986; Suki et al. 1985; Taylor 1985; Williamson 1977) despite the non-existence of a definition of the variable diuretic potency in clinical pharmacology up to now; and secondly, equating 'high ceiling' with 'high potency' (DuBose 1989). The error concerning the relative potency of different types of diuretics has its primary origin in

basic research and/or in the uncritical extrapolation of basic findings on the pharmacodynamics of diuretics to clinical pharmacology (Leary & Reyes 1988; Reyes et al. 1988a). Small animal species, such as mice and rats, have been and are used to define the pharmacodynamic characteristics of diuretics shortly after the syntheses of these drugs; the usual consequence of this practice is that by the time a new diuretic is first studied in man it has already been labelled with respect to its (hitherto undefined) diuretic potency. Studies in rats have operational limitations, e.g. it is difficult to collect urine for at least 24 hours after drug administration; consequently previous evaluations have often been of too short a duration toadequate1y record the effects of a diuretic on urinary excretions. This research limitation, together with a lack of proper feedback from the bedside to the basic

47

Effects of Diuretics on Urinary Outputs

Comparisons with PLA

Urinary potassium output (mmol)

o

20

60

40

o to 6h

6 to 24h

o to 24h

PLA A PLA B TOR 2.5

NS

NS

NS

TOR 5

NS

NS

NS

TOR 10

NS

TOR 20

***

NS NS

FUR 40

** **

NS NS

HCTZ 25

NS

** NS

Fig. 5. Mean urinary potassium excretions (0 = 0 to 6 hours, • = 6 to 24 hours) after randomised, double-blind, crossover oral administration of single doses of various formulations to the same number of healthy subjects (14) in 2 different studies; PLA A, TOR 5, TOR 10, FUR 40 and HCTZ 25 were given in study A, and PLA B, TOR 2.5 and TOR 20 were given in study B. Comparisons with corresponding means after placebo were made using the 2-tailed paired t-test. Abbreviations: FUR 40 = furosemide 40mg; HCTZ 25 = hydrochlorothiazide 25mg; PLA = placebo; TOR 2.5 = torasemide 2.5mg; TOR 5 = torasemide 5mg; TOR 10 = torasemide 10mg; TOR 20 = torasemide 20mg; NS = p> 0.05; * = p < 0.05; ** = p < 0.01; *** = p < 0.001 (adapted from Reyes et al. I 988a, with permission from Progress in Pharmacology, and from Reyes, Leary & van der Byl, unpublished data).

laboratory have caused most investigators to restrict primary descriptions and further appraisals of the renal excretory actions of diuretics in small animal species to the period between 1.5 and 8 hours after dosing (see Leary & Reyes 1988; Reyes et al. 1988a for extensive lists of references). In this Urinary magnesium output (mmol) 0

2

4

time distal tubular diuretics do not complete their excretory effect and loop diuretics induce an increase in the excretions of chloride, sodium and fluid. Thus, the total excretory action of some diuretics at certain doses as well as the biphasic effects (excretory actions and rebounds) which folComparisons with PLA

6

o to 6h

6 to 24h

o to

**

NS NS

NS NS NS

** NS

**

**

•••

24h

PLA A PLA B TOR 2.5 TOR 5 TOR 10 TOR 20 FUR 40 HCTZ 25

r==

** *** ** **

Fig. 6. Mean urinary magnesium excretions (0 = 0 to 6 hours, • = 6 to 24 hours) after randomised, double-blind, crossover oral administration of single doses of various formulations to the same number of healthy subjects (14) in 2 different studies; PLA A, TOR 5, TOR 10, FUR 40 and HCTZ 25 were given in study A, and PLA B, TOR 2.5 and TOR 20 in study B. Comparisons with corresponding means after placebo were made using the 2-tailed paired t-test. Abbreviations: FUR 40 = furosemide 40mg; HCTZ 25 = hydrochlorothiazide 25mg; PLA = placebo; TOR 2.5 = torasemide 2.5mg; TOR 5 = torasemide 5mg; TOR 10 = torasemide IOmg; TOR 20 = torasemide 20mg; NS = p > 0.05; * = p < 0.05; ** = p < 0.01; *** = p < 0.001 (adapted from Reyes et al. 1988a, with permission from Progress in Pharmacology, and from Reyes, Leary & van der Byl, unpublished data).

48

Drugs 41 (Suppl. 3) 1991

low administration of some diuretics in certain doses are disregarded in pharmacological investigations conducted in small animal species. As a consequence, loop diuretics have been considered as the most potent drugs of this class with respect to renal excretory actions. Experiments in larger animal species, such as rabbits, dogs and monkeys, in which urine collection may be observed easily for longer than a few hours after dosing, have been carried out infrequently and have not exposed the mistaken concept about the potency of diuretics. In some of these studies the collection of urine was also restricted to less than 8 hours after diuretic administration, and studies in which urine collections were extended between 20 and 24 hours did not clarify the issue of diuretic potency either, because they did not Gompare the actions of loop and distal tubular diuretics. Many studies on the effects of diuretics on urinary excretions carried out in healthy subjects have not been sufficiently prolonged to show the full action of distal tubular diuretics on renal excretions and/or the full biphasic excretory action of loop diuretics, since urine collections were limited to less than 12 hours after dosing (see Leary & Reyes 1988; Reyes et al. 1988a for extensive list of references).

4. Diuretic-Induced Changes in Urinary Potassium and Magnesium Excretions 4.1 Distal Tubular Diuretics Common formulations of distal tubular diuretics increase 24-hour kaliuresis and magnesiuresis (tables II and V, figs 5 and 6) [Reyes & Leary 1981 b, 1984b]. These elevations stem from increases in urinary potassium and magnesium outputs, which occur during the first hours after dosing, and from the: less intense increases which take place later (tables II and V, figs 5 and 6). At 1.5 hours after administration of hydrochlorothiazide 25mg, the kidney is removing more sodium and potassium from plasma than magnesium (fig. 7), whereas at 6 hours after dosing the instantaneous renal clearance of magnesium is more elevated, with respect to the post-placebo clear-

ance, than the instantaneous renal clearance of potassium (table VI, fig. 8). Thus, the effect of distal tubular diuretics on the renal excretion of magnesium is delayed with respect to the effects of these drugs on the renal excretions of water, chloride, sodium and potassium. This finding has suggested that distal tubular diuretics might increase magnesiuresis mostly by an indirect mechanism, rather than by direct blockade of magnesium reabsorption from the preurine (for comprehensive reviews see Reyes 1985, 1987b, 1989; Reyes & Leary 1984a,b). 4.2 Loop Diuretics High dose formulations of loop diuretics (e.g. furosemide 80mg, muzolimine 40mg and torasemide 20mg) tend to decrease urinary potassium excretion with respect to its post-placebo counterpart during the 6- to 24-hour period after dosing (tables III, V and VI, figs 5 and 9). These minor (small) rebounds in potassium excretion occur despite an important activation of the renin-angiotensin-aldosterone system secondary to the intense natriuretic effect of these formulations in the first 6 hours after dosing (tables III and V, figs 4 and 7). 4.3 Potassium-Retaining Diuretics Amiloride 5 and 10mg caused reductions in 24hour kaliuresis, which resulted from decreases in the urinary output of potassium during the 0- to 6- and the 6- to 24-hour periods after dosing, in parallel with increases in natriuresis (table IV). Amiloride 5 and 10mg tended to retain magnesium, but this directional tendency was of no great magnitude (table IV). 4.4 Comparative Kaliuretic Effect of Common Diuretic Classes All common formulations of distal tubular diuretics increase 24-hour kaliuresis and magnesiuresis (tables II and V, fig. 6); common formulations of loop diuretics do not affect these variables or they may elevate them only slightly (table III, fig. 6), and high dose formulations ofloop diuretics elevate 24-hour kaliuresis and magnesiuresis to the

49

Effects of Diuretics on Urinary Outputs

After PLA (mi · min - 1 )

Change in IRCs at 1.5 hours post-dose (%) 0

Na

TOR 2.5

1.05

TOR 5

1.07

TOR 10

1.07

TOR 20

105

FUR 40

1.07

HCTZ 25

1.07

•-

• -

300

••• ••• ••• •••

0

K

TOR 2.5

16.0

TOR 5

135

TOR 10

13.5

TOR 20

16.0

FUR 40

13.5

HCTZ 25

13.5

60

TOR 2.5

4.9

TOR 5

3.9

TOR10

3.9

TOR 20

4.9

FUR 40

3.9

HCTZ 25

3.9

120

NS



..

NS

•••

• -. -. -.NS 0

Mg

600

150

300

•••

..

•••

Fig_ 7. Changes from placebo values of instantaneous renal clearances (IRCs) of sodium, potassium and magnesium at 1.5 hours after randomised, double-blind, crossover oral administration of single doses of various formulations to the same number of healthy subjects (14) in 2 different studies; PLA, TOR 5, TOR 10, FUR 40 and HCTZ 25 were given in one study, and PLA, TOR 2.5 and TOR 20 in the other. All values after HCTZ 25 and magnesium values after FUR 40 were derived from 13 subjects, all values after TOR 5 were derived from 12 subjects, and all values after TOR 10 were derived from 10 subjects. Comparisons between means from which percentages were derived and means after placebo were made using the 2-tailed paired t-test. Abbreviations: FUR 40 = furosemide 40mg; HCTZ 25 = hydrochlorothiazide 25mg; PLA = placebo; TOR 2.5 = torasemide 2.5mg; TOR 5 = torasemide 5mg; TOR 10 = torasemide 10mg; TOR 20 = torasemide 20mg; NS = p > 0.05 ; * = p < 0.05; ** = p < 0.01 ; *** = p < 0.001 (adapted from Reyes et al. 1990c, with permission from Progress in Pharmacology and Clinical Pharmacology).

Drugs 41 (Suppi. 3) 1991

50

Table VI. Instantaneous renal clearances (mi' min- 1) [mean ± SEM] after randomised, double-blind, crossover single doses of placebo and diuretics in 14 healthy subjects (hour 0800) [Leary et al. 1990, with permission from the Journal of International Medical Research]

Urinary variable

Treatment

6 hours post-dose

24 hours post-dose

Chloride

Placebo Furosemide 80mg HCTZ 25mg Placebo Furosemide 80mg HCTZ 25mg Placebo Furosemide 80mg HCTZ 25mg Placebo Furosemide 80mg HCTZ 25mg Placebo Furosemide 80mg HCTZ 25mg Placebo Furosemide 80mg HCTZ 25mg

1.61 ± 0.14 1.45 ± 0.15

0.53 0.12 0.57 0.38 0.09 0.39 3.4 2.5 3.7 0.83

Sodium

Potassium

Calcium

Magnesium

Creatinine

3.32 ± 0.18"""ttt 1.14 ± 0.11 1.13 ± 0.11 2.24 13.9 18.8 17.6 2.34 2.45 2.30 6.2 8.5 8.8 190 164 185

± ± ± ± ± ± ± ± ± ± ± ± ±

0.13"""ttt 0.7 1.4"" 1.3" 0.22 0.24 0.22 0.6 0.7""" 0.9"" 18 15 15

0.31 0.60 2.5 1.4 2.8 57 62 58

± 0.06 ± 0.01""" ± 0.04ttt ± 0.04 ± 0.01""" ± ± ± ± ±

0.03ttt 0.3 0.2" O.4t 0.08

± 0.04""" ± 0.06"ttt ± 0.2 ± 0.2""" ± O.4ttt ± 5 ± 8 ± 5

Abbreviation: HCTZ = hydrochlorothiazide.

Comparisons between the mean instantaneous renal clearances of each urinary solute at the same time after the different treatments (furosemide 80mg vs placebo, HCTZ 25mg vs placebo, and HCTZ 25mg vs furosemide 80mg) were made using the 2-tailed paired t-test; only p values lower than 0.05 are quoted: ", "" and """ indicate differences from placebo (p < 0.05, p < 0.01 and p < 0.001, respectively), and t and ttt indicate differences from furosemide 80mg (p < 0.05 and p < 0.001, respectively) .

same extent as common formulations of distal tubular diuretics (tables III and V, fig. 6). Amiloride 5 and 10mg diminish the 24-hour renal output of potassium substantially and 24-hour magnesiuresis to a much less extent (table IV).

5. Rebounds in Urinary Fluid and Solute Flows Following the Positive Excretory Actions 0/ Diuretics 5.1 Existence, Magnitude and Duration When the 24-hour urinary flows of fluid, chloride, sodium, potassium and magnesium after administration of a loop diuretic to healthy subjects are considered with respect to post-placebo flows, the sharp elevations in excretions which take place within a few (0.5 to 6) hours after dosing with the active medication are followed by directional rebounds (table III, figs I to 6) [Leary & Reyes 1988; Reyes 1987a,b, 1989; Scheen 1988]. The ex-

istence of some of the directional rebounds after some loop-diuretic formulations (e.g. rebounds in urinary magnesium flow after torasemide 2.5mg and furosemide 40mg) may not be apparent from depictions such as that of figure 6, because in some cases the rebounds start too late after the twelfth hour after dosing or they are mild in intensity, and/ or they exhibit a minimum and return to baseline within the 12- to 24-hour observation period (Reyes, Leary & van der Byl, unpublished data). It would be necessary to have fractional collections of urine between 12 and 24 hours after dosing, for the detection of late, mild or transient rebounds directly, but this was not done in the studies reviewed here to avoid disturbing the sleep of the study subjects. However, when instantaneous renal clearances are considered, it is readily apparent that at 1.5 hours after dosing all common formulations ofloop diuretics (e.g. furosemide 40mg, torasemide 2.5, 5 and IOmg) exert directionally excretory ef-

Effects of Diuretics on Urinary Outputs

51

After PLA

Change in IRCs at 6 hours post-dose (%j

(ml·min- 1 j

o

.NS _NS NS. NS""NS

-20

Na

K

Mg

TOR 2.5

1.43

TOR 5

1.19

TOR 10

1.19

TOR 20

1.43

FUR 40

1.19

HCTZ 25

1.19

TOR 2.5

15.2

TOR 5

12.0

TOR 10

12.0

TOR 20

15.2

FUR 40

12.0

HCTZ 25

12.0

TOR 2.5

6.6

TOR 5

4.4

TOR 10

4.4

TOR 20

6.6

FUR 40

4.4

HCTZ 25

4.4

I

NS



NS

40

80

•••

NS

--. .NS --.

I

••

INS



NS

NS

•••

8. Changes from placebo values of instantaneous renal clearances (IRCs) of sodium, potassium and magnesium at 6 hours after randomised, double-blind, crossover oral administration of single doses of various formulations to the same number of healthy subjects (14) in 2 different studies; PLA, TOR 5, TOR 10, FUR 40 and HCTZ 25 were given in one study, and PLA, TOR 2.5 and TOR 20in the other. Comparisons between means from which percentages were derived and means after placebo were made using the 2-tailed paired t-test. Abbreviations: FUR 40 = furosemide 40mg; HCTZ 25 = hydrochlorothiazide 25mg; PLA = placebo; TOR 2.5 = torasemide 2.5mg; TOR 5 = torasemide 5mg; TOR 10 = torasemide 10mg; TOR 20 = torasemide 20mg; NS = p> 0.05; * = p < 0.05; ** = p < 0.01; *** = p < 0.001 (adapted from Reyes et al. 1990c, with permission from Progress in Pharmacology and Clinical Pharmacology). Fig.

52

fects (fig. 7), and at 6 hours after dosing they may be elevating the urinary excretions of sodium and potassium or may already be inducing rebounds in them, while they are invariably increasing urinary magnesium excretion (fig. 8). At 24 hours after dosing, all common formulations of loop diuretics induce a directional decrease in the renal clearances of electrolytes (fig. 9). Instantaneous renal clearances and corresponding urinary solute flows may be equated at 24 hours after dosing, because at that time the serum concentrations of the electrolytes shown in figure 9 did not differ from their post-placebo counterparts (Reyes et al. 1988a; Reyes, Leary & van der Byl, unpublished data). However, it must be considered that urinary solute flows and instantaneous renal clearances at 24 hours after dosing with loop diuretics are biased estimators, given that instantaneous renal clearances are evaluated from urinary solute flows and that conceiving cumulative urinary excretions as monotonically increasing sigmoid functions of time implies that derived urinary solute flows are monotonically decreasing over the intervals which follow their maxima (figs I and 2). Consequently, the value of any urinary solute flow at 24 hours after dosing is the minimal value that the flow function may attain after its peak within the observation period (figs 1 and 2). When urinary flows remain above post-placebo flows during the 24 hours after active drug administration, as occurs for distal tubular diuretics (table II, figs 1 and 3 to 7), their values during the last hours of collection, inferred through the mathematical approach used, present no relevant bias with respect to corresponding post-placebo flows. However, when rebounds occur sometime between 6 and 24 hours after dosing, as happens in response to loop diuretics, urinary solute flows at 24 hours after dosing are or may be magnified expressions of the rebounds if the actual flow is in the process of returning or has already returned to baseline. Despite this apparent shortcoming, the existence of an instantaneous renal clearance at 24 hours after dosing with a diuretic that has a lower value than its corresponding post-placebo variable indicates that a rebound is occurring or has occurred, pro-

Drugs 41 (Suppl. 3) 1991

vided no difference exists between the plasma concentrations of the solute involved after placebo and after the diuretic, as was the case in these studies (fig. 9) [Reyes et al. 1988a; Reyes, Leary & van der Byl, unpublished data]. The magnitude of the rebound is positively related to the dose (Stallings et al. 1979), as shown for torasemide in figure 9, to the magnitude of the forced excretions which precede the rebounds (figs 3 to 6) and to the maximal urinary flow after dosing (fig. 10), and it is negatively related to the time from dosing to maximal urinary flow (fig. 11). Whether the magnitude of the forced excretions which precede the rebounds (figs 3 to 6) and/or the rates at which they occur (figs 10 and 11), both of which are dose-related in positive fashion, determine the magnitude and/or the time course of the rebounds remains to be investigated. Common formulations of distal tubular diuretics do not lead to the development of rebounds between 6 and 24 hours after dosing, when single doses are administered to healthy subjects (tables II, V and VI, fig. 9). 5.2 Situations in which Loop Diuretics Do Not Produce Rebounds in Urinary Excretions

5.2.1 Patients with Oedema The administration of common doses of loop diuretics (e.g. torasemide IOmg) to patients with cardiac or renal oedema who are not compensated does not cause late-after-dosing rebounds in urinary excretions within 24 hours of the first dose (Broekhuysen et al. 1986; Scheen et al. 1986). Repeated once-daily administration is associated with rebounds as oedema subsides, but the onset of rebounds in patients with pathophysiological disorders that tend to cause sodium and water retention is delayed with respect to the onset of rebounds in healthy subjects, as may be inferred by comparing the results of Hamdy et al. (1984a,b) after administration of a single dose of furosemide 40mg to patients with cardiac insufficiency with those of Reyes et al. (l988a) in healthy subjects. Delayed rebounds were also found after administration of 6mg of the loop diuretic piretanide to patients with

53

Effects of Diuretics on Urinary Outputs

After

PLA

-30

-60

Na

K

Mg

TOR 2.5

0.32

TOR 5

0.25

TOR 10

0.25

TOR 20

0.32

FUR 40

0.25

HCTZ 25

0.25

TOR 2.5

2.8

TOR 5

2.4

TOR 10

2.4

TOR 20

2.8

FUR 40

2.4

HCTZ 25

2.4

TOR 2.5

1.7

TOR 5

2.0

TOR 10

2.0

TOR 20

1.7

FUR 40

2.0

HCTZ 25

2.0

-NS_

Change in IRCs at 24 hours post-dose (%)

(mi· min- 1 )

..

o

30

_NS

•••

-.NS.

NS

NS_

NS_

NS

NS

- -

NS

Fig. 9. Changes from placebo values of instantaneous renal clearances (IRCs) of sodium, potassium and magnesium at 24 hours after randomised, double-blind, crossover oral administration of single doses of various formulations to the same number of healthy subjects (14) in 2 different studies; PLA, TOR 5, TOR 10, FUR 40 and HCTZ 25 were given in one study, and PLA, TOR 2.5 and TOR 20 in the other. Comparisons between means from which percentages were derived and means after placebo were made using the 2-tailed paired t-test. Abbreviations: FUR 40 = furosemide 40mg; HCTZ 25 = hydrochlorothiazide 25mg; PLA = placebo; TOR 2.5 = torasemide 2.5mg; TOR 5 = torasemide 5mg; TOR 10 = torasemide IOmg; TOR 20 = torasemide 20mg; NS = p> 0.05; * = p < 0.05; ** = p < 0.01; *** = p < 0.001 (adapted from Reyes et al. 1990c, with permission from Progress in Pharmacology and Clinical Pharmacology).

54

Drugs 41 (Suppl. 3) 1991

predialysis renal insufficiency (Sjostrom et al. 1977). It may be inferred that the magnitude of the rebounds is negatively related to the extracellular fluid volume, and that the time of their commencement after dosing is positively related to the extracellular fluid volume. 5.2.2 Low Sodium Diet When healthy volunteers follow a very low sodium diet (between 15 and. 20 mmol daily), rebounds in kaliuresis do nbt Occur after administration of furosemide 40mg (Wilcox et al. 1984), perhaps because potassium excretion into the preurine is enhanced by a steadily increased activity of the renin-angiotensin-aldosterone system which stems from the low sodium intake. 5.2.3 High Doses in Renal Insufficiency The intravenous administration of very high doses of loop diuretics (e.g. between 60 and 200mg of torasemide) to patients with advanced chronic renal insufficiency resulted in no rebounds within the 24 hours after medication, but delayed rebounds occurred at a later time (Kliitsch et al. 1988; Mourad et al. 1988). It is unclear whether this late onset is due to the alteration in the pharmacokinetics of diuretics present in advanced renal insufficiency, to the expansion of extracellular fluid volume present in this condition, or to a combination of these factors. 5.3 Situation in Which Distal Tubular Diuretics Yield Rebounds in Urinary Excretions In a randomised, double-blind, crossover study, placebo and · hydrochlorothiazide 25mg were administered once daily for 4 days to healthy subjects (Leary, Reyes & van der Byl, unpublished data). Urinary excretions on the first day of treatment with hydrochlorothiazide 25mg showed the usual differences from post-placebo excretions (e.g. table V, figs 3 to 6). On the fourth day of treatment, hydrochlorothiazide 25mg did not increase 24-hour diuresis, chloriuresis or natriuresis, but the rise in

24-hour kaliuresis it had caused on the first day of treatment remained unchanged. The urinary outputs of fluid, chloride, sodium and potassium that took place over the first 6 hours after administration of hydrochlorothiazide 25mg on the fourth day of treatment were higher than corresponding outputs after placebo; however, between 6 and 24 hours after dosing the urinary outputs of fluid, chloride, and sodium were lower after hydrochlorothiazide 25mg than after placebo. Thus, rebounds occurred which partially accounted for the lack of 24-hour diuretic, chloriuretic and natriuretic effects of hydrochlorothiazide 25mg on the fourth day of treatment. The urinary output of potassium did not constitute a rebound during the late after-dosing observation period on the fourth day of treatment, but it was elevated with respect to corresponding post-placebo excretion as it had been on the first day of treatment. The mechanisms of the rebounds in urinary excretions which develop during repeated once-daily administration of hydrochlorothiazide 25mg to healthy subjects are unknown; given that there is a rebound in natriuresis while kaliuresis remains elevated, an activation of the renin-angiotensinaldosterone system could be implicated. 24-hour urinary excretions after a few days of once-daily administration of hydrochlorothiazide 25mg to healthy subjects resemble, both in magnitude and time course, the excretions following single dosing with common low dose formulations of torasemide (2.5 and 5mg). That 24-hour kaliuresis is increased after repeated medication with once-daily hydrochlorothiazide 25mg, but that it is unaffected by single doses oftorasemide 2.5 or 5mg, constitutes the only relevant difference detected between the excretory patterns compared (Leary, Reyes & van der Byl, unpublished data). 5.4 Rebounds as a Fingerprint of Loop Diuretics When new diuretics are studied, the existence of rebounds in the flows of urine and of urinary chloride and sodium during the 6 to 24 hours after

55

Effects of Diuretics on Urinary Outputs

After PLA (mmol' h- 1)

Change in maximal urinary flow (%) -100

Na

TOR 2.5

14.0

TOR 5

12.7

TOR 10

12.7

TOR 20

14.0

FUR 40

12.7

HCTZ 25

12.7

0

• ..

--.... --

TOR 2.5

4.7

TOR 5

4.0

TOR 10

4.0

TOR 20

4.7

FUR 40

4.0

HCTZ 25

4.0

~

...



TOR 2.5

0.48

TOR 10

0.48

TOR 20

0.34

FUR 40

0.48

HCTZ 25

0.48

•••

... 120

60

I NS



~

0.34

TOR 5

•••

NS

0

Mg

600

•••

0

K

300

NS

..

•••

..

..

80

160

INS

I

••• NS

Fig. 10. Changes from placebo values of maximal urinary flows of sodium, potassium and magnesium after separate, randomised, double-blind, crossover oral administration of single doses of various formulations to the same number of healthy subjects (14) in 2 different studies; PLA, TOR 5, TOR 10, FUR 40 and HCTZ 25 were given in one study, and PLA, TOR 2.5 and TOR 20 in the other. Comparisons between means from which percenta~s were derived and means after placebo were made using the 2-tailed paired t-test. Abbreviations: FUR 40 = furosemide 40mg; HCTZ 25 = hydrochlorothiazide 25mg; PLA = placebo; TOR 2.5 = torasemide 2.5mg; TOR 5 = torasemide Smg; TOR 10 = torasemide 10mg; TOR 20 = torasemide 20mg; NS = p > 0.05; ** ;= p < 0.01; *** = p < 0.001 (adapted from Reyes et al. 1990c, with permission from Progress in Pharmacology and Clinical Pharmacology).

56

Drugs 41 (Suppl. 3) 1991

Table VII. Maximal urinary flows and times from dosing to maximal urinary flows (mean ± SEM) after randomised, double-blind, crossover single doses of placebo and diuretic in 14 healthy subjects (hour 0800) [from Leary et al. 1990, with permission from the Journal of International Medical Research] Urinary variable

Medication

Maximal urinary flow (fluid variable in L· h- 1 , solute variables in mmol· h- 1)

Fluid

Placebo Furosemide 80mg HCTZ 25mg Placebo Furosemide 80mg HCTZ 25mg Placebo Furosemide 80mg HCTZ 25mg Placebo Furosemide 80mg HCTZ 25mg Placebo Furosemide 80mg HCTZ 25mg Placebo Furosemide 80mg HCTZ 25mg

0.19 0.57 0.29 11.1 134.9 29.0 10.1 106.0 25.9 4.0

Chloride

Sodium

Potassium

Calcium

Magnesium

7.9 5.3 0.36 0.96 0.40 0.32 0.68 0.44

± 0.02 ± 0.04***

5.5 ± 0.5 1.6 ± 0.1*0*

± 0.02**ttt ± 1.1

3.8 5.4 0.6 3.0 5.7 0.6 3.0 4.0 2.0 3.4 5.8 1.6 4.1 6.3 2.4 5.1

± 15.6***

± 2.3***ttt ± 1.1 ± 10.2*** ± 1.8***ttt ± 0.3 ± 0.6ttt ± 0.5*tt ± 0.03 ± 0.09*** ± 0.04ttt ± 0.03 ± 0.07*** ± 0.05*tt

Abbreviation: HCTZ = hydrochlorothiazide. Statistical differences between treatments: *, ** and *** indicate differences from placebo (p

and tt and ttt indicate differences from furosemide 80mg (p

Time to maximal urinary flow (h)

6. Time Courses of Urinary Excretions 6.1 Maximal Urinary Flows Due to the rapid and intense effect of loop diuretics on urinary excretions, maximal flows of urinary fluid, chloride and sodium are higher after administration of common formulations of loop diuretics than after common formulations of distal tubular diuretics (fig. 10). Maximal flows of urinary fluid, chloride and sodium after a loop diuretic are positively related with the dose (fig. 10), [Reyes et al. 1990c].

± 0.1'** ± 0.2***ttt ± 0.4 ± 0.1*** ± 0.3ttt

± 0.4 ± 0.1***

± 0.3*ttt ± 0.5 ± 0.2*** ± 0.3ttt

< 0.05, p < 0.01

< 0.01 and p < 0.001, respectively).

separate administration of different single doses of a substance to healthy subjects, under the conditions considered in this review, could be added as a criterion for identifying the thick ascending limb of the loop of Henle as the main site of renal action.

± 0.3*'ttt ± 0.5 ± 0.1*** ± 0.2*0*ttt ± 0.4

and p

< 0.001, respectively),

6.2 Times to Maximal Urinary Flows Times from dosing to maximal urinary flows of urine and of urinary solutes whose excretion is increased by diuretics are shorter after administration of common formulations of loop diuretics than after administration of common formulations of distal tubular substances (table VII, fig. 11), in keeping with established knowledge about the time course of the urinary excretory actions of these 2 classes of diuretics. After various doses of the loop diuretic torasemide, the times from dosing to the maximal urinary flows of urine, chloride, sodium, potassium and magnesium appear to be negatively related to the dose (fig. 11) [Reyes et al. 1990c]. Common low dose formulations of loop diuretics (e.g. torasemide 2.5 and 5mg) produce urinary excretions of fluid, chloride and sodium whose time courses tend

57

Effects of Diuretics on Urinary Outputs

After

PLA

(hours)

Change in time to maximal urinary flow (%)

-60

-90

Na

K

Mg

TOR 2.5

3.9

TOR 5

3.5

TOR 10

3.5

TOR 20

3.9

FUR 40

3.5

HCTZ 25

3.5

TOR 2.5

3.0

TOR 5

3.1

TOR 10

3.1

TOR 20

3.0

FUR 40

3.1

HCTZ 25

3.1

TOR 2.5

4.1

TOR 5

5.3

TOR 10

5.3

TOR 20

4.1

FUR 40

5.3

HCTZ 25

5.3

-30

•••

..

••• •••

--.



..

o

NS. NS_ -

NS_

-NS_

Fig. 11. Changes from placebo values of times to maximal urinary flows of sodium, potassium and magnesium after randomised, double-blind, crossover oral administration of single doses of various formulations to the same number of healthy subjects (14) in 2 different studies; PLA, TOR 5, TOR 10, FUR 40 and HCTZ 25 were given in one study, and PLA, TOR 2.5 and TOR 20 in the other. Comparisons between means from which percentages were derived and means after placebo were made using the 2-tailed paired t-test. Abbreviations: FUR 40 = furosemide 40mg; HCTZ 25 = hydrochlorothiazide 25mg; PLA = placebo; TOR 2.5 = torasemide 2.5mg; TOR 5 = torasemide 5mg; TOR 10 = torasemide IOmg; TOR 20 = torasemide 20mg; NS = p > 0.05; * = p < 0.05; ** = p < 0.0 I; *** = p < 0.00 I (adapted from Reyes et al. 199Oc, with permission from Progress in Pharmacology and Clinical Pharmacology).

Drugs 41 (Suppl. 3) 1991

58

to resemble those of common doses of distal tubular diuretics such as hydrochlorothiazide 25mg (table VII, fig. II) [Reyes et al. 1990c]. Times from administration oftorasemide 2.5 and 5mg to maximal excretions of fluid, chloride and sodium (fig. 11) are substantially longer than those after administration of high doses ofloop diuretics such as torasemide 20mg. (fig. 11) and furosemide 80mg (table VII) [Leary et al. 1990; Reyes et al. 1990c].

References Broekhuysen J, Deger F, Douchamps J, Ducarne H, Herchuelz A. Torasemide, a new potent diuretic. Double-blind comparison with furosemide. European Journal of Clinical Pharmacology 31 (Supp!.): 29-34, 1986 Cuvelier R, Pellegrin P, Lesne M, van Ypersele de Strihou C. Site of action of torasemide in man. European Journal of Clinical Pharmacology 31 (Supp!.): 15-19, 1986 Davis DS. (Translator: J. Warman-Gryj) Nomografia y ecuaciones empiricas, pp. 99-100, Compania Editora Continental, S.A., Mexico, 1965 Dclargc J. Chcmistry and pharmacological properties of the pyridinc-3-sulfonylurea derivative torasemide. Arzneimittcl-Forschung 38(1):144-150, 1988 DuBose TD. Diuretics. In Seldin DW, Giebisch G (Eds) The regulation of acid-base balance, pp. 569-585, Raven Press, New York, 1989 Godfrey K. Comparing thc means of several groups. New England Journal of Medicine 313: 1450-1456, 1985 Hamdy RC, Vinsol) M, Robbins AD. Struthers LPL, Chapman SF. et al. Diuretic potency of loop, thiazidc and potassium sparing agcnts: a reappraisal of relative activity. In Puschett JB, Greenberg A (Eds) Diuretics. Chemistry, pharmacology and clinical applications, pp. 403-406, Elsevier Science Publishing Co. Inc .. New York, 1984a Hamdy RC, Vinson M, Robbins AD, Struthers LPL, Chapman SF, et a!. 24 hour urinary electrolyte profile following frusemide, amiloride and a combination of these drugs, Frumil™ In Puschelt JB, Greenberg A (Eds) Diuretics. Chemistry, pharmacology and clinical applications, pp. 364-366, Elsevier Science Publishing Co. Inc., New York, 1984b Hanisch M. Pharmacodynamic studies with muzolimine (BAY g 2821) in healthy volunteers: an overyiew. Clinical Nephrology 19 (Supp!. I): S32-S36, 1983 Klutsch K, Grosswendt J, Haecker W. Single dose comparison of torasemideand furosemide in patients with advanced renal failure. Arzneimittel-Forschung 38 (I): 200-204, 1988 Lameire N ,Dodion 'L. Acute and chronic effects of torasemide in healthy volunteers. Arzneimittel-Forschung 38(1): 167-171, 1988 Lant A. Diuretics. Clinical pharmacology and therapeutic use (part I). Drugs 29: 57-87, 1985a Lant A. Diuretics. Clinical pharmacology and therapeutic use (part II). Drugs 29: 162-168, 1985b Leary WP, Reyes AJ. Diuretics. South African Medical Journal 59: 9-13, 1981 Leary WP, Reyes AJ. Kaliuresis induced by various diuretics. In Andreucci VE, Dal Canton A (Eds) Diuretics. Basic, pharmacological, and clinical aspects, pp. 503-505, Martinus Nijhoff Publishing, Boston, 1987 Leary WP, Reyes AJ. Renal excretory actions of diuretics in man:

correction of various current errors and redefinition of basic concepts. Progress in Pharmacology 6/3: 153-156, 1988 Leary WP, Reyes AJ, van der Byl K. Urinary magnesium and zinc excretions after two different single doses of amiloride in healthy adults. Current Therapeutic Research 34: 205-216, 1983 Leary WP, Reyes AJ, van der Byl K. Effects of a combination of hydrochlorothiazide and amiloride on urinary magnesium excretion in healthy adults. Current Therapeutic Research 35: 293-300, 1984 Leary WP, Reyes AJ, van der Byl K. The effects of single doses of muzolimine upon urinary solute and fluid excretion. Zeitschrift fUr Kardiologie 74 (Supp!. 2): 135-140, 1985a Leary WP, Reyes AJ, van der Byl K, Acosta-Barrios TN. Effects of captopril, hydrochlorothiazide and their combination on timed urinary excretions of water and solutes. Journal of Cardiovascular Pharmacology 7 (Supp!. I): S56-S62, 1985b Leary WP, Reyes AJ, Wynne RD, van der By! K. Renal excretory actions of furosemide, of hydrochlorothiazide and of the vasodilator flosequinan in healthy subjects. Journal of International Medical Research 18: 120-141, 1990 Louis TA, Lavori PW, Bailar Je, Polansky M. Crossover and selfcontrolled designs in clinical research. New England Journal of Medicine 310: 24-31,1984 Mourad G, Haecker W, Mion C. Dose-dependent salidiuretic efficacy of torasemide in comparison to furosemide and placebo in advanced renal failure. Arzneimittel-Forschung 38 (I): 205208, 1988 Ottenbacher KJ. Scientific vs. statistical inference: the problem of multiple contrasts in scientific approach. American Journal of Medical Sciences 295: 172-177, 1988 Prichard BNC, Brogden RN. Xipamide. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy. Drugs 30: 312-313, 1985 Puschett JB. Sites and mechanisms of action of diuretics in the kidney. Journal of Clinical Pharmacology 21: 564-574, 1981 Puschett JB. Clinical pharmacologic implications in diuretic selection. American Journal of Cardiology 57: 6A-13A, 1986 Reyes AJ. Deleterious effects of antihypertensive treatment on magnesium turnover. Progress in Pharmacology 6/1: 51-87, 1985 Reyes AJ. Diuretics in heart failure. In Puschett JB, Greenberg A (Eds) Diuretics II. Chemistry, pharmacology and clinical applications, pp. 332-344, Elsevier Science Publishing Co. Inc., New York, 1987a Reyes AJ. Interactions between magnesium and drugs in congestive heart failure. Magnesium-Bulletin 9: 93-109, 1987b Reyes AJ. Therapy with diuretics in congestive heart failure. Progress in Pharmacology 6/3: 167-192, 1988 Reyes AJ. Mechanisms and extent of the decrease in magnesiuresis induced by antikaliuretic diuretics in man. In Itokawa y, Durlach J (Eds) Magnesium in health and disease, pp. 415422, John Libbey, London, 1989 Reyes AJ, Leary WP. A mathematical model for the clinical pharmacology of diuretics. Current Therapeutic Research 30: 227-235, 1981a Reyes AJ, Leary WP. 24-h urine volume, urinary electrolyte outputs and plasma potassium concentration as functions of xipamide dose. Current Therapeutic Research 29: 120-125, 1981b Reyes AJ, Leary WP. Cardiovascular toxicity of diuretics related to magnesium depletion. Human Toxicology 3: 351-372, 1984a Reyes AJ, Leary WP. Diuretics and magnesium. Magnesium-Bulletin 6: 87-99, 1984b Reyes AJ, Leary WP. Instantaneous clearance: a new tool for the clinical pharmacology of diuretics. In Puschett JB, Greenberg A (Eds) Diuretics. Chemistry, pharmacology and clinical applications, pp. 532-534, Elsevier Science Publishing Co. Inc., New York, 1984c Reyes AJ, Leary WP. The magnesiuric effects of several single

Effects of Diuretics on Urinary Outputs

doses ofxipamide in healthy adults. Brazilian Journal ofMedical and Biological Research 17: 285-291 , 1984d Reyes AJ , Leary WP. Natriuretic potency of various djuretics. In Andreucci VE, Dal Canton A (Eds) Diuretics: basic, pharmacological, and clinical aspects, pp. 506-508, Martinus Nijhoff Publishing, Boston, 1987 Reyes AJ , Leary WP, van der Byl K. Blunting of diuretic-induced increases in urinary magnesium and potassium outputs by betaadrenergic blockade in healthy subjects. Magnesium-Bulletin 7: 121-139, 1985 Reyes AJ , Leary WP, van der Byl K. Instantaneous renal clearance derived by the UY mathematical model. In Puschett JB, Greenberg A (Eds) Diuretics III. Chemistry, pharmacology and clinical applications, Elsevier Science Publishing Co. Inc., pp. 69-71 , New York, 1990a Reyes AJ, Leary WP, van der Byl K. The UY mathematical model of urinary fluid and solute continuous flows. In Puschett JB, Greenberg A (Eds) Diuretics III. Chemistry, pharmacology and clinical applications, Elsevier Science Publishing Co. Inc., pp. 72-74, New York, 1990b Reyes AJ, Leary WP, van der Byl K. Excretions of urinary fluid and solutes after single doses of furosemide and hydrochlorothiazide and of four different single doses of the diuretic torasemide in healthy subjects. In Kriick et al. (Eds) Torasemide: Clinical Pharmacology and Therapeutic Applications. Progress in Pharmacology and Clinical Pharmacology Vol. 8/ 1, pp. 4771 , Gustav Fischer Verlag, Stuttgart, 1990c Reyes AJ, Leary WP, van der Byl K, Maharaj B. Renal excretory pharmacodynamics of diuretics in man: comparison between furosemide, hydrochlorothiazide and torasemide. Progress in Pharmacology Vol. 6/ 3, pp. 83-151, Gustav Fischer Verlag, Stuttgart, 1988a Reyes AJ, Leary WP, van der Byl K, Santoni PJ. Effects of the angiotensin-I converting enzyme inhibitor perindopril on timed urinary excretion of water and solutes in healthy subjects. Current Therapeutic Research 44: 619-629, 1988b Roberts CJC, Daneshmend TK. Assessment of natriuretic drugs. British Journal of Clinical Pharmacology 12: 465-474, 198 I

59

Romano PE. The insignificance of a probability value of p < 0.05 in the evaluation of medical scientific studies. Journal of Laboratory and Clinical Medicine II I: 501-503, 1988 Scheen AJ. Dose-response curve for torasemide in healthy volunteers. Arzneimittel-Forschung 38(1): 156-159, 1988 Scheen AJ, Vancrombreucq JC, Delarge J, Luyckx AS. Diuretic activity oftorasemide and furosemide in chronic heart failure: a comparative double-blind cross-over study. European Journal of Clinical Pharmacology 31 (Suppl.): 35-42, 1986 Sjostrom P, Beermann B, Odlind B. Pharmacokinetic-pharmacodynamic relationship of piretanide in healthy and uremic subjects. Scandinavian Journal of Urology and Nephrology 21: 55-64, 1987 Smith DG, Clemens J, Crede W, Harvey M, Gracely EJ. Impact of mUltiple comparisons in randomized clinical trials. American Journal of Medicine 83: 545-550, 1987 Stallings SB, Childress J, Maynard SM, Sawyer WT. Comparison of natriuretic and diuretic effects of single and divided doses of furosemide. American Journal of Hospital Pharmacy 36: 6871 , 1979 Suki WN, Stinebaugh BJ, Frommer P, Eknoyan G. Physiology of diuretic action. In Seldin DW, Giebisch G (Eds) The kidney. Physiology and pathophysiology, pp. 2127-2162, Raven Press, New York, 1985 Taylor SH. Diuretics in cardiovascular therapy. Perusing the past, practising in the present, preparing for the future. Zeitschrift fiir Kardiologie 74 (Sup pI. 2): 2-12, 1985 Wilcox CS, Mitch WE, Kelly RA, Friedman PA, Souney PF, et al. Factors affecting potassium balance during frusemide administration. Clinical Science 67: 195-203, 1984 Williamson HE. Furosemide and ethacrynic acid. Journal of Clinical Pharmacology 17: 633-672, 1977

Author's address: Prof. A.J. Reyes. Institute of Cardiovascular Theory, Sotelo 3908, I 1700 Montevideo, Uruguay.

Effects of diuretics on outputs and flows of urine and urinary solutes in healthy subjects.

The effects of single oral doses of common formulations of diuretics (i.e. formulations on the market or designed to be marketed) on 24-hour diuresis ...
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