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Furosemide
A Clinical Evaluation of Its Diuretic Action
By WILLIAM B. STASON, M.D., PAUL J. CANNON, M.D.,
HENRY 0. HEINEMANN, M.D.,
AND
JOHN H. LARAGH, M.D.
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where they were given a diet of constant composition. Metabolic ward techniques and analytic
procedures for blood and urine have been reported previously.15 In the balance studies patients had been on a constant diet for at least 4
days prior to administration of diuretics. In
evaluation of the efficacy of different diuretic
regimens, at least 1 day intervened between
treatment days. In studies of acid-base balance
the diet was of fixed composition throughott,
and the diuretic was administered only after
urinary excretion of hydrogen ion had been stable
for 2 to 3 days. Urinary hydrogen ion excretion
was calculated as the sum of the urinary excretion of ammonium plus titratable acid minus
bicarbonate. Incremental changes in urine volume and excretion of sodium, potassium, and
chloride were calculated by subtracting the mean
amount excreted in 24 hours on the control
day(s) from that excreted on the day of drug
administration.
Renal clearance studies were performed on
two normal volunteers on constant normal salt
diets. One was studied under hydropenic conditions, the other during water diuresis. In each
instance furosemide was administered orally in
a single dose of 200 mg after control periods indicated a steady state of urinary flow. Procedures
and calculations involved in clearance studies
have been previously reported.15' 16 Hydropenia
was produced by deprivation of water for 15
hours and antidiuresis was assured by administering Pitressin intravenously in a priming dose
of 5 ,tg/kg and 350 ,utg per hour in the sustaining infusion at 1 cc/minute. Water diuresis was
induced by an oral water load and maintained
by administration of amounts equal to urinary
output.
Furosemide was supplied in 40 or 50-mg tablets.* The amount administered ranged from 40
mg to 1,800 mg per day. Intravenous furosemide
as the sodium salt in water at pH 9.4 was
supplied in 2 cc ampules containing 10 mg/cc
and was administered without dilution in 10 to
20-mg doses.
FUROSEMIDE (4 chloro-N- [2-furyl methyl] -5-sulfamyl-anthranilic acid) (fig. 1)
is a new and potent diuretic compound which
is effective when given either orally or parenterally. Structurally it has in common with substituted thiazides a sulfamyl-benzene grouping.
Animal studies have revealed it to be a
most effective diuretic in both rats and dogs,
resulting in maximum diuretic effects of up to
two thirds of the glomerular filtration rate.1' 2
Clearance data,3 4 micropuncture studies,5 6
and stop-flow analyses7 indicate sites of action
in both the proximal and distal tubules, including the ascending limb of the loop of
Henle. Toxicological evaluation suggests an
extremely wide margin of therapeutic safety.8'9
Clinical studies to date have indicated that
it is extremely potent and well tolerated.10-14
The present study was undertaken to investigate the clinical effectiveness of furosemide in various edematous states and to
elucidate further the characteristics of its
diuretic action.
Methods
Thirty-nine patients and seven normal volunteers were studied. Their diagnoses appear in
table 1. All exhibited abnormal retention of renal
sodium and water, and most had proved to be
refractory to meralluride, thiazides, acetazolamide, and spironolactone administered singly or
in combination.
Twenty-eight patients were studied on the
medical wards of Presbyterian Hospital. The remaining 11 patients and all seven normal volunteers were admitted to our metabolism ward
From the Department of Medicine, Columbia University, College of Physicians and Surgeons, the
Presbyterian Hospital, and the Francis Delafield Hospital, New York, New York.
Work was supported by Grants HE-01275 and
HE-05741 from the National Institutes of Health,
U. S. Public Health Service.
*Supplied by the
Hoechst
Pharmaceuticals, Inc.,
Cincinnati, Ohio.
910
Circulation, Volume XXXIV, November 1966
911
FUROSEMIDE
Table 1
Patients Studied
Number
Diagnosis
25
Congestive heart failure
Rheumatic heart disease
Arteriosclerotic heart disease
Hypertensive heart disease
Idiopathic myocardial hypertrophy
Constrictive pericarditis
Chagas heart disease
Cirrhosis with ascites
Nephrotic syndrome
Malignant effusions
Essential hypertension
9
11
1
2
1
1
7
2
4
1
7
46
Normal subjects
Total
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Results
Clinical Effectiveness and Individuality of
Response
Natriuretic and diuretic responses to
furo-
impressive. Figure 2 depicts
increases in urinary excretion rates of sodium,
potassium, and chloride and weight loss induced over a 24-hour period in nine edematous patients by oral administration of a
standard dose of furosemide. Increase in
daily excretion of sodium ranged from 26 to
semide
were
470 mEq and weight loss from 0.4 to 2.7 kg.
The responsiveness of different patients to
a given dosage of furosemide varied considerably (figs. 2 to 4) and often could not be
anticipated from the degree of responsiveness
to prior diuretics. During diuresis sodium was
the predominant cation accompanied by varying amounts of potassium. Chloride excretion
Ci
NH
Cl
-CH2
NvK --C H
~~~0
H2NO2S
H2NO2S
COOH
S02
CHLOROTHIAZIDE
FUROSEMI DE
NH2
COOH
ANTHRANILIC ACID
Figure
Structural formulae of furosemide and related
Circulation, Volume XXXIV, November 1966
Dose-Response Relationships in Edematous
Patients
Doses of furosemide employed ranged from
40 mg/day in a single dose to 1,800 mg/day
in three equally divided doses. A graduated
increase in diuretic response was achieved by
increasing doses in patients with a variety
of fluid retaining states (table 2). In a normal subject (fig. 5) chloride and sodium
excretion increased in nearly straight line
fashion through the 300-mg dose. Significant
but smaller increments in natriuresis and
chloruresis were observed with doses above
this level. Potassium excretion increased with
increasing dosages at a much slower rate
until a plateau appeared at levels in excess
of 120 mg.
Special Situations
Electrolyte Abnormalities
Furosemide produced an effective diuresis
in six edematous patients with marked electrolyte disturbances which included metabolic
acidosis or alkalosis, hyponatremia, hypochloremia, and hypokalemia.
Azotemia
Diuresis was achieved in four patients with
chronic renal disease in whom the blood urea
nitrogen levels ranged from 51 to 117 mg%.
However, in these patients diuretic responses
were reduced and higher doses were required.
Pulmonary Edema
1
pounds.
usually exceeded the sum of sodium and
potassium (fig. 2).
The effectiveness of furosemide declined
when it was administered continuously (fig.
3), but intermittent administration usually
restored responsiveness to its natriuretic action.
Hypokalemia was often observed during diuresis (fig. 3). Ordinarily this could be controlled by administering the drug intermittently, by supplementing the regimen with
oral potassium, or by the simultaneous administration of spironolactone.
com-
Furosemide was administered intravenously
to three patients with pulmonary edema. A
dose of 10 or 20 mg was given and then
STASON ET AL.
912
EFFECT OF FUROSEMIDE UPON ELECTROLYTE EXCRETION
600
500 _
400 _
Cirrhosis with
Ascites
Refractory Congestive
Heart Failure
i
K+
m Na+
X Ci-
A URINARY
EXCRETION
mEq/ 24hrs
300
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200 _
100
_
0
-
A WGT
kg /24 hrs
I-:--: I
UA
M.S.
E.H.
I
-2
-4
5
-
P.E.
I.S.
I.S.
M.R.
N.S.
CT.
J.0.
Figure 2
Increments in 24-hour electrolyte excretion and weight change produced by
of furosemide of 40 mg four times daily in nine edematous patients.
a
standard dosage
repeated in 1 hour if no response was apparent. All three patients responded with
diureses ranging from 600 cc to 2,500 cc within
4 hours. This was accompanied by an impressive diminution in the clinical signs of
pulmonary congestion.
cc every 5 days for relief of dyspnea. Administration of furosemide, 200 mg two to
three times daily on alternate days increased
the interval between thoracentesis to 22 days.
Malignant Effusion
one
In three patients with effusion due to malignant disease (two pleural, one peritoneal)
furosemide retarded fluid accumulation and
diminished or eliminated the need for thoracentesis or paracentesis. One patient with
lymphosarcoma and bilateral pleural effusion
had required thoracentesis of 1,500 cc to 2,200
Treatment of Outpatients
In six patients with congestive heart failure,
with cirrhosis and ascites, and one with
ascites due to neoplastic disease furosemide
therapy was maintained for periods of 1 to
8 months. Responsiveness had been determined in each case while the patient was
hospitalized, and dosage was adjusted in the
outpatient clinic according to need. The outpatient dosage schedules varied from 40 mg
Circulation, Volume XXXIV, November 1966
913
FUROSEMIDE
URINE
o10o .NO+
150
10
No0+
100 mEq/L
[125
2001
mEq/do ioo
0
3.0
9 -
A
-5.0
4.0
200
K+
3
FLASMA
Pt /S. 74Q0
ASHO with CHF
K+
m
UVNo+
|
Refractory
|
Failure
PE
M.R
Congestive
Hoort
Cirrhosis
with
Ascites
7
A UV K+
6_
per 24hrs
5
Eq/L
mEq/da
0
100
10 01
C1m
F75
200
Eq./d
50
00
mEq/L
0
4000
3000
VOL.
20
cc/do
0
I0000
Pit.a,,t
PE
WS
l.S
CT
50
50
200
qid
,id.
WN
CT
M.S
N S
ENb
JO
0
65
Dose,
150
m,g
qsd
50
qid
50
q.i
200
bid
ti
50
50
q.d
qid
50
50
qid
qid
200
t5
WGT
kg
60
4
Figure
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MERCUHYDRIN, 2cc
7
5
ZXUVNe+/AUVK+
_
_
3
DAYS
8
0
FUROSEMIDE, mg
11
9
15
13
a
patient resistant
organomercurial.
24-hour
a
rates of urinary
control
sodium
excretion,
averaging
5.6 mEq/24 hr (range, < 1 to 18.6 mEq/24 hr). Oral
three times daily
administered intermittently on every second
or third day. Edema was adequately controlled in seven of the eight patients. The
eighth, an elderly lady with intractable congestive heart failure, had initially responded
twice daily to 300
from
in states of marked sodium retention as indicated by
Diuresis produced by furosemide in
an
loss
weight
tive failure and cirrhosis with ascites. All patients were
Figure 3
to
and
period of diuresis in patients with refractory conges-
mg
doses of furosemide varied from 50 mg q.i.d. to 200
mg
t.i.d.
with
a
12-pound
loss
of
lated
despite
continued
But,
weight.
discharge from the hospital,
therapy.
In
C.T.
Diagnosis
Congestive heart
failure (RHD)
B.S.
Congestive heart
failure (ASHD)
Congestive heart
failure (ASHD)
K.K.
Nephrotic syndrome
P.T.
Cirrhosis with
P.E.
ascites
Dose
(mg)
80
120
160
200
300
200
300
40
80
120
80
120
200
300
50
200
t.i.d.
t.i.d.
t.i.d.
t.i.d.
t.i.d.
single dose
single dose
t.i.d.
t.i.d.
t.i.d.
t.i.d.
t.i.d.
t.i.d.
t.i.d
b.i.d.
b.i.d.
Weight loss
(kg/24 hr)
0.5
0.9
0.4
0.9
1.2
1.8
4.6
0.9
1.4
2.3
0.8
0.7
1.0
1.1
0.9
1.6
Five patients are presented in whom the dose of furosemide was progressively increased
during the course of therapy. One day intervenes between treatment days. Diuretic response is
estimated by weight loss. The steady, gradual increase in response with increase in dose is
illustrated.
Circulation, Volume XXXIV, November 1966
general,
dosages required for outpatients were higher
Table 2
Dose-Response in Patients with Edema
Patient
after
fluid reaccumu-
914
STASON ET AL.
Cf300
0
URINARY
EXCRETION
mEq/6hrs 200
Effect on Potassium Excretion and the Urinary
Na/K Ratio
/
(00
(200 to 800 mg/day). Combination of furosemide with any of the other diuretic agents
resulted in natriuretic and diuretic effects
which equalled or exceeded the sum of responses observed when the drugs were administered singly.
F
1/
+
K
+6
In general patients with refractory edema
tended to excrete more potassium per unit of
natriuresis than patients who had larger diuretic responses. This is apparent from the
fact that the ratio of sodium to potassium
excreted
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100
200
300
SINGLE ORAL
400
500 600
DOSE(mg)
Figure 5
Dose
was
response
administern
a normal subject. Furosemide
ed every fourth day in a single dose
Xcurve in
the urine output during the 6 hours
thereafter sepai rated from the balance of the day's
24-hour collect,ion and considered to represent the
diuretic effect of the drug. Return to control body
weight was tak :en as an indication that the patient
had returned t(o a base line prior to each treatment
day.
at 7 a.m. and
than those during hospitalization, perhaps due
to less rigid control of sodium intake and
activity.
Comparison with Other Agents and Effect of
Combined Therapy
Furosemide frequently produced an effective diuresis in patients previously refractory
to conventional agents. When compared with
chlorothiazide (3 g/ day), azetazolamide (750
mg/day), and meralluride (2 cc I.M.), furosemide, in submaximal doses, was capable of
inducing considerably greater natriuresis than
the maximal doses of these other agents
(fig. 6). Direct comparison with ethacrynic
acid indicated that in equal doses furosemide
was somewhat less potent. However, in four
patients with refractory edema, large doses
of furosemide (400 to 1,800 mg/day) produced natriuresis of the same order of magnitude as that produced by ethacrynic acid
as
a
result
of
diuresis
induced
by
furosemide was lower in patients who lost
small amounts of weight during less diuresis
than in those who responded with large diuresis (fig. 4). In 13 studies the ratio of the
increase in urinary sodium excretion to that
of
potassium
(
AUNa+/AvUK+ )
.
r
0.6 in
refractory patients to 12.5
ranged
in
from
responsive
ones and averaged 3.6. Notwithstanding the
favorable Na+/K+ ratios in responsive patients,
some
of this
group
24 hour urinary
K+
exhibited
a
considerable
loss and developed hy-
pokalemia.
Combination with Spironolactone
The addition of an aldosterone antagonist
the regimen of patients receiving furosemide potentiated the natriuretic and reduced
its kaliuretic effect. In four patients with congestive heart failure (fig. 7) AUVNa+/AUVKincreased and a fall in the serum potassium
was prevented or lessened. In two of the four
patients, who were more refractory to diuretics,
marked potentiation of both natriuretic and
diuretic effects was observed.
to
Effect
on
Acid-Base Balance
An acid balance study of a patient with
congestive heart failure maintained on a fixed
low sodium diet is illustrated in figure 8.
Hydrogen ion excretion increased, especially
on the first day of drug administration. This
was due to increased urinary excretion of
both ammonium and titratable acid. Bicarbonate excretion did not change significantly.
Concomitantly blood pH
rose
from 7.47 to
Circulation, Volume XXXIV, November 1966
915
FUROSEMIDE
COMBINATION OF FUROSEMIDE WITH
ETHACRYNIC ACID, CHLOROTHIAZIDE, ACETAZOLAMIDE Es MERCUHYDRIN
A URINARY
EXCRETION
mEo,/24hrs
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A WEIGHT
kg/24hrs
- 4'L
FUROSEMIDE, 200mg tid
ETHACRYNIC A.. 200mg tid _
CHLOROTHIAZIDE, lgm tid
ACETAZOLAMIDE, 250mg tid
SPIRONOLACTONE, 25mg qid
MERCUHYORIN, 2cc
Figure 6
Effects of furosemide in comparison and in combination with other agents. Data from three
patients.
7.50 and serum bicarbonate from 32.7 to 35.2
mEq/L.
Mild extracellular alkalosis was observed in
seven patients studied similarly. Blood pH
increased from a mean of 7.43 to a mean of
7.48, and serum bicarbonate increased from
a mean of 26.4 mEq/ L to a mean of 29.6
mEq/L. In five of these patients the pH of
the urine fell during the first day of therapy;
in the other two it increased. In three patients bicarbonate excretion increased slightly
in association with a rather large diuresis; in
the other four it remained unchanged.
Renal Clearances
Figure 9 presents results of two renal clearance studies on normal subjects, one during
water diuresis and the other under maximal
antidiuresis. Onset of diuresis after oral administration occurred within the first 30
Circulation, Volume XXXIV, November 1966
minutes. Peak diuretic and natriuretic effects
were reached 30 to 90 minutes after drug
administration, and the action was largely
dissipated in 4 hours.
During water diuresis urine flow after furosemide reached a peak of 25.7 ml/min, representing a tubular rejection fraction for water
of 28.8% of the filtered load. The rejection
fraction of sodium peaked at 17%. Glomerular
filtration rate (Cl1n) fell slightly during peak
diuresis; renal plasma flow (CPAH) did not
change significantly. The free water clearance
decreased by 5.0 ml/min during peak diuresis
and approached zero on the decending limb
of the diuresis between 150 and 180 minutes
after drug administration.
Under hydropenic conditions urine flow
during diuresis reached a maximum of 22.8
ml/ min. The tubular rejection fraction of
water peaked at 32.8%, that of sodium at 27%.
STASON ET AL.
916
antagonists in eight of 21 patients, (2) transient increase in blood urea nitrogen to levels
over 30 mg% (14/26), (3) asymptomatic
hyperuricemia (levels greater than 5.5 mg%)
(11/16), (4) anorexia and nausea in two,
(5) hepatic precoma following a 1.4 kg diuresis in a patient with severe liver disease,
(6) occasional postural hypotension following
massive diuresis, and (7) hyponatremia and
EFFECT OF ALDOSTERONE ANTAGONISTS
ON FUROSEMIDE DIURESIS
5
4
3_ _
PLASMA K
mEq/L
_
39.1z
20
i8
6
'4
A UVNQ+
A UV K+F
per 24hrs
2
8
Pt. M. R. 65 0
ASHL2 with CHF
-6
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A WGT kg/24hrs -5
-8
-9
FUROSEMIDE,
mg qid
PLASMA
_
150
F
Li
50
_______
*
50
20(10
..:
SPIRONOLACTONE
50mg qid
Pot ient
Figure 7
Effect of aldosterone antagonists on furosemide
diuresis. In four different patients spironolactone enhanced natriuretic and retarded kaliuretic effect of
furosemide.
Glomerular filtration rate (CI0) was low
during control period (av. 66.6 cc/min) despite the lack of evidence of overt renal
disease. However, it rose moderately during
diuresis reaching a maximum of 28% above
control. Renal plasma flow (CPAHI) increased
markedly at the onset of diuresis but thereafter returned to or slightly above control
levels. The capacity for water reabsorption
(TeHw,o ) became negative during peak diuresis
and remained so until the end of the study.
Toxicity
No true toxic effects were observed. White
blood cell counts, urinalyses, liver function
tests including serum glutamic oxalacetic
transaminase and alkaline phosphatase, and
fasting blood sugar levels were unaffected.
Hematocrit values frequently increased following diuresis.
Side effects included (1) hypokalemia of
sufficient degree to require potassium supplementation or the addition of aldosterone
HCO - 35 %.- *\4~A
3
L
mE q/ L 30-]
25-1
7.61
75-
pH
7.4-
URINARY EXCRETION
1001
50mm/do--
NH +
----
.............
25
TA
Eq/dm OJ
mm/do
pH
mm/do
oJ
7.06.0-
50i
01
kg
.........................
.
....... ...
......
601
WGT
...................
......
5.0 -
H+
.................
.................
...................
55..............
50
FUROSEMIDE
DAYS
50qid
_
l
l
l
l
Figure 8
Effect of furosemide on urinary acid excretion in a patient with congestive heart failure.
Circulation, Volume XXX1V, November 1966
FUROSEMIDE
917
WATER DAURESIS
125
C IN
cc
/min.
100
75
700-
CPAH
cc/min.
5
25
URINE
VOLUME
and
C os/m
cc
Volume
E
Cit2
20
15
10
COJ
/min.
0
HYDROPENIA
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
CIN
cc/min.
75E
&
ANTIDIURESIS
100r
50
600
CPAH
cc/min.
550
500
0
25
450
400
20-F
URINE
VOLUME
and
CosM
cc/min.
10-
T20
COSM
V/
5-
Control 0
t'
40
80
120
160 200 240
TTIME IN MINUTES
Furosemide 200 mg Po
Figure 9
Influence of furosemide given orally on renal hemodynamics, solute, and water excretion in two normal
subjects.
hypochloremia in two patients maintained on
a regimen of spironolactone supplemented by
intermittent furosemide.
Discussion
This study of 39 edematous patients and
of seven normal volunteers extends earlier
reports'0-14 of the effectiveness of furosemide
as a natriuretic and diuretic agent. Our data
indicate that this agent is often effective in
patients refractory to other diuretics. In maximal doses the potency of furosemide approaches that of ethacrynic acid,'7 and it
exceeds the potency of thiazides, mercurials
or acetazolamide. Furthermore, its effects appear to add to those of the other diuretics.
Circulation, Volume XXX1V, November 1966
Indeed, the combination of furosemide with
either thiazides or carbonic anhydrase inhibitors produced unusually beneficial effects
which at times appeared more than additive.
The rapidity of onset of its diuretic action,
3 to 5 minutes when administered intravenously, and less than 30 minutes when administered orally, makes furosemide useful
in the treatment of acute situations such as
pulmonary edema. The relatively brief duration of its natriuretic action, 1 to 2 hours
when given intravenously, and 4 to 6 hours
when given orally, allows induction of diuresis
which is easily controlled by adjustment of
dose and by the frequency of administration.
Responsiveness to a given dosage of furosemide varied considerably from patient to
patient. It is therefore important in initiating
treatment to begin with a small dose, for
example 40 mg, and adjust this upward stepwise over a range of 40 to 600 mg one to three
times daily until the desired response is
achieved. The gradual and predictable increase in response which can be achieved with
increase in dosage over an unusually broad
therapeutic dose range when considered together with its unusual potency points to a
broad spectrum of clinical usefulness for
furosemide in the management of edematous
patients.
Like other diuretics the effectiveness of
furosemide diminishes with continuous administration. Intermittent therapy, when the
drug was given 1 to 3 days consecutively,
proved more efficacious in mobilizing edema
fluid than continuous therapy and was less
likely to produce electrolyte or acid disturbances. Observations in outpatients indicated
that furosemide retains its effectiveness over
prolonged periods and is well tolerated.
During a furosemide diuresis sodium and
chloride were the predominant ions excreted.
However, at times appreciable potassium excretion was also induced and hypokalemia
often resulted. The hypokalemia induced by
furosemide could be controlled by intermittent therapy, by the addition of potassium
supplements, and by combination with an
aldosterone antagonist. The latter regimen has
918
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the advantage of potentiating natriuresis in
refractory patients.
The ability of furosemide to produce an
effective diuresis in more resistant patients
with a variety of electrolyte disturbances
which included metabolic alkalosis, acidosis,
hyponatremia, hypochloremia, hypokalemia,
and azotemia is a characteristic similar to that
reported for ethacrynic acid and points up the
distinctly greater potency of these two newer
diuretics. This characteristic of these two
agents portends their special usefulness in
patients with refractory or complicated
edema. However, greater potency clearly increases the hazard of producing overdiuresis
or iatrogenic electrolyte disturbances which
develop not as toxic effects but as pharmacological consequences of excessive diuretic
action. Especially during the initial phases of
therapy with these drugs the patient should
be carefully followed and serum electrolytes
frequently checked. Stepwise increases in dosage and intermittent rather than daily therapy
are advisable at least at the beginning.
Stop-flow studies7 suggest that the kaliuresis following furosemide occurs primarily because of an increased distal tubular secretion.
The importance of endogenous aldosterone
activity as a determinant of the magnitude
of diuretic-induced K+ loss has been documented in studies of ethacrynic acid."7 The
view that distal Na+-K+ exchange induced
by furosemide is likewise augmented by a
secondary or underlying increase in aldosterone secretion is suggested by ( 1 ) the increased
tendency for hypokalemia to occur during
diuresis in those clinical situations characterized by elevated aldosterone secretion such
as cirrhosis or refractory cardiac edema and
(2) by the ability of spironolactone to increase the Na + /K + ratio during furosemide
diuresis. The occurrence of hypokalemia in
patients, despite a favorable urinary Na + /
K + ratio, suggests that the magnitude of
the sodium load delivered to ion exchange
sites in the distal nephron during a furosemide diuresis is another major factor determining the amount of K+ loss induced by
the drug.
STASON ET AL.
Acid-base balance studies indicate that the
extracellular alkalosis following furosemide
administration results both from an increased
total hydrogen ion excretion, most prominent
on the first day of drug administration, and
from potassium loss. The drug increased the
excretion of both titratable acidity and ammonium, but bicarbonate excretion was little
affected, thus verifying'8' 19 that furosemide
has little or no carbonic anhydrase-inhibiting
activity. The unusual potentiation of furosemide diuresis by carbonic anhydrase inhibitors
supports this view.
Renal clearance studies failed to indicate
any consistent effect of oral furosemide on
renal hemodynamics, a finding which differs
from the significant increases in filtration rate
and renal blood flow reported by others when
the drug was given intravenously3'20,21
During maximal water diuresis administration
of 200 mg of furosemide to our normal volunteer resulted in a tubular rejection of water
of 28.8% of glomerular filtrate and under
maximal antidiuresis 32.8%. The respective
fractions of filtered sodium excreted during
diuresis in these studies were 17% and 27%.
Vorburger,20 in administering the drug intravenously to patients with renal functional
impairment, found tubular rejection of water
to reach 60% and that of sodium 48% of the
filtered load. Since the extent of these natriuretic and diuretic effects exceeds what would
be expected (according to current concepts)
to result from inhibition of sodium reabsorption in the loop of Henle and distal tubules,
a prominent site of action in the proximal
tubule is implied. That both CH2O and
TC112o decreased during furosemide diuresis
agrees with findings of Buchborn and Anastasakis3 and Suki and associates4 and points
to a site of action in the ascending limb of
the loop of Henle as well as in more cortical
diluting segments of the distal tubule. Hence
furosemide appears to differ in its mode of
action from thiazide diuretics which have
been demonstrated16 22 to inhibit CH20 but
have no effect on TCH20. Micropuncture studies5 6 and stop-flow analyses7 suggest that
furosemide has effects on both the proximal
Circulation, Volume XXXIV, November 1966
919
FUROSEMIDE
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and distal nephron, and Hook's observation23 in dogs that furosemide abolishes the
normal medullary sodium gradient lends further support to an effect on the loop of Henle.
In dogs furosemide is capable of increasing
the saliuretic response to maximal doses of
hydrochlorothiazide but to a degree which
is less than additive.24 When superimposed
on a maximal ethacrynic acid diuresis, furosemide produced only small, inconsistent increases in sodium excretion.24 These results
suggest that furosemide has sites of action
additional to those of hydrochlorothiazide but
similar to those of ethacrynic acid. In our
study the fact that furosemide was able to
produce a significant increase in the saliuretic and diuretic responses to ethacrynic
acid when administered concomitantly with
it can probably be attributed to the submaximal doses of both agents employed.
Chloride excretion after furosemide always
exceeded that of sodium in both the clearance and balance studies. This might suggest
a primary action of the drug to block chloride
reabsorption. While this hypothesis cannot
be excluded, the facts that sodium plus potassium outputs exceeded chloride in many
studies and that K+ and H+ excretions were
accelerated by the drug, and the lack of
any precedent for primary chloride inhibition
by diuretics make it seem far more likely
that furosemide blocks sodium reabsorption.
Primary inhibition of sodium transport in the
proximal and distal nephron, interference with
passive chloride reabsorption as a consequence
of the effects on sodium, and subsequent
exchange of some of the rejected sodium for
potassium and hydrogen ions would explain
the pattern of urinary excretion observed.
Summary
The physiological effects of furosemide, a
new diuretic agent chemically related to thiazide diuretics, have been evaluated in seven
normal subjects and in 39 patients with edema
of varied origin.
The compound exhibited an unusually
broad dose-response curve so that increasing
diuresis could be induced with oral doses of
Circulation, Volume XXXIV, November 1966
from 40 mg once daily to 600 mg three times
daily. At the higher dosages furosemide was
significantly more effective than conventional
thiazide diuretics and exhibited an order of
potency which can be achieved with ethacrynic acid.
In many of its diuretic properties furosemide resembled thiazide agents. The natriuresis and diuresis which it produced was
associated with a disproportionate loss of
chloride and potassium and the consequent
production of degrees of hypokalemic alkalosis.
However, physiological studies indicate that
furosemide is qualitatively and quantitatively
more similar to ethacrynic acid than to thiazide agents. Thus, furosemide, like ethacrynic
acid and unlike thiazide diuretics acted to
interfere with both urinary concentration
(TCH20) during antidiuresis and to block
urinary dilution (CH20) during water diuresis.
It also caused a negative urinary hydrogen
balance during diuresis.
The data suggest that furosemide acts to
block sodium chloride reabsorption in the
ascending limb of Henle's loop and in more
cortical distal diluting segments. The magnitude of its effects suggests that it also may
interfere with proximal sodium chloride reabsorption. Ion exchange sodium reabsorptive
mechanisms appear unaffected and become
overactive during drug administration thereby accounting for the observed increases in
potassium and hydrogen ion excretions.
Because of its properties furosemide was
especially useful intravenously as an adjunct
in the treatment of acute pulmonary edema
and for oral maintenance therapy in the
treatment of difficult or refractory edematous
patients, many of whom exhibit associated
electrolyte derangements or azotemias. In
these difficult situations, for maximum diuresis and to avoid problems associated with K+,
H+ and Cl- depletion, intermittent therapy
added to a maintenance schedule which utilizes aldosterone antagonists or chloride and
potassium supplements appears advisable.
Furosemide, also like ethacrynic acid, was
capable of adding to the natriuretic action of
920
STASON ET AL.
all other types of diuretic agents. This observation provides additional evidence for the
existence of a number of different tubular
transport processes located at different sites
in the nephron which can participate in
sodium conservation.
13. VEREL, D., STENTIFORD, N. H., RAHMAN, F.,
A1ND SAYNOR, R.: Clinical trial of furosemide.
Lancet 2: 1088, 1964.
14. HUTCHEON, D. E., MEHTA, D., AND ROMANO,
A.: Diuretic action of furosemide. Arch Intern Med (Chicago) 115: 542, 1965.
15. CANNON, P. J., AMES, R. P., AND LARAGH, J. H.:
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Circulation, Volume XXXIV, November 1966
Furosemide: A Clinical Evaluation of Its Diuretic Action
WILLIAM B. STASON, PAUL J. CANNON, HENRY O. HEINEMANN and JOHN
H. LARAGH
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Circulation. 1966;34:910-920
doi: 10.1161/01.CIR.34.5.910
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