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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.

FUROSEMIDE (4 chloro-N- [2-furyl meth-yl] -5-sulfamyl-anthranilic acid) (fig. 1)

is a new and potent diuretic compound whichis effective when given either orally or paren-terally. Structurally it has in common with sub-stituted 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 totwo thirds of the glomerular filtration rate.1' 2Clearance data,3 4 micropuncture studies,5 6and stop-flow analyses7 indicate sites of actionin both the proximal and distal tubules, in-cluding the ascending limb of the loop ofHenle. Toxicological evaluation suggests anextremely wide margin of therapeutic safety.8'9Clinical studies to date have indicated thatit is extremely potent and well tolerated.10-14The present study was undertaken to in-

vestigate the clinical effectiveness of furose-mide in various edematous states and toelucidate further the characteristics of itsdiuretic action.

MethodsThirty-nine patients and seven normal volun-

teers were studied. Their diagnoses appear intable 1. All exhibited abnormal retention of renalsodium and water, and most had proved to berefractory to meralluride, thiazides, acetazola-mide, and spironolactone administered singly orin combination.

Twenty-eight patients were studied on themedical wards of Presbyterian Hospital. The re-maining 11 patients and all seven normal volun-teers were admitted to our metabolism ward

From the Department of Medicine, Columbia Uni-versity, College of Physicians and Surgeons, thePresbyterian Hospital, and the Francis Delafield Hos-pital, 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.

910

where they were given a diet of constant composi-tion. Metabolic ward techniques and analyticprocedures for blood and urine have been re-ported previously.15 In the balance studies pa-tients had been on a constant diet for at least 4days prior to administration of diuretics. Inevaluation of the efficacy of different diureticregimens, at least 1 day intervened betweentreatment days. In studies of acid-base balancethe diet was of fixed composition throughott,and the diuretic was administered only afterurinary excretion of hydrogen ion had been stablefor 2 to 3 days. Urinary hydrogen ion excretionwas calculated as the sum of the urinary excre-tion of ammonium plus titratable acid minusbicarbonate. Incremental changes in urine vol-ume and excretion of sodium, potassium, andchloride were calculated by subtracting the meanamount excreted in 24 hours on the controlday(s) from that excreted on the day of drugadministration.

Renal clearance studies were performed ontwo normal volunteers on constant normal saltdiets. One was studied under hydropenic condi-tions, the other during water diuresis. In eachinstance furosemide was administered orally ina single dose of 200 mg after control periods in-dicated a steady state of urinary flow. Proceduresand calculations involved in clearance studieshave been previously reported.15' 16 Hydropeniawas produced by deprivation of water for 15hours and antidiuresis was assured by adminis-tering Pitressin intravenously in a priming doseof 5 ,tg/kg and 350 ,utg per hour in the sustain-ing infusion at 1 cc/minute. Water diuresis wasinduced by an oral water load and maintainedby administration of amounts equal to urinaryoutput.

Furosemide was supplied in 40 or 50-mg tab-lets.* The amount administered ranged from 40mg to 1,800 mg per day. Intravenous furosemideas the sodium salt in water at pH 9.4 wassupplied in 2 cc ampules containing 10 mg/ccand was administered without dilution in 10 to20-mg doses.

*Supplied by the Hoechst Pharmaceuticals, Inc.,Cincinnati, Ohio.

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FUROSEMIDE

Table 1Patients Studied

Diagnosis Number

Congestive heart failureRheumatic heart diseaseArteriosclerotic heart diseaseHypertensive heart diseaseIdiopathic myocardial hypertrophyConstrictive pericarditisChagas heart disease

Cirrhosis with ascitesNephrotic syndromeMalignant effusionsEssential hypertensionNormal subjects

Total

259

111211

72417

46

Results

Clinical Effectiveness and Individuality ofResponse

Natriuretic and diuretic responses to furo-semide were impressive. Figure 2 depictsincreases in urinary excretion rates of sodium,potassium, and chloride and weight loss in-duced over a 24-hour period in nine edema-tous patients by oral administration of a

standard dose of furosemide. Increase indaily excretion of sodium ranged from 26 to470 mEq and weight loss from 0.4 to 2.7 kg.The responsiveness of different patients to

a given dosage of furosemide varied consid-erably (figs. 2 to 4) and often could not beanticipated from the degree of responsivenessto prior diuretics. During diuresis sodium was

the predominant cation accompanied by vary-

ing amounts of potassium. Chloride excretion

Ci NH-CH2

~~~0

H2NO2S COOH

FUROSEMI DE

Cl NvK --C H

H2NO2S S02

CHLOROTHIAZIDE

NH2

COOH

ANTHRANILIC ACID

Figure 1

Structural formulae of furosemide and related com-

pounds.


usually exceeded the sum of sodium andpotassium (fig. 2).The effectiveness of furosemide declined

when it was administered continuously (fig.3), but intermittent administration usuallyrestored responsiveness to its natriuretic action.Hypokalemia was often observed during diu-resis (fig. 3). Ordinarily this could be con-trolled by administering the drug intermit-tently, by supplementing the regimen withoral potassium, or by the simultaneous admin-istration of spironolactone.

Dose-Response Relationships in EdematousPatients

Doses of furosemide employed ranged from40 mg/day in a single dose to 1,800 mg/dayin three equally divided doses. A graduatedincrease in diuretic response was achieved byincreasing doses in patients with a varietyof fluid retaining states (table 2). In a nor-mal subject (fig. 5) chloride and sodiumexcretion increased in nearly straight linefashion through the 300-mg dose. Significantbut smaller increments in natriuresis andchloruresis were observed with doses abovethis level. Potassium excretion increased withincreasing dosages at a much slower rateuntil a plateau appeared at levels in excessof 120 mg.

Special SituationsElectrolyte AbnormalitiesFurosemide produced an effective diuresis

in six edematous patients with marked electro-lyte disturbances which included metabolicacidosis or alkalosis, hyponatremia, hypochlo-remia, and hypokalemia.

AzotemiaDiuresis was achieved in four patients with

chronic renal disease in whom the blood ureanitrogen levels ranged from 51 to 117 mg%.However, in these patients diuretic responseswere reduced and higher doses were required.

Pulmonary EdemaFurosemide was administered intravenously

to three patients with pulmonary edema. Adose of 10 or 20 mg was given and then

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EFFECT OF FUROSEMIDE UPON ELECTROLYTE EXCRETION

Refractory CongestiveHeart Failure

i K+m Na+X Ci-

Cirrhosis withAscites

P.E. I.S. M.R. I.S. N.S. CT. M.S. E.H. J.0.

Figure 2

Increments in 24-hour electrolyte excretion and weight change produced by a standard dosageof furosemide of 40 mg four times daily in nine edematous patients.

repeated in 1 hour if no response was ap-

parent. All three patients responded withdiureses ranging from 600 cc to 2,500 cc within4 hours. This was accompanied by an im-pressive diminution in the clinical signs ofpulmonary congestion.

Malignant EffusionIn three patients with effusion due to ma-

lignant disease (two pleural, one peritoneal)furosemide retarded fluid accumulation anddiminished or eliminated the need for thora-centesis or paracentesis. One patient withlymphosarcoma and bilateral pleural effusionhad required thoracentesis of 1,500 cc to 2,200

cc every 5 days for relief of dyspnea. Ad-ministration of furosemide, 200 mg two tothree times daily on alternate days increasedthe interval between thoracentesis to 22 days.

Treatment of OutpatientsIn six patients with congestive heart failure,

one with cirrhosis and ascites, and one withascites due to neoplastic disease furosemidetherapy was maintained for periods of 1 to8 months. Responsiveness had been deter-mined in each case while the patient was

hospitalized, and dosage was adjusted in theoutpatient clinic according to need. The out-patient dosage schedules varied from 40 mg


600

500 _

400 _

A URINARYEXCRETIONmEq/ 24hrs

300

200 _

100 _

0-

A WGT -2

kg /24 hrs-4-5

912

II-: --: I UIA


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FUROSEMIDE

URINE Pt /S. 74Q0 FLASMAASHO with CHF

o10o .- 150

NO+ 2001 [125 No0+

mEq/do ioo 100 mEq/L

0

-5.0

K+ 200 4.0 K+3.0 mEq/L

mEq/da0

1001 100

C1- 200 F75

m Eq./d 00 50 mEq/L0

40003000

VOL.

20 0cc/do

I00000

65

WGTkg

60

MERCUHYDRIN, 2cc 0 8

FUROSEMIDE, mg _ _

DAYS 3 5 7 9 11 13 15

Figure 3Diuresis produced by furosemide in a patient resistantto an organomercurial.

twice daily to 300 mg three times dailyadministered intermittently on every secondor third day. Edema was adequately con-

trolled in seven of the eight patients. Theeighth, an elderly lady with intractable con-

gestive heart failure, had initially responded

3

10 | Refractory Congestive Hoort Cirrhosis with

9 - | Failure Ascites

A UVNo+ 7

A UVK+ 6_

per 24hrs 5

Pit.a,,t PE M.R PE WS WN l.S CT CT N S M.S ENb JO

Dose, 150 50 50 200 50 50 200 50 50 50 50 200

m,g qsd qid q.i bid qid ,id. ti q.d qid qid qid t5

Figure 4

ZXUVNe+/AUVK+ and weight loss from a 24-hour

period of diuresis in patients with refractory conges-

tive failure and cirrhosis with ascites. All patients were

in states of marked sodium retention as indicated by

control rates of urinary sodium excretion, averaging

5.6 mEq/24 hr (range, <1 to 18.6 mEq/24 hr). Oral

doses of furosemide varied from 50 mg q.i.d. to 200

mg t.i.d.

with a 12-pound loss of weight. But, after

discharge from the hospital, fluid reaccumu-

lated despite continued therapy. In general,

dosages required for outpatients were higher

Dose-Response inTable 2

Patients with Edema

Diagnosis

Congestive heartfailure (RHD)

Congestive heartfailure (ASHD)

Congestive heartfailure (ASHD)

Nephrotic syndrome

Cirrhosis withascites

Dose(mg)

80 t.i.d.120 t.i.d.160 t.i.d.200 t.i.d.300 t.i.d.200 single dose300 single dose

40 t.i.d.80 t.i.d.

120 t.i.d.80 t.i.d.120 t.i.d.200 t.i.d.300 t.i.d50 b.i.d.200 b.i.d.

Five patients are presented in whom the dose of furosemide was progressively increasedduring the course of therapy. One day intervenes between treatment days. Diuretic response isestimated by weight loss. The steady, gradual increase in response with increase in dose isillustrated.


913

Patient

C.T.

P.E.

B.S.

K.K.

P.T.

Weight loss(kg/24 hr)

0.50.90.40.91.21.84.60.91.42.30.80.71.01.10.91.6


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(200 to 800 mg/day). Combination of furose-mide with any of the other diuretic agentsresulted in natriuretic and diuretic effectswhich equalled or exceeded the sum of re-sponses observed when the drugs were ad-ministered singly.

Effect on Potassium Excretion and the UrinaryNa/K Ratio

(00 F

Dose response Xwas administernat 7 a.m. andthereafter sepai24-hour collect,diuretic effectweight was takhad returned t(

/ In general patients with refractory edematended to excrete more potassium per unit of

1/ natriuresis than patients who had larger diu-+

retic responses. This is apparent from theK +6 fact that the ratio of sodium to potassium

excreted as a result of diuresis induced by

furosemide was lower in patients who lostsmall amounts of weight during less diuresis

100 200 300 400 500 600 than in those who responded with large diu-SINGLE ORAL DOSE(mg) resis (fig. 4). In 13 studies the ratio of theFigure 5 increase in urinary sodium excretion to that

of potassium (AUNa+/AvUK+ ) ranged fromcurve in a normal subject. Furosemide . red every fourth day in a single dose

0.6 in refractory patients to 12.5 in responsivethe urine output during the 6 hours ones and averaged 3.6. Notwithstanding therated from the balance of the day's favorable Na+/K+ ratios in responsive patients,ion and considered to represent the some of this group exhibited a considerableof the drug. Return to control body 24 hour urinary K+ loss and developed hy-:en as an indication that the patiento a base line prior to each treatment pokalemia.

day.

than those during hospitalization, perhaps dueto less rigid control of sodium intake andactivity.

Comparison with Other Agents and Effect ofCombined Therapy

Furosemide frequently produced an effec-tive diuresis in patients previously refractoryto conventional agents. When compared withchlorothiazide (3 g/ day), azetazolamide (750mg/day), and meralluride (2 cc I.M.), furose-mide, in submaximal doses, was capable ofinducing considerably greater natriuresis thanthe maximal doses of these other agents(fig. 6). Direct comparison with ethacrynicacid indicated that in equal doses furosemidewas somewhat less potent. However, in fourpatients with refractory edema, large dosesof furosemide (400 to 1,800 mg/day) pro-

duced natriuresis of the same order of magni-tude as that produced by ethacrynic acid

Combination with Spironolactone

The addition of an aldosterone antagonistto the regimen of patients receiving furose-mide potentiated the natriuretic and reducedits kaliuretic effect. In four patients with con-

gestive heart failure (fig. 7) AUVNa+/AUVK-increased and a fall in the serum potassiumwas prevented or lessened. In two of the fourpatients, who were more refractory to diuretics,marked potentiation of both natriuretic anddiuretic effects was observed.

Effect on Acid-Base Balance

An acid balance study of a patient withcongestive heart failure maintained on a fixedlow sodium diet is illustrated in figure 8.Hydrogen ion excretion increased, especiallyon the first day of drug administration. Thiswas due to increased urinary excretion ofboth ammonium and titratable acid. Bicarbon-ate excretion did not change significantly.Concomitantly blood pH rose from 7.47 to


300

URINARYEXCRETIONmEq/6hrs 200

Cf-

0

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COMBINATION OF FUROSEMIDE WITHETHACRYNIC ACID, CHLOROTHIAZIDE, ACETAZOLAMIDE Es MERCUHYDRIN

A URINARYEXCRETIONmEo,/24hrs

A WEIGHTkg/24hrs

- 4'LFUROSEMIDE, 200mg tid

ETHACRYNIC A.. 200mg tid _CHLOROTHIAZIDE, lgm tid

ACETAZOLAMIDE, 250mg tidSPIRONOLACTONE, 25mg qidMERCUHYORIN, 2cc

Figure 6Effects of furosemide in comparison and in combination with other agents. Data from threepatients.

7.50 and serum bicarbonate from 32.7 to 35.2mEq/L.Mild extracellular alkalosis was observed in

seven patients studied similarly. Blood pHincreased from a mean of 7.43 to a mean of7.48, and serum bicarbonate increased froma mean of 26.4 mEq/L to a mean of 29.6mEq/L. In five of these patients the pH ofthe urine fell during the first day of therapy;in the other two it increased. In three pa-tients bicarbonate excretion increased slightlyin association with a rather large diuresis; inthe other four it remained unchanged.

Renal Clearances

Figure 9 presents results of two renal clear-ance studies on normal subjects, one duringwater diuresis and the other under maximalantidiuresis. Onset of diuresis after oral ad-ministration occurred within the first 30


minutes. Peak diuretic and natriuretic effectswere reached 30 to 90 minutes after drugadministration, and the action was largelydissipated in 4 hours.During water diuresis urine flow after furos-

emide reached a peak of 25.7 ml/min, repre-senting a tubular rejection fraction for waterof 28.8% of the filtered load. The rejectionfraction of sodium peaked at 17%. Glomerularfiltration rate (Cl1n) fell slightly during peakdiuresis; renal plasma flow (CPAH) did notchange significantly. The free water clearancedecreased by 5.0 ml/min during peak diuresisand approached zero on the decending limbof the diuresis between 150 and 180 minutesafter drug administration.Under hydropenic conditions urine flow

during diuresis reached a maximum of 22.8ml/ min. The tubular rejection fraction ofwater peaked at 32.8%, that of sodium at 27%.


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EFFECT OF ALDOSTERONE ANTAGONISTSON FUROSEMIDE DIURESIS

5

PLASMA K 4 _

mEq/L 3_ _

39.1z20i86'4

A UVNQ+ 2A UVK+Fper 24hrs 8

AWGT - _kg/24hrs -5

-6

-8

-9 20(150 50 50

FUROSEMIDE, F _______mg qid Li *

SPIRONOLACTONE50mg qidPot ient

Figure 7Effect of aldosterone antagonists on furosemidediuresis. In four different patients spironolactone en-hanced natriuretic and retarded kaliuretic effect offurosemide.

Glomerular filtration rate (CI0) was lowduring control period (av. 66.6 cc/min) de-spite the lack of evidence of overt renaldisease. However, it rose moderately duringdiuresis reaching a maximum of 28% abovecontrol. Renal plasma flow (CPAHI) increasedmarkedly at the onset of diuresis but there-after returned to or slightly above controllevels. The capacity for water reabsorption(TeHw,o ) became negative during peak diuresisand remained so until the end of the study.

ToxicityNo true toxic effects were observed. White

blood cell counts, urinalyses, liver functiontests including serum glutamic oxalacetictransaminase and alkaline phosphatase, andfasting blood sugar levels were unaffected.Hematocrit values frequently increased fol-lowing diuresis.

Side effects included (1) hypokalemia ofsufficient degree to require potassium sup-plementation or the addition of aldosterone

antagonists in eight of 21 patients, (2) tran-sient increase in blood urea nitrogen to levelsover 30 mg% (14/26), (3) asymptomatichyperuricemia (levels greater than 5.5 mg%)(11/16), (4) anorexia and nausea in two,(5) hepatic precoma following a 1.4 kg diu-resis in a patient with severe liver disease,(6) occasional postural hypotension followingmassive diuresis, and (7) hyponatremia and

Pt. M. R. 65 0

ASHL2 with CHF

PLASMA

HCO - 35%.- *\4~A3 30-]mE q/ L L

25-17.61

pH 75-7.4-

URINARY EXCRETION

NH + 100150-

mm/do-- ----

............. .................

TA 25mEq/dOJ ...... ...................

mm/do oJ

7.0-pH 6.0-

....... ...5.0 - . .........................

H+ 50imm/do 01

601WGT 55-kg

50

...... .................

...................

..............

FUROSEMIDE _ 50qid

DAYS l l l l

Figure 8

Effect of furosemide on urinary acid excretion in a pa-tient with congestive heart failure.

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WATER DAURESIS125

C IN 100

cc /min.75

700-

CPAH 5

cc/min.

URINEVOLUME

andC os/m

cc /min.

Volume25 E20 Cit215

10

COJ

0

HYDROPENIA & ANTIDIURESIS100rCIN 75E

cc/min. 50

600

CPAH 550cc/min. 500

4500400

URINEVOLUME

andCosMcc/min.

2520-F T20

10- COSMV/

5-

Control 0 40 80 120 160 200 240

t' TTIME IN MINUTES

Furosemide 200 mg Po

Figure 9

Influence of furosemide given orally on renal hemo-dynamics, solute, and water excretion in two normalsubjects.

hypochloremia in two patients maintained ona regimen of spironolactone supplemented byintermittent furosemide.

Discussion

This study of 39 edematous patients andof seven normal volunteers extends earlierreports'0-14 of the effectiveness of furosemideas a natriuretic and diuretic agent. Our dataindicate that this agent is often effective inpatients refractory to other diuretics. In maxi-mal doses the potency of furosemide ap-proaches that of ethacrynic acid,'7 and itexceeds the potency of thiazides, mercurialsor acetazolamide. Furthermore, its effects ap-pear to add to those of the other diuretics.

Circulation, Volume XXX1V, November 1966

Indeed, the combination of furosemide witheither thiazides or carbonic anhydrase inhibi-tors produced unusually beneficial effectswhich at times appeared more than additive.The rapidity of onset of its diuretic action,

3 to 5 minutes when administered intraven-ously, and less than 30 minutes when ad-ministered orally, makes furosemide usefulin the treatment of acute situations such aspulmonary edema. The relatively brief dura-tion of its natriuretic action, 1 to 2 hourswhen given intravenously, and 4 to 6 hourswhen given orally, allows induction of diuresiswhich is easily controlled by adjustment ofdose and by the frequency of administration.

Responsiveness to a given dosage of furos-emide varied considerably from patient topatient. It is therefore important in initiatingtreatment to begin with a small dose, forexample 40 mg, and adjust this upward step-wise over a range of 40 to 600 mg one to threetimes daily until the desired response isachieved. The gradual and predictable in-crease in response which can be achieved withincrease in dosage over an unusually broadtherapeutic dose range when considered to-gether with its unusual potency points to abroad spectrum of clinical usefulness forfurosemide in the management of edematouspatients.

Like other diuretics the effectiveness offurosemide diminishes with continuous ad-ministration. Intermittent therapy, when thedrug was given 1 to 3 days consecutively,proved more efficacious in mobilizing edemafluid than continuous therapy and was lesslikely to produce electrolyte or acid distur-bances. Observations in outpatients indicatedthat furosemide retains its effectiveness overprolonged periods and is well tolerated.During a furosemide diuresis sodium and

chloride were the predominant ions excreted.However, at times appreciable potassium ex-cretion was also induced and hypokalemiaoften resulted. The hypokalemia induced byfurosemide could be controlled by intermit-tent therapy, by the addition of potassiumsupplements, and by combination with analdosterone antagonist. The latter regimen has

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the advantage of potentiating natriuresis inrefractory patients.The ability of furosemide to produce an

effective diuresis in more resistant patientswith a variety of electrolyte disturbanceswhich included metabolic alkalosis, acidosis,hyponatremia, hypochloremia, hypokalemia,and azotemia is a characteristic similar to thatreported for ethacrynic acid and points up thedistinctly greater potency of these two newerdiuretics. This characteristic of these twoagents portends their special usefulness inpatients with refractory or complicatededema. However, greater potency clearly in-creases the hazard of producing overdiuresisor iatrogenic electrolyte disturbances whichdevelop not as toxic effects but as pharma-cological consequences of excessive diureticaction. Especially during the initial phases oftherapy with these drugs the patient shouldbe carefully followed and serum electrolytesfrequently checked. Stepwise increases in dos-age and intermittent rather than daily therapyare advisable at least at the beginning.

Stop-flow studies7 suggest that the kaliure-sis following furosemide occurs primarily be-cause of an increased distal tubular secretion.The importance of endogenous aldosteroneactivity as a determinant of the magnitudeof diuretic-induced K+ loss has been docu-mented in studies of ethacrynic acid."7 Theview that distal Na+-K+ exchange inducedby furosemide is likewise augmented by asecondary or underlying increase in aldoster-one secretion is suggested by ( 1 ) the increasedtendency for hypokalemia to occur duringdiuresis in those clinical situations character-ized by elevated aldosterone secretion suchas cirrhosis or refractory cardiac edema and(2) by the ability of spironolactone to in-crease the Na + /K + ratio during furosemidediuresis. The occurrence of hypokalemia inpatients, despite a favorable urinary Na + /K + ratio, suggests that the magnitude ofthe sodium load delivered to ion exchangesites in the distal nephron during a furose-mide diuresis is another major factor deter-mining the amount of K+ loss induced bythe drug.

Acid-base balance studies indicate that theextracellular alkalosis following furosemideadministration results both from an increasedtotal hydrogen ion excretion, most prominenton the first day of drug administration, andfrom potassium loss. The drug increased theexcretion of both titratable acidity and am-monium, but bicarbonate excretion was littleaffected, thus verifying'8' 19 that furosemidehas little or no carbonic anhydrase-inhibitingactivity. The unusual potentiation of furose-mide diuresis by carbonic anhydrase inhibitorssupports this view.Renal clearance studies failed to indicate

any consistent effect of oral furosemide onrenal hemodynamics, a finding which differsfrom the significant increases in filtration rateand renal blood flow reported by others whenthe drug was given intravenously3'20,21During maximal water diuresis administrationof 200 mg of furosemide to our normal vol-unteer resulted in a tubular rejection of waterof 28.8% of glomerular filtrate and undermaximal antidiuresis 32.8%. The respectivefractions of filtered sodium excreted duringdiuresis in these studies were 17% and 27%.Vorburger,20 in administering the drug intra-venously to patients with renal functionalimpairment, found tubular rejection of waterto reach 60% and that of sodium 48% of thefiltered load. Since the extent of these natri-uretic and diuretic effects exceeds what wouldbe expected (according to current concepts)to result from inhibition of sodium reabsorp-tion in the loop of Henle and distal tubules,a prominent site of action in the proximaltubule is implied. That both CH2O andTC112o decreased during furosemide diuresisagrees with findings of Buchborn and Ana-stasakis3 and Suki and associates4 and pointsto a site of action in the ascending limb ofthe loop of Henle as well as in more corticaldiluting segments of the distal tubule. Hencefurosemide appears to differ in its mode ofaction from thiazide diuretics which havebeen demonstrated16 22 to inhibit CH20 buthave no effect on TCH20. Micropuncture stud-ies5 6 and stop-flow analyses7 suggest thatfurosemide has effects on both the proximal


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and distal nephron, and Hook's observa-tion23 in dogs that furosemide abolishes thenormal medullary sodium gradient lends fur-ther support to an effect on the loop of Henle.

In dogs furosemide is capable of increasingthe saliuretic response to maximal doses ofhydrochlorothiazide but to a degree whichis less than additive.24 When superimposedon a maximal ethacrynic acid diuresis, furose-mide produced only small, inconsistent in-creases in sodium excretion.24 These resultssuggest that furosemide has sites of actionadditional to those of hydrochlorothiazide butsimilar to those of ethacrynic acid. In ourstudy the fact that furosemide was able toproduce a significant increase in the sali-uretic and diuretic responses to ethacrynicacid when administered concomitantly withit can probably be attributed to the sub-maximal doses of both agents employed.

Chloride excretion after furosemide alwaysexceeded that of sodium in both the clear-ance and balance studies. This might suggesta primary action of the drug to block chloridereabsorption. While this hypothesis cannotbe excluded, the facts that sodium plus po-tassium outputs exceeded chloride in manystudies and that K+ and H+ excretions wereaccelerated by the drug, and the lack ofany precedent for primary chloride inhibitionby diuretics make it seem far more likelythat furosemide blocks sodium reabsorption.Primary inhibition of sodium transport in theproximal and distal nephron, interference withpassive chloride reabsorption as a consequenceof the effects on sodium, and subsequentexchange of some of the rejected sodium forpotassium and hydrogen ions would explainthe pattern of urinary excretion observed.

SummaryThe physiological effects of furosemide, a

new diuretic agent chemically related to thia-zide diuretics, have been evaluated in sevennormal subjects and in 39 patients with edemaof varied origin.The compound exhibited an unusually

broad dose-response curve so that increasingdiuresis could be induced with oral doses ofCirculation, Volume XXXIV, November 1966

from 40 mg once daily to 600 mg three timesdaily. At the higher dosages furosemide wassignificantly more effective than conventionalthiazide diuretics and exhibited an order ofpotency which can be achieved with ethacry-nic acid.

In many of its diuretic properties furose-mide resembled thiazide agents. The natri-uresis and diuresis which it produced wasassociated with a disproportionate loss ofchloride and potassium and the consequentproduction of degrees of hypokalemic alkalo-sis.However, physiological studies indicate that

furosemide is qualitatively and quantitativelymore similar to ethacrynic acid than to thia-zide agents. Thus, furosemide, like ethacrynicacid and unlike thiazide diuretics acted tointerfere with both urinary concentration(TCH20) during antidiuresis and to blockurinary dilution (CH20) during water diuresis.It also caused a negative urinary hydrogenbalance during diuresis.The data suggest that furosemide acts to

block sodium chloride reabsorption in theascending limb of Henle's loop and in morecortical distal diluting segments. The magni-tude of its effects suggests that it also mayinterfere with proximal sodium chloride re-absorption. Ion exchange sodium reabsorptivemechanisms appear unaffected and becomeoveractive during drug administration there-by accounting for the observed increases inpotassium and hydrogen ion excretions.Because of its properties furosemide was

especially useful intravenously as an adjunctin the treatment of acute pulmonary edemaand for oral maintenance therapy in thetreatment of difficult or refractory edematouspatients, many of whom exhibit associatedelectrolyte derangements or azotemias. Inthese difficult situations, for maximum diure-sis and to avoid problems associated with K+,H+ and Cl- depletion, intermittent therapyadded to a maintenance schedule which uti-lizes aldosterone antagonists or chloride andpotassium supplements appears advisable.

Furosemide, also like ethacrynic acid, wascapable of adding to the natriuretic action of

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all other types of diuretic agents. This obser-vation provides additional evidence for theexistence of a number of different tubulartransport processes located at different sitesin the nephron which can participate insodium conservation.

References1. MUSCHAWECK, R., AND HAJDU, P.: Interna-

national Furosemide Symposium. Bad Hom-burg, Germany, 1963.

2. DEETJEN, P.: International Furosemide Sympo-sium. Bad Homburg, Germany, 1963.

3. BUCHBORN, E., AND ANASTASAKIS, S.: Site andmechanism of action of furosemide on thedistal nephron in man. Klin Wschr 42: 1127,1964.

4. SUKI, W., RECTOR, F. C., JR., AND SELDIN,D. W.: Site of action of furosemide and othersulfonamide diuretics in the dog. J Clin In-vest 44:1458, 1965.

5. DEETJEN, P.: Mikropunktionsuntersuchungen zurWirkung von Furosemid. Pfluigers Archiv 284:184, 1965.

6. MALNiC, G., VIEIRA, F. L., AND ENOKIBARA, H.:Effect of furosemide on chloride and waterexcretion in single nephrons of rat kidney.Nature 208: 80, 1965.

7. SuzuKi, F., KLurscH, K., AND HEIDLAND, A.:Stop-flow studies on the mechanism of actionof furosemide. Klin Wschr 42: 569, 1964.

8. MUSCHAWECK, R., AND HAJDU, P.: Saliureticactivity of chlor-N-( 2 furyl methyl )-5-sul-famyl-anthranilic acid. Arzneimittelforschung14: 44, 1964.

9. THOMS, R. K., SPRINGMAN, F. R., AND WILSON,H. E.: Toxicological evaluation of furosemide:A new diuretic agent. Farmaco (Prat) 19:544, 1964.

10. KLEINFELDER, H.: Experimental investigationsand clinical experiences on a new diuretic.Deutsch Med Wschr 88: 1695, 1963.

11. LARIZZA, P., BRUNETTI, P., NENcI, G., AND COLI,L.: Clinical experience with the new diureticfurosemide. Med Klin 59: 1284, 1964.

12. STOKES, W., AND NUNN, L. C. A.: A new effec-tive diuretic-Lasix. Brit Med J 2: 910, 1964.

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 In-tern Med (Chicago) 115: 542, 1965.

15. CANNON, P. J., AMES, R. P., AND LARAGH, J. H.:Methylenebutyryl phenoxyacetic acid: Noveland potent natriuretic and diuretic agent.JAMA 185: 854, 1963.

16. HEINEMANN, H. O., DEMARTINI, F. E., ANDLARAGH, J. H.: Effect of chlorothiazide onrenal excretion of electrolytes and free water.Amer J Med 26: 853, 1959.

17. CANNON, P. J., HEINEMANN, H. O., STASON, W.B., AND LARAGH, J. H.: Ethacrynic acid:Effectiveness and mode of diuretic action inman. Circulation 31: 5, 1965.

18. BERMAN, L. B., AND EBRAHIMI, A.: Experienceswith furosemide in renal disease. Proc SocExp Biol Med 118: 333, 1965.

19. AMBROSOLI, S., ET AL.: Clinical research on thediuretic activity of furosemide. Minerva Nefrol11: 56, 1964.

20. VORBURGHER, C.: Acute effect of the diureticfurosemide on the glomerular filtrate, on renalhemodynamics, on the water, sodium, andpotassium excretion, and on the oxygen con-sumption of the kidney. Klin Wschr 42: 833,1964.

21. SCHIRMEISTER, J., AND WILLMAN, H.: Uric acidand other clearances after intravenous admin-istration of furosemide. Klin Wschr 42: 623,1964.

22. EARLEY, L. E., KAHN, M., AND ORLOFF, J.:Effects of infusions of chlorothiazide on uri-nary dilution and concentration in the dog.J Clin Invest 40: 857, 1961.

23. HOOK, J. B., AND WILLIAMSON, H. E.: Effect offurosemide on renal medullary sodium gradient.Proc Soc Exp Biol Med 118: 373, 1965.

24. HOOK, J. B., AND WILLIAMSON, H. E.: Additionof the saluretic action of furosemide to thesaluretic action of certain other agents. JPharmacol Exp Ther 148: 88, 1965.


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H. LARAGHWILLIAM B. STASON, PAUL J. CANNON, HENRY O. HEINEMANN and JOHN

Furosemide: A Clinical Evaluation of Its Diuretic Action

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