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Pharmacodynamic effects of a new diuretic drug, ethacrynic acid∗
Pharmacodynamic
Effects
Drug, ALRERY
N.
OSVALDO
Ethacrynic
THACRYKIC
M.D., F.A.c.c., GADDO ONESTI, M.D., ROBERT SELLER,
BRES,
acid
structurally
curials
animal
natruretic zide.2j3 patients purpose
is a
clinical
has
also
diuretic
has demonstrated
greater
than
effectiveness been
chlorothia-
in edematous
demonstrated.4v5
The
of this report is to present our investiga-
tive survey
of the diuretic
effectiveness
of the
efficacy
other
with
drug
and antihypertensive and
currently
to compare
available
ORAL DIURETIC ASSAY
its
diuretic
nonedemaInpatient Study: A group of hospitalized: tous patients was studied to determine the effect of varying doses of ethacrynic acid on urinary electrolyte excretion. Each patient was allo\ved 1 gm. sodium daily in his diet. Twenty-foollr hour urine specimens were collected and analyzed for sodium, potassium, chloride and creatinine. \vhrn the 24 hour urinary excretion of sodium was reduced to approximately 90 per cent of intake. ethacrynic acid was administered. Five patients received 50 mg. (50 mg. o.d.); 3 patients received 101, mg. (50 mg. b.i.d.) ; 7 patients received 200 mg. (100 mg. b.i.d.) ; and 6 patients received 400 mg. (100 q.i.d.) of cthaTwenty-four hour urine collections \vere crynic acid. again obtained after administration of the drug. and the electrolyte and creatinine excretions \vcrv measured. An acute, 48 hour \\-eight loss reOutpatient Study: sponse was determined in a group or hubjects who regularly attended the outpatient Diru-et& Clinic. All patients were in mild to moderate congestive heart failure due to arteriosclerotic or rheumatic heart disAll patients were maintained on daily digitalis ease. preparations; but diuretic therapy \vas discontinued for three weeks prior to the initial administration of ethacrynic acid. The patients were advised to continue their usual physical activities. Dietary salt reduction consisted only of the avoidance of extra table salt and excessively salty foods. Yaryinq dosages of ethacrynic acid ranging from 100 to 600 mg. daily were administered, for two consecutive days. ‘I‘he
compounds. METHODS
AND
MATERIALS
INTR.4VENOUS DIURETIC ASSAY A group of 8 hospitalized, nonedematous patients was studied to determine the effect of intravenous ethacrynic acid on renal function and water and electrolyte excretion. None of these patients suffered from clinical renal or cardiac diseases. A second group of 5 hospitalized, edematous patients was studied similarly. Among the second group, 3 had cardiac edema, 1 had nephrotic syndrome and 1 had cirrhosis of the liver. All patients were maintained on 1 gm. sodium daily in the diet for at least three days prior to the investigation. The studies were performed in the morning in the fasting state? after deprivation of water and food for 12 hours. Blood samples were taken via an indwelling heparinized polyethylene catheter. Urine was collected through an indwelling bladder catheter. After three 30-minute control study periods, ethacrynic acid was administered intravenously in the dosage of 0.5 mg.jkg. body weight dissolved in 20 cc. isotonic saline. The effect of drug administration was then studied at 30 minute intervals thereafter for a total of five hours. The following parameters were measured : para-aminohippurate clearance (renal plasma flow), inulin clearance (glomerular filtration rate), uric acid clearance, plasma osmolarity, hemato* From the Section Pa. VOLUME
of Vascular
16, JULY 1965
XI.D., I~..~.c.c
crit, urine flow, urine osmolarity and urine electrolyte (sodium, potassium and chloride) excretion. Osmolar clearance was calculated according to the formula, Cosm = (UosmjPosm) X 1.. Tubular reabsorption of solute-free water was calculated according to the formula, ToH,,, = Cosm -1.. \vhere V is the urine flow in ml./min. and Losm and Posm are the solute concentrations of urine and of plasma in milliosmol./kg. of water.
agent
In the ex-
derivatives.’
KD.,
Pennsylvania
to the organomer-
the drug
properties Its
new
unrelated
or the thiazide
perimental
Acid*
RAMIREZ, M.D., CHARLES HEIDER, M.D. and JOHN H. MOYER, Philadelphia,
E
of a New Diuretic
Diseases and Kenology,
Hahnemann
99
Medical
Coll~gc- and
I Hospital. Plhil;~d~lphia,
Brest et al.
100
TABLE I Averqr
Tune-Response
Effects
Following
Intravenous
Administration
and Five Edematous P;rr.*meter
CrouD”
---
----
~
I
0
of Ethacrynic
~- Time After Drug (One-Half
2
Acid in Eight
Nonedematous
Subjects Hour
Periods)
------.--.---
----_
3
4
5
6
7
R
9
5323 761$
287 491:
169 291
113 210
97 178
84 135
72 112
70 94
87 148t
69 122:
65 109
60 85
55 75
52 69
43 55
47 65
115 132
104 94
95 81
94 74
I
2.3 23
1.9 20
2.2 20
20
41 5 45.3
41.5 45.3
41.4 45.3
41.1 45.0
41.1 45.3
10
(&q./min.)
1 2
102 4x
2081 t 1253:
K (,,Eq.,‘min.)
1 2
61 69
208 g 2305
Cl (rEq.,‘min.)
1 2
110 31
2265 $ 18295
13695 I4705
613t 822 5
314 431t
197 250
143 175
NnjK
1 2
22 1.2
10.95
10.95 7 9s
6.59 5.3f
4.6 4 3t
2.9 5 ot
2 26
1 2
40.8 46 0
41.5 45.8
1 2
85 7 3
8.9 8.1
5.05 70
3.88 5.4
4.15 4.5f
3.89 4.4t
3 8§ 4.4t
4.18 4.15
4.5s 3.46
4.65 3.3t
5.05 4.3t
T’ I,?<)
1 2
1 28 I 0
-0.2s 0.7
0.10 00
0.49 0.2
0.55 0.1
0.6$ 0.3
0.65 03
0.5g 0.3
0.76 0.4
0.69 04
0.7% 0.3
C-osmolarity
1 2
24 1.8
15.69 12.55
10 10 11.65
5.1x 7.15
3.2 4.51
2.7 33
2.1 2.6
1.8 24
19 2.1
1.7 1.7
1.7 1.7
Plasma
1 2
290 302
289 302
290 300
291 300
289 299
289 302
289 299
290 299
289 303
289 300
289 300
1 2
657 664
2885 348 Q
2926 3046
31x5 3195
355 5 340 Q
3849 3635
425 8 381 Q
4338 405 L
4885 4155
493s 414$
500 p 488t
1 2
12 10
15.85 11.15
1o.og 11 65
4.8§ 6 9s
2.7 4.2t
2.1 3.1
1.5 2.3
1.3 2.1
1.2 1 .6
1 I 1.4
1.0 1 .o
How
1 2
434 395
468 448
359: 387
347: 371
389 346
345: 339
347t 367
383 375
376 361
368 373
371 398
filtration
1 2
73 53
59t 43:
63 45
66 43:
Nn
ratio
Hemnrocrir
(7)
C-uric
(cc./min
Urine Urme Renal
awl
)
osmolarity osmolariry How (cc.,/min.) plasma
Glomerular rate
1277: 1259: 1406 201 P
6 7%
42.1 46.0
65 55
88t 60
42.5 45.8
621 47
42.5 45.8
41.9 45.5
6Ot 43:
59t 45
65 44
1.8
63 49
* t i 5
Group Differs Differs Differs
1 = 8 nonedematous subjects; sienificanilv from conn~l (0 < s&ificantl; from control 0 < significantly from control (,b <
acute weight determined. ANTIHYPERTENSIVE
loss response
Group 2 = 0.011. 0.05). 0.001).
to these
5 edematous
doses
subjects
was then
STUDY
Fifteen ambulatory patients with blood pressures greater than 150/l 00 mm. Hg were randomly selected The age range was 37 from the Hypertension Clinic. to 66 years. There were 4 male and 11 female paAfter tients; 14 were Negro and one was Caucasian. an initial diagnostic evaluation, these subjects were placed on daily placebo medication for a minimum of three weeks. The patients returned to the clinic at weekly intervals, at which time blood pressure and physical signs and symptoms were recorded. After the control period the 15 patients were treated with ethacrynic acid alone. The drug was The dosbegun in an initial dosage of 50 mg. daily. age was gradually increased, at biweekly intervals, to a maximum of 400 mg. daily in those patients who failed to achieve a significant antihypertensive response at a lower dosage level.* * The achievement of normotension (140/90 mm. Hg) or a reduction in mean arterial blood pressure (diastolic pressure plus one third of the pulse pressure) of 20 mm. Hg or more was considered significant.
No specific dietary restriction, other than the avoidance of grossly salty foods and added table salt, was advised during the course of this study; and electrolyte supplements were not given. Determinations of blood urea nitrogen, serum uric acid and electrolytes (sodium, potassium and chlorides) were performed during the control period and after treatment with ethacrynic acid. RESULTS
INTRAVENOUS
DIURETIC
ASSAY
Renal Hemodynamics: The acute intravenous administration of ethacrynic acid resulted in an initial transient increase in renal plasma flow and glomerular filtration rates, but this effect was followed thereafter by a decrease in renal hemodynamics (Table I). Reduction in renal blood flow and glomerular filtration rate was evident within one and one-half hours after intravenous injection. The maximal decrease in renal plasma flow was 20 per cent ($I < 0.05) in the nonedematous group and 15 per cent in the edematous patients. The maximal reducTHE
AMERICAN
JOURNAL
OF
CARDIOLOGY
New
Diuretic
Drug, TABLE
Incrense
of
Urinary
Electrolyte
16,
JULY
1965
101
Acid
II
Above Control in Response to Varyillg Dosages of Ethacrynic .\citi Administered Orally (per 24 hr. Urine Collection ) Excretion
tion in glomerular filtration rate was 19 per cent in both groups. Maximal decrease in renal plasma flow occurred two and one-half hours after intravenous administration in both groups. Maximal reduction in glomerular filtration rate occurred between two and three hours. Arterial blood pressure was measured by conventional sphygmomanometer in all patients throughout the clearance studies, and no significant changes were noted. l?inP Elrctrolyte Excretion: There was an immediate increase in natruresis which was maximal during the first 30 minutes and was of the order of 1940 per cent for the nonedematous group and 2500 per cent for the edematous patients. The natruretic effect lasted three hours in the nonedematous group but was still evident after five hours in the edematous group. The over-all increase in sodium excretion during the five hour study was 368 per cent in the nonedematous group and 895 per cent in the edematous group. -4 significant increase in chloride cxcrction paralleled the natruresis in both the excretion of chloride groups ; however. was consistently greater than that of sodium. The excretion of potassium also increased in both groups, the maximal occurring during the first 30 minutes. The sodium-potassium excretion ratio increased in both groups. 1Sine Flow and Osmolarity: An immediate increase in urine flow, from an average of 1.2 to an average of 15.8 ml., min., occurred during the first 30 minutes in the nonedematous group; and a significant increase in urine flow lasted one hour and 30 minutes. In the edematous group a significant increase in urine flow lasted two hours, with the maximal increase, from 1.0 to 11.6 ml./min., occurring at one hour. There was an immediate drop in urine osmolarity in both groups, lasting during the entire period of study. Maximal decrease in urine osmolarity VOLUME
Ethacrynic
occurred during the first hour of stud!. in both The tubular reabsorption of free water groups. (TcHzO) was consistently decreased in both groups throughout the study. Osmolar clearance increased in both groups, paralleling the increase in urine flow. Plasma osmolarity and hematocrit showed no significant changes Followthroughout the study in both groups. ing a transient initial increase? uric acid clcarante was consistently and significantly- drcreasrd thereafter in both groups. ORAL
DICRETIC
ASSAY
The 24 hour urine elcctrolytc excretion response to varying dosages of ethacrynic acid is recorded in Table II. There was a progressive increase in natruretic and kaluretic activity as the daily dose was increased from 50 to 400 mg. The maximal effective daily dose of 400 mg. produced an average increase, above control levels, of 195.8 mEc]. of sodium and 75.6 of potassium per 24 hour urine collection (11 < 0.01). Outfiatient Stud,;: The acute 48 hour response by weight loss is shown in Table 111. The weight loss elicited by the administration of different doses of ethacrynic acid dail!- for two days ranged from 1.82 to 5.75 pounds. A dose of 400 mg. daily for two days resulted in an average weight loss of 5.75 pounds in 12 patients. The response to all dosages studied (190 trig., 200 mg., 400 mg. and 600 mg.) was statistically significant. Side reactions encountered during the study of acute 48 hour weight loss are tabulated in Table IV. Inpatient
S’tucly:
ANTIHYPERTENSIVE
STUDY
The blood pressure responses are tabulated in Table v. The figures reported are averages of the blood pressure readings obtained during the control and study periods. Of the 15 pa-
102
Brest et al TABLE 111
Acute
48 Hour
-
Case No. -__..__. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 Mean p value
‘rABLE
Weight Change in Pounds Dosagc Levels
-------Daily
on Four
Side Reactions
Dosqp------
100’ ~-----No. 19
2002
-4.00 -2.00 -1.75 +2.50 -0.75 -1.50 -2.00 -2.75 -2.50 -4.00 f0.75 -0.75 +0.75 -5.75 -0.75 -0.25 -6.75 -2.25 -1.00
-2.50 -8.00 -3.00 -2.15 +3.25 f2.25 -1 .oo -3.25 +3.25 -3.25 -5.75 -4.00 -2.75 -1.75 +0.75 -1.75
1.82
1.89 <0.05
16
-p--Daily
(mg.) 4003 of Patients---------. 12
6004
-9.00 -4.75 -4.25 +0.25 -0.50 -6.50 +2.00 -2.50 -15.00 -10.00 -8.00 -10.75 ,,_ .,.
-5.00 -4.50 -1.00 -2.75 0.00 f2.00 -2.75 -4.50 -1 .oo -2.50 -10.25
1 = 50 mg. b.i.d.; 2 = 100 mg. b.i.d.; q.i.d.; and p = 200 mg. t.i.d.
of Acute
48
Dosagc--(ms.)
Side Reaction (no. of patients)
100
200
400
600
4 3 0 0 0 1 2 1 2
2 0 1 1 1 2 1 2 2
2 0 1 1 0 0 0 2 5
1 1 0 4 1 0 1 1 6
11
:‘: 5.75
I”
Encountered During Study Hour Weight Loss
2.88 <0.02 3 = 100 mg.
tients in this group, 8 (53%) obtained a significant blood pressure reduction in the supine position and one of the 8 became normotensive. Likewise, in the erect position 8 patients obtained a significant antihypertensive response but 3 of them became normotensive. Side reactions encountered included nausea (2 patients), abdominal cramps (2 patients), diarrhea (2 patients), anorexia (1 patient), nasal stuffiness (1 patient) and weakness (1 patient). The therapeutic effects on serum electrolytes, blood urea nitrogen and serum uric acid are tabulated in Table VI. Significant changes in mean difference of serum potassium and chlorides, urea nitrogen and uric acid were noted. Significant reductions in potassium and chlorides occurred, along with significant increases in urea nitrogen and uric acid. Despite the development of hyperuricemia, no instances of clinical gout were encountered during the course of this study. DISCUSSION
The results of the intravenousdiuretic assay indicate that ethacrynic acid is an extremely potent
GU GI
CNS Other
Nocturia Fre(quency Anorexia Nausea Vomiting IIeadache Dizziness Weakness 1,eg cramps
GU = genitourinary, CNS = central nervous
GI = system.
gastrointestinal
and
diuretic and natruretic drug. The chloruretic and kaluretic effects of the compound are also substantial, with chloruresis being even greater than natriuresis. Of particular interest is the rapid onset of action. Increase in urine flow, natruresis and chloruresis appear within minutes following intravenous administration (Fig. 1 and 2). In comparison with parenteral mercurial diuretics, ethacrynic acid appears to have a much more rapid onset of action ; on the other hand, its diuretic activity is shorter, being spent within five hours. It is notable that in the edematous patients studied, where the average glomerular filtration rate was significantly less than in the nonedematous group, the natruretic effect obtained was proportionately greater and more prolonged than in the nonedematous subject. Over-all, it would appear that parenteral administration of the drug will have particular usefulness in patients with severe cardiac decompensation (e.g., acute pulmonary edema), in whom rapid diuretic action is required. Furthermore, since marked sodium excretion occurred in the presence of severely reduced glomerular filtration rates, it may be anticipated that ethacrynic acid will also be a useful diuretic agent in the presence of edema associated with advanced renal functional impairment. In the hydropenic state, ethacrynic acid produced a significant decrease in urine osmolarity with a decrease in the reabsorption of free In the hydrated subject, water (TC~Z~>. Cannon et al.‘j and Goldberg and co-workers7 reported a decrease in free water clearance THE
AMERICAN
JOURNAL
OF CARDIOLOCY
New
l>iuretic
Drug,
Pressure
Response
TABLE
Blood -~Control
Ethacrynic
1 Cl.?
:kid
”
to Ethacrynic
Acid
B.P.-
(mm. Ha) hl.ran
1 2 3 4 5 h 7
8 9 10 11
6b 45 37 54 40 49 53 4x 56 53 49
1’ F M M E‘ 1’ F I’ t: F F
Ii lx I\’ w N N x N N N .\I
‘I‘ABLE
Biochemical
Changes
Sodium
(mliq.
1..1
l..) c,w
1
2 3 4 S 6
x ‘I
II) II 12 13 14 15 A bfr,,n p v,llllr
CXrlnridrs (rnCq.,I..) L: K
c:
-
R
c:
K
148 135 134 150 132 143
14x Ii4 146 146 146 141
4 S 4 4 3 5
0 0 3 0 7 n
3 4 3 3 3 4
14x 148 140 140 130 140 1411 14”
140 140 l-S4 130 IS6 152 141 131
4 4 4 4 4 4 4 47
8 R 0 x 6 3 2
3 3 3 7 3 44 4 h 4 0 4 0 3 3
+4 >o
7x I
-0 co
4 9 0 ‘1 7
i
100 102 103 100 105 in3
592 01
196/115 190/120 17R/130 168,“llO 170;126 150/104 194/120 158/114 205,‘128 186/104 16OjlOO 178/118 165’, 132 228/118 19n/100
142 143 146 129 140 119 144 128 153 131 120 138 143 154 130
Acid ‘l‘herapy
RUN (m9.T) C: R
103 100 100 92 95 9s
I 100 xx too 102 100 9x 104 103 10s
.Mean
“I
After Ethacrynic
Pot.trsiurn
(mk.
143 142 143 132 135 121 144 130 162 132 137 176 144 160 13s
204,112 174.128 164,116 10s 120 Ii5 105 210,112 1’0, 110 228, 130 1X8 104 1x5 114 17x Il.5 1X8 122 23X 122 195,105
Erect
100 93 103 lni 100 93 103
26 19 IX 18 12 20
32 23 25 13 21 22
1.i
19 15 21 17 13 55 SO 22
11 19 15 11 34 2x 1’1
-4 214 ,co 01
+s
9 01
3
TIME
4
( l/2
I
I
5
6
I
7
8
5.3 5.6 6.0 4.8 5.1
6 7 8.6 10.7 6.5 5.2
5.1 6.0 68
10.4 9.8 103
5’5 6 3 1.9
‘7’3 12.5 8 0
16,
JULY
1965
(Cu,o). These combined findings indicate a probable site of action of ethacrynic acid in the ascending limb of the loop of Henlc. The decrease in renal plasma flow and ~lomerular filtration rate which accompanies the diuretic action of the drug is likely related to an accompanying transient reduction in total blood \.olume. According to current concepts, uric acid is filtered by the glomeruli, completeI>. reabsorbed in the proximal tubules and subsequently secreted in the distal segments of the nephrons. It is conceivable that the decrease in uric acid clearance which follows intravenous administration of ethacrynic acid is due to decreased distal tubular secretion of uric acid. Although uric acid clearance ultimately diminished significantly in all subjects, a transient increase in uric acid clearance occurred in 3 casts during the initial 30 minutes following intravenous
-non-edematous ----edematous
3
r7
IO 1
FIG. 1. 1Jrine jhw Jollorving intravenous ethacrynic acid. Diuresis follows within minutes after intravenous administration. VOLUME
IO4 118 139 109 12X 120 143 100 116 111 96 123 136 138 106
134 90 145 105 lS8 130 136 ‘96 166 110 14s 10x 205 112 120 90 150 100 154,90 118 85 150 110 166 122 200. 108 150,85
11s 126 133 111 124 118 150 110 116 103 110 121 150 134 107
subjects
9
HR. PERIODS
% ) R
146/100 17O/lOi lhOj120 138,“)x 160/106 150:102 220,115 ISO/ 154/98 140/RS 1 so/90 148;lOB 192’130 lX2,~llO 162 ‘80
subjects
----edematous
1 2
Acid
bg. C
+2 872
-non-edematous
L-
Uric
\lC.lrl
-1I1T
I
2
I
3
TIME
4 ( l/2
5
6
7
I
r
8
9
I
subjects subjects
)
IO
HR. PERIODS)
FIG. 2. Sodium excretionfollowzn,~ intrarznouse//mcyic Marked natruresis accompanies the rapid diuretic tion of the drug.
acid.
ac-
104
Brest et al. TABLE WI
uretics
or with parenteral meralluride” (Table On the other hand, its short duration of action (approximately eight hours) may make it less desirable than certain other oral diuretic compounds, with respect to the need for frequency of administration. The antihypertensive study indicates that the oral drug possesses antihypertensive effectiveness which also compares favorably with that of other potent oral diuretics (Table VIII). As a result of prolonged use, significant reduction in serum potassium and chlorides may be encountered along with significant increases in blood urea nitrogen and serum uric acid. In certain instances, these electrolytic and metabolic effects could lead to significant clinical problems.
Acute 48 Hour Weight Loss in Pounds* Comparison of Various Diuretic .4gents Methyclothiazide. Chlorthalidone. Polythiazide. Trichlormethiazide. Quinethazone. Benzthiazide. Hydroflumethiazide. Benzydroflumethiazide. Cyclothiazide..
1 ,3 2.2 2.5 2.7 2.8 3 .O 3.2 3.3 3.3 3.6 4.5 5.8
Hydrochlorothiazide
Meralluride............................. Ethacrynic .4cid, * Employing
maximal
VII).
effective
dosages.
SUMMARY administration. This dual action has been previously reported with the thiazide derivatives.8 The oral diuretic assay indicates that oral administration of the drug also results in a substantial diuretic action, the effects on electrolyte balance being similar to those observed during the intravenous assay. Of the dosages studied, 400 mg. daily produced the maximal natriuresis. The acute 48 hour weight loss response obtained with 400 mg. of ethacrynic acid, was in fact, more favorable than that previously obtained (in similar studies) with other potent oral di-
Ethacrynic acid is an extremely potent diuretic and natriuretic agent. Its rapid onset of action following intravenous administration suggests particular usefulness in patients with severe cardiac decompensation, e.g., acute pulmonary edema. Furthermore, the parenteral drug appears to be effective despite reduced glomerular filtration rates, and, therefore, may be useful in the treatment of edema associated with advanced renal functional impairment. Oral administration of ethacrynic acid also results in potent diuretic activity, with substantial antihypertensive effectiveness as well. The
TABLE vm Blood Pressure Response
Drug Regimen Acetazolamide (daily)t Acetazolamide (intermittent)f Chlorothiazideff Hydrochlorothiazidel/ Flumethiazides ChlorthalidoneT Quinethazoney Ethacrynic acid#
No. of Pts. 19 14 50 54 17 30 29 15
to Various
Diuretic
Regimens
Supine-Mean B.P. Reduced >20 mm. Hg or Normotensive Normotensive c* No. No. /0 o/o 2 1 9 11 2 5 5 1
11 7 18 20 12 17 17 7
3 2 18 21 7 12 12 8
16 14 36 39 41 40 41 53
-
Erect
Normotensive* cr. No. ,I(> 4 0 12 12 8 8 7 3
21 0 24 22 47 27 24 20
Mean B.P. Reduced >20 mm. Hg or Normotensive GNo. ic 4 2 23 21 9 15 12 8
21 14 46 39 53 50 41 53
* Blood pressure reduced to 140/90 mm. Hg or less. t 250-500 mg. of acetazolamide daily. $ 250-500 mg. of acetazolamide, four days per week. g The dosage of chlorothiazide and flumethiazide was 500 mg. b.i.d. 1150 mg. b.i.d. of hydrochlorothiazide daily. 7 The dosage of chlorthalidone and quinethazone was 100-200 mg. daily. # 150-400 mg. of ethacrynic acid daily. THE AMERICANJOURNAL OF CARDIOLOGY
New
Diuretic
Drug,
oral compound compares favorably with other potent oral diuretics and with parenteral meralluridc. REFERENCES I. Sc~~tx~r.
E. M.. CRAGOE, E. .J., BICKING, J. B., BOLIIOIXR. \\:. A. and SPRAGUE, J. M. Alpha, betaunsaturated ketone derivatives of aryloxyacetic acids. a new class of diuretics. J. Med. Pharm.
Chm.. 5 : 660, 1962. 2. BACR. J. E.. Russo, H. F.,
MICHAELSON, .I. K. and BE\.E:R. K. JH. A new class of diuretic-saluretic aqrnts. the alpha, beta-unsaturated ketone derivati\cs of aryloxyacctic acids. Ph-armacologist, 4: 158,
1962. 3. BAI.R. J. E;.. MICHAELSON, J. K.,
Russo, H. F. and B~.I.FR. K. H. 2,3-Dichloro-4-(2-methylenebutyryl i-phenoxyacetic acid, a novel and potent diurrtic-saluretic agent. Fed. Pm.. 22: 598. 1963. 4. MI-1.~1~. K. E. W., FARRELLY, R. 0. and NORTII.
VOLUME 16, JULY 1965
Ethacrynic
Akid
.J. 1). K.
1‘:thacrynic
105 acid:
A new
oral
diuretic.
&it. hf. J.. 1: 1521. 1963. 5. DALEY, crynic
D. and EVANS. B. Diuretic action of cthaarid on conRestive heart failurr. Brit. .\I. J.:
2: 1169, 1963. 6. CLANNON, P. .I., AMES. R.
P. and LARAGII. J. H. Methylenebutyryl phenoxyacetir acid. Novrl and potent natruretic and diuretic aqc‘nt. ./.;l.AI.A., 185: 854. 1963. 7. GOLDBERG, M., MCCURDY, D. K.. FOLTZ. E. L. and BLUEMLE, I,. \Y. Effects of ethacrynic acid (a new saluretic agent) on renal diluting and conccntrating mechanisms: Evidence for site of action in the loop of Henle. ./. Clin. Znwsl.. 43: 201, 1964. 8. DUARTE. C., DREWUS, I,. S., KODAMA. R., BREST, A. N. and MOYER. .I. H. Uric acid excretion patterns following intravenous hydrochlorothiazide. Am. J. Cnrdrol., 8: 815. 1961. 9. SWARTZ, C., SELLER, R., Fucrrs, M., BREST, I\, N. and MOYER, J. J3. Five years’ experience with the evaluation of diuretic agents. Ciwcnloi,o,z. 28 : 1042, 1963.
Effects
Drug, ALRERY
N.
OSVALDO
Ethacrynic
THACRYKIC
M.D., F.A.c.c., GADDO ONESTI, M.D., ROBERT SELLER,
BRES,
acid
structurally
curials
animal
natruretic zide.2j3 patients purpose
is a
clinical
has
also
diuretic
has demonstrated
greater
than
effectiveness been
chlorothia-
in edematous
demonstrated.4v5
The
of this report is to present our investiga-
tive survey
of the diuretic
effectiveness
of the
efficacy
other
with
drug
and antihypertensive and
currently
to compare
available
ORAL DIURETIC ASSAY
its
diuretic
nonedemaInpatient Study: A group of hospitalized: tous patients was studied to determine the effect of varying doses of ethacrynic acid on urinary electrolyte excretion. Each patient was allo\ved 1 gm. sodium daily in his diet. Twenty-foollr hour urine specimens were collected and analyzed for sodium, potassium, chloride and creatinine. \vhrn the 24 hour urinary excretion of sodium was reduced to approximately 90 per cent of intake. ethacrynic acid was administered. Five patients received 50 mg. (50 mg. o.d.); 3 patients received 101, mg. (50 mg. b.i.d.) ; 7 patients received 200 mg. (100 mg. b.i.d.) ; and 6 patients received 400 mg. (100 q.i.d.) of cthaTwenty-four hour urine collections \vere crynic acid. again obtained after administration of the drug. and the electrolyte and creatinine excretions \vcrv measured. An acute, 48 hour \\-eight loss reOutpatient Study: sponse was determined in a group or hubjects who regularly attended the outpatient Diru-et& Clinic. All patients were in mild to moderate congestive heart failure due to arteriosclerotic or rheumatic heart disAll patients were maintained on daily digitalis ease. preparations; but diuretic therapy \vas discontinued for three weeks prior to the initial administration of ethacrynic acid. The patients were advised to continue their usual physical activities. Dietary salt reduction consisted only of the avoidance of extra table salt and excessively salty foods. Yaryinq dosages of ethacrynic acid ranging from 100 to 600 mg. daily were administered, for two consecutive days. ‘I‘he
compounds. METHODS
AND
MATERIALS
INTR.4VENOUS DIURETIC ASSAY A group of 8 hospitalized, nonedematous patients was studied to determine the effect of intravenous ethacrynic acid on renal function and water and electrolyte excretion. None of these patients suffered from clinical renal or cardiac diseases. A second group of 5 hospitalized, edematous patients was studied similarly. Among the second group, 3 had cardiac edema, 1 had nephrotic syndrome and 1 had cirrhosis of the liver. All patients were maintained on 1 gm. sodium daily in the diet for at least three days prior to the investigation. The studies were performed in the morning in the fasting state? after deprivation of water and food for 12 hours. Blood samples were taken via an indwelling heparinized polyethylene catheter. Urine was collected through an indwelling bladder catheter. After three 30-minute control study periods, ethacrynic acid was administered intravenously in the dosage of 0.5 mg.jkg. body weight dissolved in 20 cc. isotonic saline. The effect of drug administration was then studied at 30 minute intervals thereafter for a total of five hours. The following parameters were measured : para-aminohippurate clearance (renal plasma flow), inulin clearance (glomerular filtration rate), uric acid clearance, plasma osmolarity, hemato* From the Section Pa. VOLUME
of Vascular
16, JULY 1965
XI.D., I~..~.c.c
crit, urine flow, urine osmolarity and urine electrolyte (sodium, potassium and chloride) excretion. Osmolar clearance was calculated according to the formula, Cosm = (UosmjPosm) X 1.. Tubular reabsorption of solute-free water was calculated according to the formula, ToH,,, = Cosm -1.. \vhere V is the urine flow in ml./min. and Losm and Posm are the solute concentrations of urine and of plasma in milliosmol./kg. of water.
agent
In the ex-
derivatives.’
KD.,
Pennsylvania
to the organomer-
the drug
properties Its
new
unrelated
or the thiazide
perimental
Acid*
RAMIREZ, M.D., CHARLES HEIDER, M.D. and JOHN H. MOYER, Philadelphia,
E
of a New Diuretic
Diseases and Kenology,
Hahnemann
99
Medical
Coll~gc- and
I Hospital. Plhil;~d~lphia,
Brest et al.
100
TABLE I Averqr
Tune-Response
Effects
Following
Intravenous
Administration
and Five Edematous P;rr.*meter
CrouD”
---
----
~
I
0
of Ethacrynic
~- Time After Drug (One-Half
2
Acid in Eight
Nonedematous
Subjects Hour
Periods)
------.--.---
----_
3
4
5
6
7
R
9
5323 761$
287 491:
169 291
113 210
97 178
84 135
72 112
70 94
87 148t
69 122:
65 109
60 85
55 75
52 69
43 55
47 65
115 132
104 94
95 81
94 74
I
2.3 23
1.9 20
2.2 20
20
41 5 45.3
41.5 45.3
41.4 45.3
41.1 45.0
41.1 45.3
10
(&q./min.)
1 2
102 4x
2081 t 1253:
K (,,Eq.,‘min.)
1 2
61 69
208 g 2305
Cl (rEq.,‘min.)
1 2
110 31
2265 $ 18295
13695 I4705
613t 822 5
314 431t
197 250
143 175
NnjK
1 2
22 1.2
10.95
10.95 7 9s
6.59 5.3f
4.6 4 3t
2.9 5 ot
2 26
1 2
40.8 46 0
41.5 45.8
1 2
85 7 3
8.9 8.1
5.05 70
3.88 5.4
4.15 4.5f
3.89 4.4t
3 8§ 4.4t
4.18 4.15
4.5s 3.46
4.65 3.3t
5.05 4.3t
T’ I,?<)
1 2
1 28 I 0
-0.2s 0.7
0.10 00
0.49 0.2
0.55 0.1
0.6$ 0.3
0.65 03
0.5g 0.3
0.76 0.4
0.69 04
0.7% 0.3
C-osmolarity
1 2
24 1.8
15.69 12.55
10 10 11.65
5.1x 7.15
3.2 4.51
2.7 33
2.1 2.6
1.8 24
19 2.1
1.7 1.7
1.7 1.7
Plasma
1 2
290 302
289 302
290 300
291 300
289 299
289 302
289 299
290 299
289 303
289 300
289 300
1 2
657 664
2885 348 Q
2926 3046
31x5 3195
355 5 340 Q
3849 3635
425 8 381 Q
4338 405 L
4885 4155
493s 414$
500 p 488t
1 2
12 10
15.85 11.15
1o.og 11 65
4.8§ 6 9s
2.7 4.2t
2.1 3.1
1.5 2.3
1.3 2.1
1.2 1 .6
1 I 1.4
1.0 1 .o
How
1 2
434 395
468 448
359: 387
347: 371
389 346
345: 339
347t 367
383 375
376 361
368 373
371 398
filtration
1 2
73 53
59t 43:
63 45
66 43:
Nn
ratio
Hemnrocrir
(7)
C-uric
(cc./min
Urine Urme Renal
awl
)
osmolarity osmolariry How (cc.,/min.) plasma
Glomerular rate
1277: 1259: 1406 201 P
6 7%
42.1 46.0
65 55
88t 60
42.5 45.8
621 47
42.5 45.8
41.9 45.5
6Ot 43:
59t 45
65 44
1.8
63 49
* t i 5
Group Differs Differs Differs
1 = 8 nonedematous subjects; sienificanilv from conn~l (0 < s&ificantl; from control 0 < significantly from control (,b <
acute weight determined. ANTIHYPERTENSIVE
loss response
Group 2 = 0.011. 0.05). 0.001).
to these
5 edematous
doses
subjects
was then
STUDY
Fifteen ambulatory patients with blood pressures greater than 150/l 00 mm. Hg were randomly selected The age range was 37 from the Hypertension Clinic. to 66 years. There were 4 male and 11 female paAfter tients; 14 were Negro and one was Caucasian. an initial diagnostic evaluation, these subjects were placed on daily placebo medication for a minimum of three weeks. The patients returned to the clinic at weekly intervals, at which time blood pressure and physical signs and symptoms were recorded. After the control period the 15 patients were treated with ethacrynic acid alone. The drug was The dosbegun in an initial dosage of 50 mg. daily. age was gradually increased, at biweekly intervals, to a maximum of 400 mg. daily in those patients who failed to achieve a significant antihypertensive response at a lower dosage level.* * The achievement of normotension (140/90 mm. Hg) or a reduction in mean arterial blood pressure (diastolic pressure plus one third of the pulse pressure) of 20 mm. Hg or more was considered significant.
No specific dietary restriction, other than the avoidance of grossly salty foods and added table salt, was advised during the course of this study; and electrolyte supplements were not given. Determinations of blood urea nitrogen, serum uric acid and electrolytes (sodium, potassium and chlorides) were performed during the control period and after treatment with ethacrynic acid. RESULTS
INTRAVENOUS
DIURETIC
ASSAY
Renal Hemodynamics: The acute intravenous administration of ethacrynic acid resulted in an initial transient increase in renal plasma flow and glomerular filtration rates, but this effect was followed thereafter by a decrease in renal hemodynamics (Table I). Reduction in renal blood flow and glomerular filtration rate was evident within one and one-half hours after intravenous injection. The maximal decrease in renal plasma flow was 20 per cent ($I < 0.05) in the nonedematous group and 15 per cent in the edematous patients. The maximal reducTHE
AMERICAN
JOURNAL
OF
CARDIOLOGY
New
Diuretic
Drug, TABLE
Incrense
of
Urinary
Electrolyte
16,
JULY
1965
101
Acid
II
Above Control in Response to Varyillg Dosages of Ethacrynic .\citi Administered Orally (per 24 hr. Urine Collection ) Excretion
tion in glomerular filtration rate was 19 per cent in both groups. Maximal decrease in renal plasma flow occurred two and one-half hours after intravenous administration in both groups. Maximal reduction in glomerular filtration rate occurred between two and three hours. Arterial blood pressure was measured by conventional sphygmomanometer in all patients throughout the clearance studies, and no significant changes were noted. l?inP Elrctrolyte Excretion: There was an immediate increase in natruresis which was maximal during the first 30 minutes and was of the order of 1940 per cent for the nonedematous group and 2500 per cent for the edematous patients. The natruretic effect lasted three hours in the nonedematous group but was still evident after five hours in the edematous group. The over-all increase in sodium excretion during the five hour study was 368 per cent in the nonedematous group and 895 per cent in the edematous group. -4 significant increase in chloride cxcrction paralleled the natruresis in both the excretion of chloride groups ; however. was consistently greater than that of sodium. The excretion of potassium also increased in both groups, the maximal occurring during the first 30 minutes. The sodium-potassium excretion ratio increased in both groups. 1Sine Flow and Osmolarity: An immediate increase in urine flow, from an average of 1.2 to an average of 15.8 ml., min., occurred during the first 30 minutes in the nonedematous group; and a significant increase in urine flow lasted one hour and 30 minutes. In the edematous group a significant increase in urine flow lasted two hours, with the maximal increase, from 1.0 to 11.6 ml./min., occurring at one hour. There was an immediate drop in urine osmolarity in both groups, lasting during the entire period of study. Maximal decrease in urine osmolarity VOLUME
Ethacrynic
occurred during the first hour of stud!. in both The tubular reabsorption of free water groups. (TcHzO) was consistently decreased in both groups throughout the study. Osmolar clearance increased in both groups, paralleling the increase in urine flow. Plasma osmolarity and hematocrit showed no significant changes Followthroughout the study in both groups. ing a transient initial increase? uric acid clcarante was consistently and significantly- drcreasrd thereafter in both groups. ORAL
DICRETIC
ASSAY
The 24 hour urine elcctrolytc excretion response to varying dosages of ethacrynic acid is recorded in Table II. There was a progressive increase in natruretic and kaluretic activity as the daily dose was increased from 50 to 400 mg. The maximal effective daily dose of 400 mg. produced an average increase, above control levels, of 195.8 mEc]. of sodium and 75.6 of potassium per 24 hour urine collection (11 < 0.01). Outfiatient Stud,;: The acute 48 hour response by weight loss is shown in Table 111. The weight loss elicited by the administration of different doses of ethacrynic acid dail!- for two days ranged from 1.82 to 5.75 pounds. A dose of 400 mg. daily for two days resulted in an average weight loss of 5.75 pounds in 12 patients. The response to all dosages studied (190 trig., 200 mg., 400 mg. and 600 mg.) was statistically significant. Side reactions encountered during the study of acute 48 hour weight loss are tabulated in Table IV. Inpatient
S’tucly:
ANTIHYPERTENSIVE
STUDY
The blood pressure responses are tabulated in Table v. The figures reported are averages of the blood pressure readings obtained during the control and study periods. Of the 15 pa-
102
Brest et al TABLE 111
Acute
48 Hour
-
Case No. -__..__. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 Mean p value
‘rABLE
Weight Change in Pounds Dosagc Levels
-------Daily
on Four
Side Reactions
Dosqp------
100’ ~-----No. 19
2002
-4.00 -2.00 -1.75 +2.50 -0.75 -1.50 -2.00 -2.75 -2.50 -4.00 f0.75 -0.75 +0.75 -5.75 -0.75 -0.25 -6.75 -2.25 -1.00
-2.50 -8.00 -3.00 -2.15 +3.25 f2.25 -1 .oo -3.25 +3.25 -3.25 -5.75 -4.00 -2.75 -1.75 +0.75 -1.75
1.82
1.89 <0.05
16
-p--Daily
(mg.) 4003 of Patients---------. 12
6004
-9.00 -4.75 -4.25 +0.25 -0.50 -6.50 +2.00 -2.50 -15.00 -10.00 -8.00 -10.75 ,,_ .,.
-5.00 -4.50 -1.00 -2.75 0.00 f2.00 -2.75 -4.50 -1 .oo -2.50 -10.25
1 = 50 mg. b.i.d.; 2 = 100 mg. b.i.d.; q.i.d.; and p = 200 mg. t.i.d.
of Acute
48
Dosagc--(ms.)
Side Reaction (no. of patients)
100
200
400
600
4 3 0 0 0 1 2 1 2
2 0 1 1 1 2 1 2 2
2 0 1 1 0 0 0 2 5
1 1 0 4 1 0 1 1 6
11
:‘: 5.75
I”
Encountered During Study Hour Weight Loss
2.88 <0.02 3 = 100 mg.
tients in this group, 8 (53%) obtained a significant blood pressure reduction in the supine position and one of the 8 became normotensive. Likewise, in the erect position 8 patients obtained a significant antihypertensive response but 3 of them became normotensive. Side reactions encountered included nausea (2 patients), abdominal cramps (2 patients), diarrhea (2 patients), anorexia (1 patient), nasal stuffiness (1 patient) and weakness (1 patient). The therapeutic effects on serum electrolytes, blood urea nitrogen and serum uric acid are tabulated in Table VI. Significant changes in mean difference of serum potassium and chlorides, urea nitrogen and uric acid were noted. Significant reductions in potassium and chlorides occurred, along with significant increases in urea nitrogen and uric acid. Despite the development of hyperuricemia, no instances of clinical gout were encountered during the course of this study. DISCUSSION
The results of the intravenousdiuretic assay indicate that ethacrynic acid is an extremely potent
GU GI
CNS Other
Nocturia Fre(quency Anorexia Nausea Vomiting IIeadache Dizziness Weakness 1,eg cramps
GU = genitourinary, CNS = central nervous
GI = system.
gastrointestinal
and
diuretic and natruretic drug. The chloruretic and kaluretic effects of the compound are also substantial, with chloruresis being even greater than natriuresis. Of particular interest is the rapid onset of action. Increase in urine flow, natruresis and chloruresis appear within minutes following intravenous administration (Fig. 1 and 2). In comparison with parenteral mercurial diuretics, ethacrynic acid appears to have a much more rapid onset of action ; on the other hand, its diuretic activity is shorter, being spent within five hours. It is notable that in the edematous patients studied, where the average glomerular filtration rate was significantly less than in the nonedematous group, the natruretic effect obtained was proportionately greater and more prolonged than in the nonedematous subject. Over-all, it would appear that parenteral administration of the drug will have particular usefulness in patients with severe cardiac decompensation (e.g., acute pulmonary edema), in whom rapid diuretic action is required. Furthermore, since marked sodium excretion occurred in the presence of severely reduced glomerular filtration rates, it may be anticipated that ethacrynic acid will also be a useful diuretic agent in the presence of edema associated with advanced renal functional impairment. In the hydropenic state, ethacrynic acid produced a significant decrease in urine osmolarity with a decrease in the reabsorption of free In the hydrated subject, water (TC~Z~>. Cannon et al.‘j and Goldberg and co-workers7 reported a decrease in free water clearance THE
AMERICAN
JOURNAL
OF CARDIOLOCY
New
l>iuretic
Drug,
Pressure
Response
TABLE
Blood -~Control
Ethacrynic
1 Cl.?
:kid
”
to Ethacrynic
Acid
B.P.-
(mm. Ha) hl.ran
1 2 3 4 5 h 7
8 9 10 11
6b 45 37 54 40 49 53 4x 56 53 49
1’ F M M E‘ 1’ F I’ t: F F
Ii lx I\’ w N N x N N N .\I
‘I‘ABLE
Biochemical
Changes
Sodium
(mliq.
1..1
l..) c,w
1
2 3 4 S 6
x ‘I
II) II 12 13 14 15 A bfr,,n p v,llllr
CXrlnridrs (rnCq.,I..) L: K
c:
-
R
c:
K
148 135 134 150 132 143
14x Ii4 146 146 146 141
4 S 4 4 3 5
0 0 3 0 7 n
3 4 3 3 3 4
14x 148 140 140 130 140 1411 14”
140 140 l-S4 130 IS6 152 141 131
4 4 4 4 4 4 4 47
8 R 0 x 6 3 2
3 3 3 7 3 44 4 h 4 0 4 0 3 3
+4 >o
7x I
-0 co
4 9 0 ‘1 7
i
100 102 103 100 105 in3
592 01
196/115 190/120 17R/130 168,“llO 170;126 150/104 194/120 158/114 205,‘128 186/104 16OjlOO 178/118 165’, 132 228/118 19n/100
142 143 146 129 140 119 144 128 153 131 120 138 143 154 130
Acid ‘l‘herapy
RUN (m9.T) C: R
103 100 100 92 95 9s
I 100 xx too 102 100 9x 104 103 10s
.Mean
“I
After Ethacrynic
Pot.trsiurn
(mk.
143 142 143 132 135 121 144 130 162 132 137 176 144 160 13s
204,112 174.128 164,116 10s 120 Ii5 105 210,112 1’0, 110 228, 130 1X8 104 1x5 114 17x Il.5 1X8 122 23X 122 195,105
Erect
100 93 103 lni 100 93 103
26 19 IX 18 12 20
32 23 25 13 21 22
1.i
19 15 21 17 13 55 SO 22
11 19 15 11 34 2x 1’1
-4 214 ,co 01
+s
9 01
3
TIME
4
( l/2
I
I
5
6
I
7
8
5.3 5.6 6.0 4.8 5.1
6 7 8.6 10.7 6.5 5.2
5.1 6.0 68
10.4 9.8 103
5’5 6 3 1.9
‘7’3 12.5 8 0
16,
JULY
1965
(Cu,o). These combined findings indicate a probable site of action of ethacrynic acid in the ascending limb of the loop of Henlc. The decrease in renal plasma flow and ~lomerular filtration rate which accompanies the diuretic action of the drug is likely related to an accompanying transient reduction in total blood \.olume. According to current concepts, uric acid is filtered by the glomeruli, completeI>. reabsorbed in the proximal tubules and subsequently secreted in the distal segments of the nephrons. It is conceivable that the decrease in uric acid clearance which follows intravenous administration of ethacrynic acid is due to decreased distal tubular secretion of uric acid. Although uric acid clearance ultimately diminished significantly in all subjects, a transient increase in uric acid clearance occurred in 3 casts during the initial 30 minutes following intravenous
-non-edematous ----edematous
3
r7
IO 1
FIG. 1. 1Jrine jhw Jollorving intravenous ethacrynic acid. Diuresis follows within minutes after intravenous administration. VOLUME
IO4 118 139 109 12X 120 143 100 116 111 96 123 136 138 106
134 90 145 105 lS8 130 136 ‘96 166 110 14s 10x 205 112 120 90 150 100 154,90 118 85 150 110 166 122 200. 108 150,85
11s 126 133 111 124 118 150 110 116 103 110 121 150 134 107
subjects
9
HR. PERIODS
% ) R
146/100 17O/lOi lhOj120 138,“)x 160/106 150:102 220,115 ISO/ 154/98 140/RS 1 so/90 148;lOB 192’130 lX2,~llO 162 ‘80
subjects
----edematous
1 2
Acid
bg. C
+2 872
-non-edematous
L-
Uric
\lC.lrl
-1I1T
I
2
I
3
TIME
4 ( l/2
5
6
7
I
r
8
9
I
subjects subjects
)
IO
HR. PERIODS)
FIG. 2. Sodium excretionfollowzn,~ intrarznouse//mcyic Marked natruresis accompanies the rapid diuretic tion of the drug.
acid.
ac-
104
Brest et al. TABLE WI
uretics
or with parenteral meralluride” (Table On the other hand, its short duration of action (approximately eight hours) may make it less desirable than certain other oral diuretic compounds, with respect to the need for frequency of administration. The antihypertensive study indicates that the oral drug possesses antihypertensive effectiveness which also compares favorably with that of other potent oral diuretics (Table VIII). As a result of prolonged use, significant reduction in serum potassium and chlorides may be encountered along with significant increases in blood urea nitrogen and serum uric acid. In certain instances, these electrolytic and metabolic effects could lead to significant clinical problems.
Acute 48 Hour Weight Loss in Pounds* Comparison of Various Diuretic .4gents Methyclothiazide. Chlorthalidone. Polythiazide. Trichlormethiazide. Quinethazone. Benzthiazide. Hydroflumethiazide. Benzydroflumethiazide. Cyclothiazide..
1 ,3 2.2 2.5 2.7 2.8 3 .O 3.2 3.3 3.3 3.6 4.5 5.8
Hydrochlorothiazide
Meralluride............................. Ethacrynic .4cid, * Employing
maximal
VII).
effective
dosages.
SUMMARY administration. This dual action has been previously reported with the thiazide derivatives.8 The oral diuretic assay indicates that oral administration of the drug also results in a substantial diuretic action, the effects on electrolyte balance being similar to those observed during the intravenous assay. Of the dosages studied, 400 mg. daily produced the maximal natriuresis. The acute 48 hour weight loss response obtained with 400 mg. of ethacrynic acid, was in fact, more favorable than that previously obtained (in similar studies) with other potent oral di-
Ethacrynic acid is an extremely potent diuretic and natriuretic agent. Its rapid onset of action following intravenous administration suggests particular usefulness in patients with severe cardiac decompensation, e.g., acute pulmonary edema. Furthermore, the parenteral drug appears to be effective despite reduced glomerular filtration rates, and, therefore, may be useful in the treatment of edema associated with advanced renal functional impairment. Oral administration of ethacrynic acid also results in potent diuretic activity, with substantial antihypertensive effectiveness as well. The
TABLE vm Blood Pressure Response
Drug Regimen Acetazolamide (daily)t Acetazolamide (intermittent)f Chlorothiazideff Hydrochlorothiazidel/ Flumethiazides ChlorthalidoneT Quinethazoney Ethacrynic acid#
No. of Pts. 19 14 50 54 17 30 29 15
to Various
Diuretic
Regimens
Supine-Mean B.P. Reduced >20 mm. Hg or Normotensive Normotensive c* No. No. /0 o/o 2 1 9 11 2 5 5 1
11 7 18 20 12 17 17 7
3 2 18 21 7 12 12 8
16 14 36 39 41 40 41 53
-
Erect
Normotensive* cr. No. ,I(> 4 0 12 12 8 8 7 3
21 0 24 22 47 27 24 20
Mean B.P. Reduced >20 mm. Hg or Normotensive GNo. ic 4 2 23 21 9 15 12 8
21 14 46 39 53 50 41 53
* Blood pressure reduced to 140/90 mm. Hg or less. t 250-500 mg. of acetazolamide daily. $ 250-500 mg. of acetazolamide, four days per week. g The dosage of chlorothiazide and flumethiazide was 500 mg. b.i.d. 1150 mg. b.i.d. of hydrochlorothiazide daily. 7 The dosage of chlorthalidone and quinethazone was 100-200 mg. daily. # 150-400 mg. of ethacrynic acid daily. THE AMERICANJOURNAL OF CARDIOLOGY
New
Diuretic
Drug,
oral compound compares favorably with other potent oral diuretics and with parenteral meralluridc. REFERENCES I. Sc~~tx~r.
E. M.. CRAGOE, E. .J., BICKING, J. B., BOLIIOIXR. \\:. A. and SPRAGUE, J. M. Alpha, betaunsaturated ketone derivatives of aryloxyacetic acids. a new class of diuretics. J. Med. Pharm.
Chm.. 5 : 660, 1962. 2. BACR. J. E.. Russo, H. F.,
MICHAELSON, .I. K. and BE\.E:R. K. JH. A new class of diuretic-saluretic aqrnts. the alpha, beta-unsaturated ketone derivati\cs of aryloxyacctic acids. Ph-armacologist, 4: 158,
1962. 3. BAI.R. J. E;.. MICHAELSON, J. K.,
Russo, H. F. and B~.I.FR. K. H. 2,3-Dichloro-4-(2-methylenebutyryl i-phenoxyacetic acid, a novel and potent diurrtic-saluretic agent. Fed. Pm.. 22: 598. 1963. 4. MI-1.~1~. K. E. W., FARRELLY, R. 0. and NORTII.
VOLUME 16, JULY 1965
Ethacrynic
Akid
.J. 1). K.
1‘:thacrynic
105 acid:
A new
oral
diuretic.
&it. hf. J.. 1: 1521. 1963. 5. DALEY, crynic
D. and EVANS. B. Diuretic action of cthaarid on conRestive heart failurr. Brit. .\I. J.:
2: 1169, 1963. 6. CLANNON, P. .I., AMES. R.
P. and LARAGII. J. H. Methylenebutyryl phenoxyacetir acid. Novrl and potent natruretic and diuretic aqc‘nt. ./.;l.AI.A., 185: 854. 1963. 7. GOLDBERG, M., MCCURDY, D. K.. FOLTZ. E. L. and BLUEMLE, I,. \Y. Effects of ethacrynic acid (a new saluretic agent) on renal diluting and conccntrating mechanisms: Evidence for site of action in the loop of Henle. ./. Clin. Znwsl.. 43: 201, 1964. 8. DUARTE. C., DREWUS, I,. S., KODAMA. R., BREST, A. N. and MOYER. .I. H. Uric acid excretion patterns following intravenous hydrochlorothiazide. Am. J. Cnrdrol., 8: 815. 1961. 9. SWARTZ, C., SELLER, R., Fucrrs, M., BREST, I\, N. and MOYER, J. J3. Five years’ experience with the evaluation of diuretic agents. Ciwcnloi,o,z. 28 : 1042, 1963.