Current Medical Research and Opinion
Vol. 4, No. 6, 1976
Bumetanide in congestive heart failure
C. KouroUklis, M.D., 0. Christensen, M.D., and
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D. Augoustakis, M.D. Cardiological Clinic of the University of Athens, Hippocration Hospital, Athens, Greece
Curr. Med. Res. Opinion, (1976), 4, 422.
Received : 2nd August 1976
Summary Bumetanide, a new diuretic exerting its major e#ect on the ascending limb of the loop Henle, was evaluated in 20 patients with congestive heart failure. Dosage ranged from I mg to 3 mg daily depending on the patient’s condition. The results after 3 and 8 days’ treatment showed that bumetanide caused a signijicant diuresis, an increased excretion of sodium, potassium and chloride, and a comparablefall in the serum levels of these electrolytes. Changes in electrolyte levels were directly related to the dose of the drug. The resultant hypochloraemia was accompanied by a slight metabolic alkalosis. A comparative crossover study between placebo, bumetanide and frusemide using equipotent doses was performed in 10 patients. Both drugs had a similar effect upon water excretion and the serum and urinary electrolytes. of
Key words: Bumetanide -,frusemide - diuretics - heart failure, congestive
Introduction Bumetanide, (3-n-butylamino-4-phenoxy-5-sulphamylbenzoicacid), is a new drug belonging to the group of potent and fast-acting high ceiling or loop diuretics.* It is a metanilamide derivative, compared to the thiazides and frusemide which are sulphanilamide derivatives.5,1* Its primary site of action is on the ascending limb of the loop of Henle, blocking the re-absorption of sodium. A secondary site is the proximal convoluted tubule, shown by a diminished re-absorption of phosphate ion^.^.^ The potency of bumetanide on a weight basis is 40 times that of frusemide, both in regard to short and long-term use.13 In this study the diuretic effect of bumetanide on patients suffering from cardiac failure was investigated.
Patients and methods Biimetanide was given to 30 in-patients with organic heart disease associated with congestive heart failure. Six patients had coronary artery disease, 12 valve disorders, 3 myocardiopathy, 5 hypertensive heart disease, and 4 chronic cor pulmonale. The 30 patients were randomly allocated into two groups, The first group, consisting of 20 patients, was given bumetanide in doses of 1 mg to 3 mg daily, depending on the degree of heart failure (Table I). In the second group of 10 patients, each patient was given bumetanide, a placebo, and an equivalent dose of 422
C. Kourouklis, 0. Christensen and D. Augoustakis
frusemide. In this part of the study, each dosage period lasted 2 days and the administration scheme and doses used are shown in Tables II and 111. Table I. Daily dose of bumetanide in 20 patients with congestiveheart failure
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No. patients
Bumetanide dose
Table II. Sequence of administration of bumetanide, frusemide and placebo to group of 10 patients Days I Bumetanide Frusemide Placebo
2
3
4
+ + + +
5
6
+ +
7
8
9
1 0 1 1 1 2 1 3 1 4
+ + + +
+ +
+ +
Table III. Comparative doses of bumetanide and frusemide in 10 patients
No. patients
Bumetanide/frusemidedose
3 3 4
1 mg/40 mg 2 mg/80 mg 3 mg/120 mg
The patients were placed on a diet consisting of about 5 g sodium chloride, and a water intake of no more than 1.5 litre daily. Administration of other diuretics and potassium was discontinued 1 week prior to administering bumetanide. Body weight, urinary output, serum and urine sodium, potassium and chloride, and standard bicarbonate levels were measured in each patient. In the first group of 20 patients these measurements were made over 3 consecutive days (short-term study), and were immediately followed by further determinations over 8 days (long-term study). Serum creatinine was measured prior to diuretic administration (for comparison) and on the 12th day at the end of the study. In the second group of 10 patients, the above measurements were made daily for 14 days. The sodium and potassium values were determined using Evans EL Flame Photometer, chloride by Schales and Schales method,’ 8 bicarbonate by Astrup pH meter, and creatinine by a modification of the Jaffe method.18
Results Short-term study In the first group of patients, bumetanide caused a decrease in body weight and an increase in water excretion related to the amount of drug given. Comparable changes were also noticed in the serum and urinary electrolyte levels. Thus there was significant natriuresis, kaliuresis, and an even greater chloride excretion. The chloride excretion always exceeded the sodium excretion. Serum sodium and potassium decreased proportional to the dose of bumetanide. The average change in serum potassium with 3 mg bumetanide daily was significant (1.260.4 mmol/l). 423
Bumetanide in congestive heart failure
Table 1V. Mean (1S.E.M.) changes in body weight, diuresis, urine and serum electrolytes, and bicarbonate levels after administration of different doses of bumetanide for 3 days ~~
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Changes
Bumetanide
Body weight (kg) Diuresis (I) Urine electrolytes: Sodium (rnmo1/1/24 hrs) Potassium (mmo1/1/24 hrs) Chloride (mmo1/1/24 hrs) Serum electrolytes: Sodium (mmol/l) Potassium (mmol/l) Chloride (mmol/l) Bicarbonate (mmol/l)
1 mg
2 mg
3 mg
- I f0.35 +0.8+0.32
+ 1.0+0.24
+ 1.3 +0.49
+40+12
+56+7
+60+16
+30-16
+38&7
+52112
+783k22
t-92119
+ 118134
-412.1 -0.4 h0.28 - 1016.2 1.250.25
-711.6 -0.610.32 - 14&4.8 +1.5i0.18
- 1.3 =k0.48
+
-2k0.64
- 1214.3 - 1.2k0.4
-18h6.7 +2.2&0.32
Note: the values show the difference between pre-study levels and the mean levels found after administration of bumetanide for 3 days Figure 1. Mean (IS.E.M.) changes in body weight and diuresis after administration of bumetanide for 8 days: 20 patients Body weight
0
-0.2
M
5 2
-0.4 -0.6
I .5
f
J=
T 1.0
B
T
T
7
8
.- 0.5
A
s
o
1
2
3
4
5
6
D:1!.\
Note: AM=difference between the mean of the total daily determinations and the pre-study values 424
C. Kourouklis, 0. Christensen and D. Augoustakis
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Bicarbonate was slightly increased. This increase, together with the fall in serum chloride indicates hypochloraemic alkalosis (Table 1%'). Long-term study After the first 3 days of the study, the same group of 20 patients continued to receive the same daily dose of bumetanide for a further 8 consecutive days. Body weight continued to decrease slightly for the first 4 days and then levelled off. Diuresis was approximately the same throughout the 8 days (Figure 1). The excretion of sodium, potassium and chloride showed a progressive decrease in the first 6 days, followed by a further smallinsignificant decrease (Figure 2). The serum levels of these electrolytes showed a dose dependent decrease, whilst the bicarbonate level increased slightly, resulting in hypochloraemic alkalosis (Table V). Figure 2. Mean (hS.E.M.) changes in electrolyte excretion (24 hours) after administration of bumetanide for 8 days: 20 patients Sodiiim
,
= 100:
Chloride
fE 50v
=4 o
I
1
3
I
4
5
6
7
8
Days
Note: AM=difference between the mean of the total daily determinationsand the pre-study values
Table V. Mean (k.9.E.M.) changesin serum electrolyte and bicarbonate levels after administration of dflerent doses of bumetanide for 8 days Changes Sodium (rnmol/l) Potassium (mmol/l> Chloride (mmol/l) Bicarbonate (mmol/l)
Bumetanide lmg
2mg
-6313.2 -0.5h0.16 -26h7.4 f1.4k0.36
-8k2 -0.7k0.24 -29 =t 3.7 1.6 k0.28
+
3-15k2.7 - 1.1 &0.3 -35h4.8 f 1.9k0.44
Note: the values show the difference between pre-study levels and the mean levels of the total daily determinations over 8 days 425
Bumetanide in congestive heart failure
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The serum creatinine slightly increased in those patients who received bumetanide for the longer period of time; mean change=0.3&0.1 mg/100 ml (p 0.05). In regard to potassium excretion, the difference between 2 mg bumetanide and 80 mg frusemide almost reached significance (p < 0.05) in favour of bumetanide (Figure 4). In comparing the electrolyte and bicarbonate serum levels in the patients of this group, it can be concluded that both diuretics bring about a decrease in sodium, potassium and chloride, and an increase in bicarbonate directly related to the drug dose, and that there is no significant difference between the two drugs (Figure 5).
Discussion Bumetanide is rapidly absorbed from the gastro-intestinaltrace and is bound 95 % to 97 %to serum protein. Between 68 % to 83 % of a given dose is excreted by the kidneys and gall bladder. It is not known which organ metabolizes the rest.4 The action of the drug given orally is rapid, beginning 30 minutes after administration. Maximum effect is seen after 60 to 90 minutes and diuresis is maintained for 5 to 6 hours.’ 3.’ The site of diuretic activity of bumetanide in the kidney is the same as for frusemide and ethacrynic acid, blocking the re-absorption of sodium in the ascending limb of the loop of Henle. In addition, there is an action on the proximal convoluted tubule.2-4.8 The animal, human volunteer’ ,4,6,13 and clinical studies’ ,*.13,1 4 - 16.l indicate that 1 mg bumetanide is equipotent to 40 mg frusemide. In regard to the onset of diuretic action, time of maximum effect, and duration of action, bumetanide, frusemide and ethacrynic acid are very similar.’,’5 In the present clinical study we studied the diuretic action of bumetanide in patients with congestive heart failure, and compared its diuretic action with that of frusemide in another group of patients, also suffering from congestive heart failure. A significant urinary excretion of sodium and potassium was observed in patients receiving bumetanide for a period of 3 days. The chloride excretion was greater, at all times exceeding the corresponding sodium excretion. This activity has been observed with all loop diuretics.’ The urinary electrolyte excretion increased as the dose of the drug increased. Similar changes were observed in the serum electrolytes. The degree of resulting hypokalaemia was directly proportional to the administered s9
426
C. Kourouklis, 0. Christensen and D. Augoustakis
Figure 3. Comparison of diuresis and body weight after administration of bumetanideand frusemide: mean values for 10 patients
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1.5
u
1
Bumetnnide Frusemide
I
I m g 40 mg
2 mg 80mg
3 iiig 120 mg
1 mg 40 mg
2 mg 80 m y
3 mg I20 m g
Note: the values shown are the difference between those for the diuretic and placebo
421
Bumetanide in congestive heart failure
Figure 4. Comparison of urine electrolyte changes after administration of bumetanide, placebo and frusemide: mean values for 10 patients
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Sodiiim
0
Potassi i i n i
::::::: Chloride 100
---. 0
Bumetanide vs. Frusemide Sodium pz0.05 Potassium p > 0.05 Chloride p>O.O5
50
0
Bumetanide ( I nig)
Placebo
Fruseinide ( 40 iiig)
150
Bumetanide vs. Placebo p 0.05 Sodium Potassium p 0.05 Chloride
$50
E 0
Bumetanide
Placebo
Frusemide ( 80 nis )
I50
Bumetanide vs. Placebo Sodium p < 0.001 Potassium p < 0.001 p < 0.001 Chloride
I00
-
Bumetanide vs. Frusemide Sodium p >0.05 Potassium p > 0.05 p > 0.05 Chloride
50
E 0
428
Bumetanide vs. Placebo Sodium p < 0.001 Potassium p >0.05 Chloride p < 0.001
Humetan ide ( 3 mg)
Placebo
Frusemide ( I20 rng)
C. Kourouklis, 0. Christensen and D. Augoustakis
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Figure 5. Comparison of serum electrolyte and bicarbonate changes in levels (AM) after administration of different doses of bumetanide and frusemide
f 2.0
+0.8
-I
1
-
+1.5-
g
-
7 "I
+0.50
;-0.5-
-1.0-
Potassium
Z I
I
c
2 +1.0-B
-1.61
-
-1.5. -2.0.
-
i
-
4
4 -
-
Bicarbonate
dose of bumetanide. Bicarbonate levels showed a slight change towards alkalosis. The degree of metabolic alkalosis was also proportional to the administered dose of diuretic. During long-term administration, bumetanide caused a significant excretion of sodium and chloride which, with the passage of time, stabilised at 50 mmol/l for sodium and 70 mmol/l for chloride. Potassium excretion fluctuated at about 50 mmol/l throughout the duration of the study. Comparable fluctuations were observed in the serum electrolytes. Long-term administration of bumetanide caused a fall in the three electrolytes, again directly proportional to the dosage of the drug. As has been shown, the urinary excretion of electrolytes was directly related to the bumetanide dosage, but optimal clinical response was observed with dosages of 1 mg to 2 mg per 24 hours. Increase in dosage did not cause a significant increase in 429
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Bumetanide in congestive heart failure
sodium excretion. In addition, a small degree of alkalosis was observed which increased with larger doses. Body weight and diuresis progressively decreased so that by the 3rd and 4th day of the study, they had stabilised. Serum creatinine increased on average by 0.3 mg per 100 ml. This small increase is unlikely to be due to a compromised renal function, but may be due to haemoconcentration.’O The activity of any diuretic is dependent on a number of pathophysiological conditions (severity of the disease, renal function, total body fluid volume, acidbase status, hormones, etc.) present at the time of administration, and on the type of diuretic administered. For this reason, bumetanide, frusemide and placebo were given cyclically as shown in Table II. In this way, the possibility of bias was minimised as much as possible, and comparison of the two drugs was reliable. Comparison of decrease in body weight, diuretic effect, urinary electrolyte excretion, change in the serum electrolytes, and changes in bicarbonate levels between bumetanide and frusemide showed both diuretics to be equally active. Statistical analysis of these parameters showed no significant differences, except for the amount of excreted potassium after 2 mg bumetanide daily, which may be a function of the small number of patients in the second group. From this and other studies, it would appear that bumetanide does not cause significant side-effects. Except for rarely found muscular cramps, evidently caused by the fall in tissue sodium, no other side-effects have been observed.1,4,13
Acknowledgement The authors wish to thank Leo Pharmaceutical Products for providing bumetanide.
References 1. Asbury, M. J., Gatenby, P. B. B., O’Sullivan, S., and Bourke, E., (1972). Bumetanide: potent new “loop” diuretic. Br. Med. J., 1,211. 2. Bollerup, A. E.,Hesse, B., and Sigurd, B., (1974). Changes of glomerular filtration rate and renal plasma flow following intravenous bumetanide in organic heart disease. Acta Pharmacol. Toxicol., 34, 305. 3. Bourke, E.,Asbury, M. J. A., O’Sullivan, S., and Gatenby, P.B. B., (1973).The sites of action of bumetanide in man. Eur. J. Pharmacol., 23,283. 4. Davies, D. L., Lant, A. F., Millard, N. R., Smith, A. J., Ward, J. W., and Wilson, G. M., (1974). Renal action, therapeutic use and phannacokinetics of the diuretic, bumetanide. Clin. Pharmacol. Ther., 15,141. 5. Feit, P. W.,(1971). Aminobenzoic acid diuretics, 2,4-substituted-3-a1nino-5-sulfamylbenzoic acid derivatives. J. Med. Chem., 14,432. 6. Henning, R., and Lundvall, O., (1973). Evaluation in man of bumetanide, a new diuretic agent. Eur. J. Clin. Pharmacol., 6,224. 7 . Hofstetter, A.,(1974). Bumetanide, a new diuretic. f n t . Urol. Nephrof.,6 , 35. 8. Karlander, S. G., Henning, R., and Lundvall, O., (1973). Renal effects of bumetanide, a new saluretic agent. Eur. J. Clin. Pharmacol., 6,220. 9. Laragh, H. J., Cannon, J. P., Stason, B. W., and Heinemann, 0. H., (1966).Physiologic and clinical observations on furosemide and ethacrynic acid. Ann. N. Y. Acad. Sci., 193,453. 10. Leth, A., (1970). Change in plasma and extracellular fluid volumes in patients with essential hypertension during long-term treatment with hydrochlorothiazide. Circulation, 24,479.
430
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C. Kourouklis, 0. Christensen and D. Augoustakis
11. Magnussen, M. P., and Eilertsen, E., (1974). Species differences in the diuretic activity and metabolism of bumetanide. Arch. Pharmacol., 282, R61. 12. New diuretics - Bumetanide and Metolazone (1974). Drug Ther. Bull., 12,49. 13. Olesen, K. H., Sigurd, B., Steiness, E., and Leth, A., (1973). Bumetanide, anew potent diuretic: a clinical evaluation in congestive heart failure. Acra Med. Scund., 193,119. 14. Olesen, K. H., Sigurd, B., Steiness, E., and Leth, A., (1973). Bumetanide. a new potent diuretic. In “Modern diuretic therapy in the treatment of cardiovascular and renal disease”. Int. Congr. Ser. 268, p. 155. Excerpta Medica, Amsterdam. 15. Ostergaard, E. H., Magnussen, M. P., Kaegaard Nielsen, C., Eilertsen, E., and Frey, H.-H., (1974). Pharmacological properties of bumetanide, a new potent diuretic. Armeim. Forsch.,22,66. 16. Ring-Larsen, H., (1974). Bumetanide in the treatment of hepatic ascites. Acra Med. Scund., 195,411. 17. Sigurd, B., Hesse, B., and Valentin, N., (1974). Bumetanide. A new potent diuretic. Dun. Med. Bull., 21, 63. 18. Wooton, D. P. I., (1964). “Microanalysis in Medical Biochemistry.” Churchill, London.
43 1
Vol. 4, No. 6, 1976
Bumetanide in congestive heart failure
C. KouroUklis, M.D., 0. Christensen, M.D., and
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D. Augoustakis, M.D. Cardiological Clinic of the University of Athens, Hippocration Hospital, Athens, Greece
Curr. Med. Res. Opinion, (1976), 4, 422.
Received : 2nd August 1976
Summary Bumetanide, a new diuretic exerting its major e#ect on the ascending limb of the loop Henle, was evaluated in 20 patients with congestive heart failure. Dosage ranged from I mg to 3 mg daily depending on the patient’s condition. The results after 3 and 8 days’ treatment showed that bumetanide caused a signijicant diuresis, an increased excretion of sodium, potassium and chloride, and a comparablefall in the serum levels of these electrolytes. Changes in electrolyte levels were directly related to the dose of the drug. The resultant hypochloraemia was accompanied by a slight metabolic alkalosis. A comparative crossover study between placebo, bumetanide and frusemide using equipotent doses was performed in 10 patients. Both drugs had a similar effect upon water excretion and the serum and urinary electrolytes. of
Key words: Bumetanide -,frusemide - diuretics - heart failure, congestive
Introduction Bumetanide, (3-n-butylamino-4-phenoxy-5-sulphamylbenzoicacid), is a new drug belonging to the group of potent and fast-acting high ceiling or loop diuretics.* It is a metanilamide derivative, compared to the thiazides and frusemide which are sulphanilamide derivatives.5,1* Its primary site of action is on the ascending limb of the loop of Henle, blocking the re-absorption of sodium. A secondary site is the proximal convoluted tubule, shown by a diminished re-absorption of phosphate ion^.^.^ The potency of bumetanide on a weight basis is 40 times that of frusemide, both in regard to short and long-term use.13 In this study the diuretic effect of bumetanide on patients suffering from cardiac failure was investigated.
Patients and methods Biimetanide was given to 30 in-patients with organic heart disease associated with congestive heart failure. Six patients had coronary artery disease, 12 valve disorders, 3 myocardiopathy, 5 hypertensive heart disease, and 4 chronic cor pulmonale. The 30 patients were randomly allocated into two groups, The first group, consisting of 20 patients, was given bumetanide in doses of 1 mg to 3 mg daily, depending on the degree of heart failure (Table I). In the second group of 10 patients, each patient was given bumetanide, a placebo, and an equivalent dose of 422
C. Kourouklis, 0. Christensen and D. Augoustakis
frusemide. In this part of the study, each dosage period lasted 2 days and the administration scheme and doses used are shown in Tables II and 111. Table I. Daily dose of bumetanide in 20 patients with congestiveheart failure
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No. patients
Bumetanide dose
Table II. Sequence of administration of bumetanide, frusemide and placebo to group of 10 patients Days I Bumetanide Frusemide Placebo
2
3
4
+ + + +
5
6
+ +
7
8
9
1 0 1 1 1 2 1 3 1 4
+ + + +
+ +
+ +
Table III. Comparative doses of bumetanide and frusemide in 10 patients
No. patients
Bumetanide/frusemidedose
3 3 4
1 mg/40 mg 2 mg/80 mg 3 mg/120 mg
The patients were placed on a diet consisting of about 5 g sodium chloride, and a water intake of no more than 1.5 litre daily. Administration of other diuretics and potassium was discontinued 1 week prior to administering bumetanide. Body weight, urinary output, serum and urine sodium, potassium and chloride, and standard bicarbonate levels were measured in each patient. In the first group of 20 patients these measurements were made over 3 consecutive days (short-term study), and were immediately followed by further determinations over 8 days (long-term study). Serum creatinine was measured prior to diuretic administration (for comparison) and on the 12th day at the end of the study. In the second group of 10 patients, the above measurements were made daily for 14 days. The sodium and potassium values were determined using Evans EL Flame Photometer, chloride by Schales and Schales method,’ 8 bicarbonate by Astrup pH meter, and creatinine by a modification of the Jaffe method.18
Results Short-term study In the first group of patients, bumetanide caused a decrease in body weight and an increase in water excretion related to the amount of drug given. Comparable changes were also noticed in the serum and urinary electrolyte levels. Thus there was significant natriuresis, kaliuresis, and an even greater chloride excretion. The chloride excretion always exceeded the sodium excretion. Serum sodium and potassium decreased proportional to the dose of bumetanide. The average change in serum potassium with 3 mg bumetanide daily was significant (1.260.4 mmol/l). 423
Bumetanide in congestive heart failure
Table 1V. Mean (1S.E.M.) changes in body weight, diuresis, urine and serum electrolytes, and bicarbonate levels after administration of different doses of bumetanide for 3 days ~~
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Changes
Bumetanide
Body weight (kg) Diuresis (I) Urine electrolytes: Sodium (rnmo1/1/24 hrs) Potassium (mmo1/1/24 hrs) Chloride (mmo1/1/24 hrs) Serum electrolytes: Sodium (mmol/l) Potassium (mmol/l) Chloride (mmol/l) Bicarbonate (mmol/l)
1 mg
2 mg
3 mg
- I f0.35 +0.8+0.32
+ 1.0+0.24
+ 1.3 +0.49
+40+12
+56+7
+60+16
+30-16
+38&7
+52112
+783k22
t-92119
+ 118134
-412.1 -0.4 h0.28 - 1016.2 1.250.25
-711.6 -0.610.32 - 14&4.8 +1.5i0.18
- 1.3 =k0.48
+
-2k0.64
- 1214.3 - 1.2k0.4
-18h6.7 +2.2&0.32
Note: the values show the difference between pre-study levels and the mean levels found after administration of bumetanide for 3 days Figure 1. Mean (IS.E.M.) changes in body weight and diuresis after administration of bumetanide for 8 days: 20 patients Body weight
0
-0.2
M
5 2
-0.4 -0.6
I .5
f
J=
T 1.0
B
T
T
7
8
.- 0.5
A
s
o
1
2
3
4
5
6
D:1!.\
Note: AM=difference between the mean of the total daily determinations and the pre-study values 424
C. Kourouklis, 0. Christensen and D. Augoustakis
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Bicarbonate was slightly increased. This increase, together with the fall in serum chloride indicates hypochloraemic alkalosis (Table 1%'). Long-term study After the first 3 days of the study, the same group of 20 patients continued to receive the same daily dose of bumetanide for a further 8 consecutive days. Body weight continued to decrease slightly for the first 4 days and then levelled off. Diuresis was approximately the same throughout the 8 days (Figure 1). The excretion of sodium, potassium and chloride showed a progressive decrease in the first 6 days, followed by a further smallinsignificant decrease (Figure 2). The serum levels of these electrolytes showed a dose dependent decrease, whilst the bicarbonate level increased slightly, resulting in hypochloraemic alkalosis (Table V). Figure 2. Mean (hS.E.M.) changes in electrolyte excretion (24 hours) after administration of bumetanide for 8 days: 20 patients Sodiiim
,
= 100:
Chloride
fE 50v
=4 o
I
1
3
I
4
5
6
7
8
Days
Note: AM=difference between the mean of the total daily determinationsand the pre-study values
Table V. Mean (k.9.E.M.) changesin serum electrolyte and bicarbonate levels after administration of dflerent doses of bumetanide for 8 days Changes Sodium (rnmol/l) Potassium (mmol/l> Chloride (mmol/l) Bicarbonate (mmol/l)
Bumetanide lmg
2mg
-6313.2 -0.5h0.16 -26h7.4 f1.4k0.36
-8k2 -0.7k0.24 -29 =t 3.7 1.6 k0.28
+
3-15k2.7 - 1.1 &0.3 -35h4.8 f 1.9k0.44
Note: the values show the difference between pre-study levels and the mean levels of the total daily determinations over 8 days 425
Bumetanide in congestive heart failure
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The serum creatinine slightly increased in those patients who received bumetanide for the longer period of time; mean change=0.3&0.1 mg/100 ml (p 0.05). In regard to potassium excretion, the difference between 2 mg bumetanide and 80 mg frusemide almost reached significance (p < 0.05) in favour of bumetanide (Figure 4). In comparing the electrolyte and bicarbonate serum levels in the patients of this group, it can be concluded that both diuretics bring about a decrease in sodium, potassium and chloride, and an increase in bicarbonate directly related to the drug dose, and that there is no significant difference between the two drugs (Figure 5).
Discussion Bumetanide is rapidly absorbed from the gastro-intestinaltrace and is bound 95 % to 97 %to serum protein. Between 68 % to 83 % of a given dose is excreted by the kidneys and gall bladder. It is not known which organ metabolizes the rest.4 The action of the drug given orally is rapid, beginning 30 minutes after administration. Maximum effect is seen after 60 to 90 minutes and diuresis is maintained for 5 to 6 hours.’ 3.’ The site of diuretic activity of bumetanide in the kidney is the same as for frusemide and ethacrynic acid, blocking the re-absorption of sodium in the ascending limb of the loop of Henle. In addition, there is an action on the proximal convoluted tubule.2-4.8 The animal, human volunteer’ ,4,6,13 and clinical studies’ ,*.13,1 4 - 16.l indicate that 1 mg bumetanide is equipotent to 40 mg frusemide. In regard to the onset of diuretic action, time of maximum effect, and duration of action, bumetanide, frusemide and ethacrynic acid are very similar.’,’5 In the present clinical study we studied the diuretic action of bumetanide in patients with congestive heart failure, and compared its diuretic action with that of frusemide in another group of patients, also suffering from congestive heart failure. A significant urinary excretion of sodium and potassium was observed in patients receiving bumetanide for a period of 3 days. The chloride excretion was greater, at all times exceeding the corresponding sodium excretion. This activity has been observed with all loop diuretics.’ The urinary electrolyte excretion increased as the dose of the drug increased. Similar changes were observed in the serum electrolytes. The degree of resulting hypokalaemia was directly proportional to the administered s9
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Figure 3. Comparison of diuresis and body weight after administration of bumetanideand frusemide: mean values for 10 patients
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Figure 4. Comparison of urine electrolyte changes after administration of bumetanide, placebo and frusemide: mean values for 10 patients
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C. Kourouklis, 0. Christensen and D. Augoustakis
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Figure 5. Comparison of serum electrolyte and bicarbonate changes in levels (AM) after administration of different doses of bumetanide and frusemide
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dose of bumetanide. Bicarbonate levels showed a slight change towards alkalosis. The degree of metabolic alkalosis was also proportional to the administered dose of diuretic. During long-term administration, bumetanide caused a significant excretion of sodium and chloride which, with the passage of time, stabilised at 50 mmol/l for sodium and 70 mmol/l for chloride. Potassium excretion fluctuated at about 50 mmol/l throughout the duration of the study. Comparable fluctuations were observed in the serum electrolytes. Long-term administration of bumetanide caused a fall in the three electrolytes, again directly proportional to the dosage of the drug. As has been shown, the urinary excretion of electrolytes was directly related to the bumetanide dosage, but optimal clinical response was observed with dosages of 1 mg to 2 mg per 24 hours. Increase in dosage did not cause a significant increase in 429
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Bumetanide in congestive heart failure
sodium excretion. In addition, a small degree of alkalosis was observed which increased with larger doses. Body weight and diuresis progressively decreased so that by the 3rd and 4th day of the study, they had stabilised. Serum creatinine increased on average by 0.3 mg per 100 ml. This small increase is unlikely to be due to a compromised renal function, but may be due to haemoconcentration.’O The activity of any diuretic is dependent on a number of pathophysiological conditions (severity of the disease, renal function, total body fluid volume, acidbase status, hormones, etc.) present at the time of administration, and on the type of diuretic administered. For this reason, bumetanide, frusemide and placebo were given cyclically as shown in Table II. In this way, the possibility of bias was minimised as much as possible, and comparison of the two drugs was reliable. Comparison of decrease in body weight, diuretic effect, urinary electrolyte excretion, change in the serum electrolytes, and changes in bicarbonate levels between bumetanide and frusemide showed both diuretics to be equally active. Statistical analysis of these parameters showed no significant differences, except for the amount of excreted potassium after 2 mg bumetanide daily, which may be a function of the small number of patients in the second group. From this and other studies, it would appear that bumetanide does not cause significant side-effects. Except for rarely found muscular cramps, evidently caused by the fall in tissue sodium, no other side-effects have been observed.1,4,13
Acknowledgement The authors wish to thank Leo Pharmaceutical Products for providing bumetanide.
References 1. Asbury, M. J., Gatenby, P. B. B., O’Sullivan, S., and Bourke, E., (1972). Bumetanide: potent new “loop” diuretic. Br. Med. J., 1,211. 2. Bollerup, A. E.,Hesse, B., and Sigurd, B., (1974). Changes of glomerular filtration rate and renal plasma flow following intravenous bumetanide in organic heart disease. Acta Pharmacol. Toxicol., 34, 305. 3. Bourke, E.,Asbury, M. J. A., O’Sullivan, S., and Gatenby, P.B. B., (1973).The sites of action of bumetanide in man. Eur. J. Pharmacol., 23,283. 4. Davies, D. L., Lant, A. F., Millard, N. R., Smith, A. J., Ward, J. W., and Wilson, G. M., (1974). Renal action, therapeutic use and phannacokinetics of the diuretic, bumetanide. Clin. Pharmacol. Ther., 15,141. 5. Feit, P. W.,(1971). Aminobenzoic acid diuretics, 2,4-substituted-3-a1nino-5-sulfamylbenzoic acid derivatives. J. Med. Chem., 14,432. 6. Henning, R., and Lundvall, O., (1973). Evaluation in man of bumetanide, a new diuretic agent. Eur. J. Clin. Pharmacol., 6,224. 7 . Hofstetter, A.,(1974). Bumetanide, a new diuretic. f n t . Urol. Nephrof.,6 , 35. 8. Karlander, S. G., Henning, R., and Lundvall, O., (1973). Renal effects of bumetanide, a new saluretic agent. Eur. J. Clin. Pharmacol., 6,220. 9. Laragh, H. J., Cannon, J. P., Stason, B. W., and Heinemann, 0. H., (1966).Physiologic and clinical observations on furosemide and ethacrynic acid. Ann. N. Y. Acad. Sci., 193,453. 10. Leth, A., (1970). Change in plasma and extracellular fluid volumes in patients with essential hypertension during long-term treatment with hydrochlorothiazide. Circulation, 24,479.
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11. Magnussen, M. P., and Eilertsen, E., (1974). Species differences in the diuretic activity and metabolism of bumetanide. Arch. Pharmacol., 282, R61. 12. New diuretics - Bumetanide and Metolazone (1974). Drug Ther. Bull., 12,49. 13. Olesen, K. H., Sigurd, B., Steiness, E., and Leth, A., (1973). Bumetanide, anew potent diuretic: a clinical evaluation in congestive heart failure. Acra Med. Scund., 193,119. 14. Olesen, K. H., Sigurd, B., Steiness, E., and Leth, A., (1973). Bumetanide. a new potent diuretic. In “Modern diuretic therapy in the treatment of cardiovascular and renal disease”. Int. Congr. Ser. 268, p. 155. Excerpta Medica, Amsterdam. 15. Ostergaard, E. H., Magnussen, M. P., Kaegaard Nielsen, C., Eilertsen, E., and Frey, H.-H., (1974). Pharmacological properties of bumetanide, a new potent diuretic. Armeim. Forsch.,22,66. 16. Ring-Larsen, H., (1974). Bumetanide in the treatment of hepatic ascites. Acra Med. Scund., 195,411. 17. Sigurd, B., Hesse, B., and Valentin, N., (1974). Bumetanide. A new potent diuretic. Dun. Med. Bull., 21, 63. 18. Wooton, D. P. I., (1964). “Microanalysis in Medical Biochemistry.” Churchill, London.
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