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Potassium loss with thiazide therapy
Potassium
loss with
thiazide
therapy
R. F. Maronde,M.D.* M. Milgrom, M.D.** J. M. Dickey, Ph.D.**” Los Angeles, Calif.
T
hirty to 40 per cent of hypertensive patients treated with thiazides have a lowering of serum potassium to below 3.5 mEq. per liter. l Although short-term balance studies have demonstrated a urinarv loss of potassium with thiazide admimstration,2~3 potassium loss with longterm therapy as a direct cause of a lowered serum potassium has been questioned’ and “exchangeable” potassium determinations have been reported as showing no significant potassium 10~s.~~~In the present study, metabolic balance methods were used in nonedematous hospitalized patients to evaluate the potassium loss associated with thiazide administration. Patient
selection
and
methods
Eight men with normal renal function, as evidenced by normal serum creatinine and blood urea nitrogen levels and with mild to moderate uncomplicated essential hypertension, who had been treated with hydrochlorothiazide as outpatients, were hospitalized and studied on the metabolic ward. All patients were instructed to stop medications 2 weeks prior to hospitalization. On the initial day of hospitalization, the dietitian interviewed the patient and From
the General Received *Professor **Assistant ***Assistant York,
16
Department Hospital. for publica;ion of Medicine Professor Professor Buffalo, N.
composed a diet which was held stationary throughout the study. This diet contained between 80 to 90 mEq. of potassium (average 86 mEq.) and between 90 to 110 mEq. of sodium per day (average 108 mEq.). All liquids were measured and all solids were weighed. The diets were prepared in the kitchen of the metabolic ward. The sodium and potassium content were ascertained from tables compiled from previous photometric analysis and checked by anaylsis of duplicate diets. The standard deviations of sodium and potassium in the diets as ascertained by this analysis were + 2.8 mEq. for sodium and f 2.0 mEq. for potassium. Because there is a significant insensible loss of sodium and potassium,’ statistical comparison between the actual diet content and the loss of these electrolytes in urine plus stool would introduce an error. Therefore, the statistical comparisons were made between the urine plus stool loss of sodium and potassium during the last 4 days of the control period and for sequential periods during the treatment period. (See “Statistical methods.“) There was a hospital control period that ranged from 7 to 14 days (average 11.3
of Medicine. University of Southern California School of Medicine. Los Anrceles. Calif. Oct.-Z% i968. and Pharmacology; Head, Clinical Pharmacology Section. of Medicine. of Biostatistics (Mediciue). Present address: Deuartment of Statistics, Y.
American Heart Journal
July, 1969
and Los Angeles
State
University
County
of New
Vol. 78, No. 1, pp. 16-21
Pofassi~un
days). Subsequently, 50 mg. of hydrochlorothiazide three times daily were prescribed for 14 to 67 consecutive days (average 33 days). Twenty-four hour urine specimens and all stools were collected. Sodium and potassium content of the 24 hour urine specimens and of 7 day ashed stool collections were determined by flame photometry. Serum and urine creatinine were measured by the Folin-Wu method. In 5 of the 8 patients, 24 hour urine-aldosterone excretion rate was determined by the method of Kliman and Peterson.8 Plasma pH, pCOZ, and HCO, were measured by the method of Astrup and associates9 during the control and treatment periods. Statistical
Results
Fig. 1 depicts the average potassium and sodium excretion in urine plus stool for the group of 8 patients during the pretreatment control period. From the sixth day of this period it is evident that the group was in balance. A dose of 150 mg. of hydrochlorothiazide daily resulted in a loss of sodium during the first 3 days of therapy followed by a period of sodium retention from the fourth to eighth day of treatment. ‘I’lle total sodium excretion \yhen averaged \I as not significantly different from the control levels. Potassium losswas also most marked during the first 3 days of hydrochlorothiazide administration, but in contrast to sodium there was no subsequent potassiuln retention. Cumulative net potassium losses are shown in Fig. 2. Serum potassium dropped from an average control level of 4.1 to 3.2 mEq. per liter by the end of the
methods
120
I 2 w s
20
17
control period and the stable treatment period. For each measured variable, the h~~pothesis of each patient’s stable treatment period mean PT eqd t0 hit3 Control periOd mean pc was tested within the hypothesis of a linear regression of PT on ,.& \vith the same coefficients for each patient. An F statistic was obtained by treating each patient’s averages as paired ohservations.
To guard against possible constant biases in the nominal potassium and sodium intakes, the nominal intakes were corrected to zero values determined from in-balance control periods. Fig. 1 shows that control period balance was attained on the sixth day of hospitalization. Following the initiation of hydrochlorothiazide treatment, extreme transient disturbance of ion balance lasted for 7 days, after which stable treatment periods were defined. For each patient, t tests were performed for changes of distribution of measured variables between the in-balance
2
loss with thiazide thurclpy
r
AVERAGE
Na+ INTAKE -
AVERAGE
K+
INTAKE
-
0 I
2I
3I DAY
Fig. 1. Control period the group of 8 patients
transitory studied.
OF
4I
5I
HOSPITALIZATION urine
plus
stool
6I
- CONTROL sodium
and
I 7
I 0
excretion
per 24 hours
I 9
I IO
PERIOD potassium
averaged
for
18
Maronde,
Milgrom,
.4m. Heart .I. July, 1969
and Dickey
Table 1. Local time averages of parameters,
No. of patients
Time
In-balance control period (variable length) Treatment Period 1 (3 days)
K+ loss
over patients*
K+
Na+
(mEq.lL.)
Period 4 (7 days) Period 5 (7 days) Period 6 (7 days)
Periods 3-7 (variable length)
139 (4) 140
(2)
140
(2)
141 (5) 140 (3) 142
(2)
(9.4) 12.7 W,“’
142
(2)
141 (3)
(18.5)
(5.6) appear
141 (4)
‘3
(3.3) -1.6 w:’
Period 7 (7 days)
Na+
(m&./L. 1
68.6 (37.5) -22.5 (22.5) -11.3 (19.1) -3.3 (18.5) -6.4
(10.5) 5.2 ‘;:;I
patients
Serum
0.0 (0.0) 38.2 (16.6) 28.2 (20. I) 3.3 6;’
between
loss
(mEn./dar)
8
Period 3 (7 days)
deviations
Serum
(m&./day)
Period 2 (4 days)
Standard
averaged (unweighted)
in parenthesis.
Table II. Comparisons, paired by patient, of stable treatment period and in-balance control period values* Blood Serum Kf
Variables
Serum
Na+
Aldosterone excretion
Blood HCOi
Blood PH
A.M.,
2
Zd
pressure standing)
(I0 Systolic
Body weight
) Diastolic
-
F m,n statistic
40.3 (.OOS)
Degree of freedom m n *Values
presented
2 6
are the F ratios
3.5 (.lO) 2 6 of control
versus
144.2 (.OOS)
26.3 (.OOS)
22.0 f.005)
16.9 (.OOS)
18.2 (.OOS)
2 6
2 6
2 6
2 6
2 6
treatment
period
first week of therapy and remained near this level. The serum and urinary creatinine levels did not change significantly. In Table I the pertinent data are averaged and presented for the control and study periods. A weight loss that averaged 1.5 Kg. for the 8 patients studied occurred within the first 3 days of hydrochlorothiazide therapy.
data.
The F-statistic
significance
levels
9.6 (.Ol)
35.2 (.OOS)
2 6 appear
2 6
in parenthesis.
This was associated with an increased urine volume and was attributed to fluid loss. There was no further significant sustained weight loss during the remainder of the study. Aldosterone excretion rose from an average control level of 10.7 to 20.8 pg per day on the fourth to eighth day of the treat-
i'ohw h'wnhe-r
78 1
Potassium
loss with thin&e
10
thertlpy
--.--Aldostercne excrelion ( rgP hr. 1
Blood PH
Blood HCOJ
10.7 (2.0)
7.438 (.022)
26.2 (3.3)
37.4 (7.0)
142 (33)
13.0
7.427 (.034) 7.460 (.021) 7.479 (.020) 7.465 (.022) 7.468 ( ,026) 7.458 ( ,033) 7.448 (.031) 7.472 (.018)
23.8
37.6
(2.0)
(5.2)
29.0
41.9 (0.5) 40.9
137 (33) 125 (34) 125 (30) 125 (33) 127 (33) 111 (7) 106
20.8 (8.4) 18.6
(1.21 17.7 216 (0.1)
19.6 :1.4)
(1.8) 29.5 (2.4) 28.5 (3.0) 29.4
(2.8) 41.4 (4.4) 43.5 (4.9) 42.3 (5.4) 44.8 (5.3) 41.1 (3.8)
(2.5) 28.5
(2.0) 29.6 (1.1) 28.7 (2.5)
81 8 (18 .I) 80 7 (18 2) 80 4 (18 l,l 78 4 (18 4) 811.4 (lK.3, 67 6 (5 2) 67 5 (S .I) 80 1 (17 9)
(12) 124 (30)
Table III. Correlation coeficients (Pearson’s r) and confidence km& of cumulative sodium and potassium losses with blood pH and bicarbonate levels and aldosterone excretion rates* I
Variables Potassium loss Pearson’s r Confidence inter\
Blood
PH
I
.51 al ( .95)
Sodium loss Pearson’s Confidence
r interval
( .95)
*There are positive are no similar
correlations correlations
with evident
(.27,
(-
- .I9 .45, .08)
ment period and did not change significantly during the remainder of the study. This represents a slight but statistically significant increase in aldosterone excretion. The individual aldosterone excretion rates are presented in graph form in Fig. 3. The blood pH, pCOn, and bicarbonate levels also showed a slight but statistically
A ldosterone excretion
I
,54 ( 33, .72)
.68;
potassium loss and increased with sodium balance figures.
Blood HCO;
blood
LIH, and
(-
.OO .28, .28)
blood
bicarbonate
71 (.28,
(-
and
aldosterone
881
.lO .42,
57)
excretion.
There
significant increase with hydrochlorothiazide therapy. Table II presents the levels of statistical significance of the control period versus the treatment period data. Discussion
The average cumulative potassium loss with hydrochlorothiazide for the group of
20
Maronde,
hfilgrom,
Am. Heart J. Jdy, 1969
and Dickey
(AVERAGE
DAYS
Fig. 2. Cumulative
OF
PER DAY 1
30 40 HYDROCHLOROTHlAZlDE
net potassium loss associated with administration
8 patients studied was 295 mEq. (Fig. 2). There was no evidence of self-correction of the potassium
LOSS
loss during
hydrochlorothia-
zide therapy. Significant sodium loss, however, occurred only during the first 3 days of therapy with subsequent sodium retention and at least partial correction of the initial loss. The aldosterone excretory rate was in the low normal range for each patient during the control period. The aldosterone excretory rate increased with therapy, and presumptively this increase was triggered by the initial sodium loss that resulted from hydrochlorothiazide adminis-
so
60
70
of 150 mg. per day of hydrochlorothiazide.
tration. The continuation of the urinary potassium loss during the period that sodium was being conserved may be a result of this mild aldosteronism. The correlation coefficients between amount of sodium excretion and aldosterone excretion and between amounts of potassium excretion and aldosterone are presented in Table III. The control serum potassium levels, exceeded 3.8 mEq. per liter in each patient. There was a statistically significant decrease in serum potassium levels with hydrochlorothiazide therapy, and this decrease was sustained. Individual serum
Potassium
loss with thinzide thfrap:c
21
-
DAYS Fig.
3. Aldosterone
excretory
levels
before
OF HYDROCHLOROTHIAZIDE and during
potassium levels were a poor index of the total potassium loss, but the 2 patients that had a serum level below 3.0 mEq. per liter did have the largest cumulative potassium loss. The slight but statistically significant increase in blood pH, pCO2, and bicarbonate levels also correlated fairly well with the potassium loss but not with the state of the sodium balance (Table III). Summary Nonedematous patients with essential hypertension were studied by metabolic techniques while hospitalized. Hydrochlorothiazide therapy resulted in a transient natriuresis which subsequently was partially compensated for by renal sodium retention. (Trinary potassium loss accompanied the natriuresis and continued during the period of the compensatory renal retention. Evidence was presented that indicate a slight but statistically significant increase in aldosterone excretion during the period of hydrochlorothiazide therapy. We are grateful for the technical Mrs. Catherine Nobe, a technologist pharmacology laboratory.
assistance of at the clinical
hydrochlorothiazide
therapy.
REFERENCES 1. Gifford, R. W., Jr.: Combined drug therapy of hypertension, in Hahnemann Symposium on Hypertensive Disease, 1958: Hypertension, Philadelphia, 19.59, W. B. Saunders Company. . . p. 361. 2. Wilkins, R. W., Hollander, W., and Chobanian, A. V.: Chlorothiazide in hvmrtension: Studies on its mode of action, Ai;. N. Y. Acad. SC. 71:465, 1958. 3. Laragh, J. H.: Some effects of chlorothiazide on electrolyte metabolism and its use in edematous states, Ann. N. Y. Acad. SC. 71:409, 1958. 4. Weiler, J. M.: Potassium depletion and benzothiadiazone drugs: A source of over concern, AM. HEART J. 63:842, 1962. 5. Talso, P. J., and Carabollo, A. J.: Effects of benzothiadiazone on serum and total body electrolytes, Ann. N. Y. ilcad. SC. 88:822, 1960. 6. Gifford, R. W., Jr., Mattox, V. R., Orvis, A. L., Sones, D. A., and Rosevear, J. W.: Effect of thiazide diuretics on plasma volume, body electrolytes, and excretion of aldosterone in hypertension, Circulation %:1197, 1961. 7. Amatruda, T. T., and Welt, L. G.: Secretion of electrolytes in thermal sweat, J. Appl. Physiol. 5:759, 1953. 8. Kliman, B., and Peterson, K. E.: Double isotope derivative assay of aldosterone in biological extracts, J. Biol. Chem. 235:1639, 1960. 9. Andersen, 0. S., Engel, K., Jorgensen, K., and Astrup, P.: A new acid-base nomogram. An improved method for the calculation of the relevant blood acid.-base data, Scand. ,.I. Clin. & I.ab. Invest. 12:177, 1960.
loss with
thiazide
therapy
R. F. Maronde,M.D.* M. Milgrom, M.D.** J. M. Dickey, Ph.D.**” Los Angeles, Calif.
T
hirty to 40 per cent of hypertensive patients treated with thiazides have a lowering of serum potassium to below 3.5 mEq. per liter. l Although short-term balance studies have demonstrated a urinarv loss of potassium with thiazide admimstration,2~3 potassium loss with longterm therapy as a direct cause of a lowered serum potassium has been questioned’ and “exchangeable” potassium determinations have been reported as showing no significant potassium 10~s.~~~In the present study, metabolic balance methods were used in nonedematous hospitalized patients to evaluate the potassium loss associated with thiazide administration. Patient
selection
and
methods
Eight men with normal renal function, as evidenced by normal serum creatinine and blood urea nitrogen levels and with mild to moderate uncomplicated essential hypertension, who had been treated with hydrochlorothiazide as outpatients, were hospitalized and studied on the metabolic ward. All patients were instructed to stop medications 2 weeks prior to hospitalization. On the initial day of hospitalization, the dietitian interviewed the patient and From
the General Received *Professor **Assistant ***Assistant York,
16
Department Hospital. for publica;ion of Medicine Professor Professor Buffalo, N.
composed a diet which was held stationary throughout the study. This diet contained between 80 to 90 mEq. of potassium (average 86 mEq.) and between 90 to 110 mEq. of sodium per day (average 108 mEq.). All liquids were measured and all solids were weighed. The diets were prepared in the kitchen of the metabolic ward. The sodium and potassium content were ascertained from tables compiled from previous photometric analysis and checked by anaylsis of duplicate diets. The standard deviations of sodium and potassium in the diets as ascertained by this analysis were + 2.8 mEq. for sodium and f 2.0 mEq. for potassium. Because there is a significant insensible loss of sodium and potassium,’ statistical comparison between the actual diet content and the loss of these electrolytes in urine plus stool would introduce an error. Therefore, the statistical comparisons were made between the urine plus stool loss of sodium and potassium during the last 4 days of the control period and for sequential periods during the treatment period. (See “Statistical methods.“) There was a hospital control period that ranged from 7 to 14 days (average 11.3
of Medicine. University of Southern California School of Medicine. Los Anrceles. Calif. Oct.-Z% i968. and Pharmacology; Head, Clinical Pharmacology Section. of Medicine. of Biostatistics (Mediciue). Present address: Deuartment of Statistics, Y.
American Heart Journal
July, 1969
and Los Angeles
State
University
County
of New
Vol. 78, No. 1, pp. 16-21
Pofassi~un
days). Subsequently, 50 mg. of hydrochlorothiazide three times daily were prescribed for 14 to 67 consecutive days (average 33 days). Twenty-four hour urine specimens and all stools were collected. Sodium and potassium content of the 24 hour urine specimens and of 7 day ashed stool collections were determined by flame photometry. Serum and urine creatinine were measured by the Folin-Wu method. In 5 of the 8 patients, 24 hour urine-aldosterone excretion rate was determined by the method of Kliman and Peterson.8 Plasma pH, pCOZ, and HCO, were measured by the method of Astrup and associates9 during the control and treatment periods. Statistical
Results
Fig. 1 depicts the average potassium and sodium excretion in urine plus stool for the group of 8 patients during the pretreatment control period. From the sixth day of this period it is evident that the group was in balance. A dose of 150 mg. of hydrochlorothiazide daily resulted in a loss of sodium during the first 3 days of therapy followed by a period of sodium retention from the fourth to eighth day of treatment. ‘I’lle total sodium excretion \yhen averaged \I as not significantly different from the control levels. Potassium losswas also most marked during the first 3 days of hydrochlorothiazide administration, but in contrast to sodium there was no subsequent potassiuln retention. Cumulative net potassium losses are shown in Fig. 2. Serum potassium dropped from an average control level of 4.1 to 3.2 mEq. per liter by the end of the
methods
120
I 2 w s
20
17
control period and the stable treatment period. For each measured variable, the h~~pothesis of each patient’s stable treatment period mean PT eqd t0 hit3 Control periOd mean pc was tested within the hypothesis of a linear regression of PT on ,.& \vith the same coefficients for each patient. An F statistic was obtained by treating each patient’s averages as paired ohservations.
To guard against possible constant biases in the nominal potassium and sodium intakes, the nominal intakes were corrected to zero values determined from in-balance control periods. Fig. 1 shows that control period balance was attained on the sixth day of hospitalization. Following the initiation of hydrochlorothiazide treatment, extreme transient disturbance of ion balance lasted for 7 days, after which stable treatment periods were defined. For each patient, t tests were performed for changes of distribution of measured variables between the in-balance
2
loss with thiazide thurclpy
r
AVERAGE
Na+ INTAKE -
AVERAGE
K+
INTAKE
-
0 I
2I
3I DAY
Fig. 1. Control period the group of 8 patients
transitory studied.
OF
4I
5I
HOSPITALIZATION urine
plus
stool
6I
- CONTROL sodium
and
I 7
I 0
excretion
per 24 hours
I 9
I IO
PERIOD potassium
averaged
for
18
Maronde,
Milgrom,
.4m. Heart .I. July, 1969
and Dickey
Table 1. Local time averages of parameters,
No. of patients
Time
In-balance control period (variable length) Treatment Period 1 (3 days)
K+ loss
over patients*
K+
Na+
(mEq.lL.)
Period 4 (7 days) Period 5 (7 days) Period 6 (7 days)
Periods 3-7 (variable length)
139 (4) 140
(2)
140
(2)
141 (5) 140 (3) 142
(2)
(9.4) 12.7 W,“’
142
(2)
141 (3)
(18.5)
(5.6) appear
141 (4)
‘3
(3.3) -1.6 w:’
Period 7 (7 days)
Na+
(m&./L. 1
68.6 (37.5) -22.5 (22.5) -11.3 (19.1) -3.3 (18.5) -6.4
(10.5) 5.2 ‘;:;I
patients
Serum
0.0 (0.0) 38.2 (16.6) 28.2 (20. I) 3.3 6;’
between
loss
(mEn./dar)
8
Period 3 (7 days)
deviations
Serum
(m&./day)
Period 2 (4 days)
Standard
averaged (unweighted)
in parenthesis.
Table II. Comparisons, paired by patient, of stable treatment period and in-balance control period values* Blood Serum Kf
Variables
Serum
Na+
Aldosterone excretion
Blood HCOi
Blood PH
A.M.,
2
Zd
pressure standing)
(I0 Systolic
Body weight
) Diastolic
-
F m,n statistic
40.3 (.OOS)
Degree of freedom m n *Values
presented
2 6
are the F ratios
3.5 (.lO) 2 6 of control
versus
144.2 (.OOS)
26.3 (.OOS)
22.0 f.005)
16.9 (.OOS)
18.2 (.OOS)
2 6
2 6
2 6
2 6
2 6
treatment
period
first week of therapy and remained near this level. The serum and urinary creatinine levels did not change significantly. In Table I the pertinent data are averaged and presented for the control and study periods. A weight loss that averaged 1.5 Kg. for the 8 patients studied occurred within the first 3 days of hydrochlorothiazide therapy.
data.
The F-statistic
significance
levels
9.6 (.Ol)
35.2 (.OOS)
2 6 appear
2 6
in parenthesis.
This was associated with an increased urine volume and was attributed to fluid loss. There was no further significant sustained weight loss during the remainder of the study. Aldosterone excretion rose from an average control level of 10.7 to 20.8 pg per day on the fourth to eighth day of the treat-
i'ohw h'wnhe-r
78 1
Potassium
loss with thin&e
10
thertlpy
--.--Aldostercne excrelion ( rgP hr. 1
Blood PH
Blood HCOJ
10.7 (2.0)
7.438 (.022)
26.2 (3.3)
37.4 (7.0)
142 (33)
13.0
7.427 (.034) 7.460 (.021) 7.479 (.020) 7.465 (.022) 7.468 ( ,026) 7.458 ( ,033) 7.448 (.031) 7.472 (.018)
23.8
37.6
(2.0)
(5.2)
29.0
41.9 (0.5) 40.9
137 (33) 125 (34) 125 (30) 125 (33) 127 (33) 111 (7) 106
20.8 (8.4) 18.6
(1.21 17.7 216 (0.1)
19.6 :1.4)
(1.8) 29.5 (2.4) 28.5 (3.0) 29.4
(2.8) 41.4 (4.4) 43.5 (4.9) 42.3 (5.4) 44.8 (5.3) 41.1 (3.8)
(2.5) 28.5
(2.0) 29.6 (1.1) 28.7 (2.5)
81 8 (18 .I) 80 7 (18 2) 80 4 (18 l,l 78 4 (18 4) 811.4 (lK.3, 67 6 (5 2) 67 5 (S .I) 80 1 (17 9)
(12) 124 (30)
Table III. Correlation coeficients (Pearson’s r) and confidence km& of cumulative sodium and potassium losses with blood pH and bicarbonate levels and aldosterone excretion rates* I
Variables Potassium loss Pearson’s r Confidence inter\
Blood
PH
I
.51 al ( .95)
Sodium loss Pearson’s Confidence
r interval
( .95)
*There are positive are no similar
correlations correlations
with evident
(.27,
(-
- .I9 .45, .08)
ment period and did not change significantly during the remainder of the study. This represents a slight but statistically significant increase in aldosterone excretion. The individual aldosterone excretion rates are presented in graph form in Fig. 3. The blood pH, pCOn, and bicarbonate levels also showed a slight but statistically
A ldosterone excretion
I
,54 ( 33, .72)
.68;
potassium loss and increased with sodium balance figures.
Blood HCO;
blood
LIH, and
(-
.OO .28, .28)
blood
bicarbonate
71 (.28,
(-
and
aldosterone
881
.lO .42,
57)
excretion.
There
significant increase with hydrochlorothiazide therapy. Table II presents the levels of statistical significance of the control period versus the treatment period data. Discussion
The average cumulative potassium loss with hydrochlorothiazide for the group of
20
Maronde,
hfilgrom,
Am. Heart J. Jdy, 1969
and Dickey
(AVERAGE
DAYS
Fig. 2. Cumulative
OF
PER DAY 1
30 40 HYDROCHLOROTHlAZlDE
net potassium loss associated with administration
8 patients studied was 295 mEq. (Fig. 2). There was no evidence of self-correction of the potassium
LOSS
loss during
hydrochlorothia-
zide therapy. Significant sodium loss, however, occurred only during the first 3 days of therapy with subsequent sodium retention and at least partial correction of the initial loss. The aldosterone excretory rate was in the low normal range for each patient during the control period. The aldosterone excretory rate increased with therapy, and presumptively this increase was triggered by the initial sodium loss that resulted from hydrochlorothiazide adminis-
so
60
70
of 150 mg. per day of hydrochlorothiazide.
tration. The continuation of the urinary potassium loss during the period that sodium was being conserved may be a result of this mild aldosteronism. The correlation coefficients between amount of sodium excretion and aldosterone excretion and between amounts of potassium excretion and aldosterone are presented in Table III. The control serum potassium levels, exceeded 3.8 mEq. per liter in each patient. There was a statistically significant decrease in serum potassium levels with hydrochlorothiazide therapy, and this decrease was sustained. Individual serum
Potassium
loss with thinzide thfrap:c
21
-
DAYS Fig.
3. Aldosterone
excretory
levels
before
OF HYDROCHLOROTHIAZIDE and during
potassium levels were a poor index of the total potassium loss, but the 2 patients that had a serum level below 3.0 mEq. per liter did have the largest cumulative potassium loss. The slight but statistically significant increase in blood pH, pCO2, and bicarbonate levels also correlated fairly well with the potassium loss but not with the state of the sodium balance (Table III). Summary Nonedematous patients with essential hypertension were studied by metabolic techniques while hospitalized. Hydrochlorothiazide therapy resulted in a transient natriuresis which subsequently was partially compensated for by renal sodium retention. (Trinary potassium loss accompanied the natriuresis and continued during the period of the compensatory renal retention. Evidence was presented that indicate a slight but statistically significant increase in aldosterone excretion during the period of hydrochlorothiazide therapy. We are grateful for the technical Mrs. Catherine Nobe, a technologist pharmacology laboratory.
assistance of at the clinical
hydrochlorothiazide
therapy.
REFERENCES 1. Gifford, R. W., Jr.: Combined drug therapy of hypertension, in Hahnemann Symposium on Hypertensive Disease, 1958: Hypertension, Philadelphia, 19.59, W. B. Saunders Company. . . p. 361. 2. Wilkins, R. W., Hollander, W., and Chobanian, A. V.: Chlorothiazide in hvmrtension: Studies on its mode of action, Ai;. N. Y. Acad. SC. 71:465, 1958. 3. Laragh, J. H.: Some effects of chlorothiazide on electrolyte metabolism and its use in edematous states, Ann. N. Y. Acad. SC. 71:409, 1958. 4. Weiler, J. M.: Potassium depletion and benzothiadiazone drugs: A source of over concern, AM. HEART J. 63:842, 1962. 5. Talso, P. J., and Carabollo, A. J.: Effects of benzothiadiazone on serum and total body electrolytes, Ann. N. Y. ilcad. SC. 88:822, 1960. 6. Gifford, R. W., Jr., Mattox, V. R., Orvis, A. L., Sones, D. A., and Rosevear, J. W.: Effect of thiazide diuretics on plasma volume, body electrolytes, and excretion of aldosterone in hypertension, Circulation %:1197, 1961. 7. Amatruda, T. T., and Welt, L. G.: Secretion of electrolytes in thermal sweat, J. Appl. Physiol. 5:759, 1953. 8. Kliman, B., and Peterson, K. E.: Double isotope derivative assay of aldosterone in biological extracts, J. Biol. Chem. 235:1639, 1960. 9. Andersen, 0. S., Engel, K., Jorgensen, K., and Astrup, P.: A new acid-base nomogram. An improved method for the calculation of the relevant blood acid.-base data, Scand. ,.I. Clin. & I.ab. Invest. 12:177, 1960.