- Email: [email protected]
THE EFFECTS OF SPIRONOLACTONE AND CHLORTHALIDONE ON ARTERIAL PRESSURE
1161
obese diabetic patients, who yet excrete large amounts of glucose, makes it unlikely that glycosuria per se is responsible for high pyruvate excretion in insulin-requiring diabetics. This excretion was at first thought to be due to exogenous insulin, since the insulin-requiring diabetics were the only subjects to have received this foreign protein ; but intravenous insulin did not alter pyruvate excretion in either healthy subjects or insulin-requiring obese diabetics. It is also unlikely that the excessive urinary pyruvate is a non-specific result of osmotic diuresis, or is due to altered pH of the urine; the rates of urine-flow and the urinary pH were similar in the three groups. There was no consistent alteration in a-oxoglutarate excretion. Differences like those seen with pyruvate might have been expected if the latter reflected only a non-specific derangement of kidney function. Takanami et al. (1960) found more a-oxoglutarate in the urine of diabetics than in that of healthy subjects; we cannot account for the difference between our results and theirs, although we used different methods. It is now more widely recognised that the clinical syndrome of diabetes mellitus cannot be attributed solely to insulin deficiency, even in those patients whose need for exogenous insulin is absolute. The excessive urinary excretion of pyruvate by many in this category (Lawrence 1951) suggests that they have a defect of carbohydrate metabolism which is not controlled by insulin. Further tests of pyruvate metabolism may lead to other biochemical criteria for differentiating the clinical types of
diabetes.
Summary and Conclusions In healthy, obese diabetic, and insulin-requiring diabetic subjects, pyruvate, a-oxoglutarate, and glucose were measured enzymatically in blood and urine, before and after ingestion of glucose, with and without insulin. Insulin-requiring diabetics, deprived of exogenous insulin, did not show the normal rise in blood-pyruvate concentration after taking glucose. When insulin was given as well, they showed a rise greater than that in healthy subjects and obese diabetics treated similarly. Insulin-requiring diabetics lost, on average, five times more pyruvate in the urine than did healthy or obese diabetic subjects. This loss was unrelated to the bloodpyruvate concentration and could not be corrected by exogenous- insulin. There were no consistent differences in the metabolic behaviour of a-oxoglutarate in the three groups of
subjects studied. suggest that some insulin-requiring diabetics have, besides an abnormality of glucose metabolism, an abnormality of pyruvate metabolism which is not corrected by insulin. This may be important for the biochemical separation of various forms of diabetes. Those results
We are grateful to Sister Betty, Sister Gweneth, and Sister Maureen for valuable help in ensuring the success of these investigations. One of us (J. A.) wishes to thank the Diabetic Association for a grant in support of part of the work. REFERENCES
Anderson, J., Marks, V., Smith, M. J. H. (1961) Lancet, i, 1325. Butterfield, W. J. H., Thompson, R. H. S. (1957) Clin. Sci. 16, 679. Lawrence, R. D. (1951) Brit. med.J. i, 373. Marks, V. (1959) Clin. chim. Acta, 4, 395. (1961) ibid. 6, 724. Miller, M., Craig, J. W., Drucker, W. R., Woodward, J. H. (1956) Yale J. Biol. Med. 29, 335. Moorehouse, J. A. (1959) J. lab. clin. Med. 54, 927. Smith, M. J. H., Taylor, K. W. (1956) Brit. med. J. ii, 1035. Takanami, A., Ohya, S., Goto, Y. (1960) TohokuJ. exp. Med. 72, 163. -
THE EFFECTS OF SPIRONOLACTONE AND CHLORTHALIDONE ON ARTERIAL PRESSURE
W. I. CRANSTON M.D. Aberd., M.R.C.P. FIRST ASSISTANT
B. E. JUEL-JENSEN M.A., B.M. Oxon., Cand. med. Copenhagen ASSISTANT
DEPARTMENT OF THE REGIUS PROFESSOR OF RADCLIFFE INFIRMARY, OXFORD
MEDICINE,
SPIRONOLACTONES may reduce arterial pressure in patients with hypertension (Sturvevant 1958, Laragh 1960), and diuretics of the benzothiadine type clearly do so (Hall and Owen 1959, Juel-Jensen and Pears 1960), though the mechanism responsible is uncertain. The plasma-volume is reduced during the 1st week or so of treatment with chlorothiazide (Dollery et al. 1959, Dustan et al. 1959, Conway and Lauwers 1960); but when chlorothiazide has been given for more than 3 weeks, no significant change in plasma-volume has been found (Winer 1958, Conway and Lauwers 1960), and the cardiac output tends to increase (Conway and Lauwers 1960)., There is thus a probable decrease in peripheral resistance at rest. Even during the early phases of treatment with chlorothiazide and chlorthalidone, hypertensive patients show a lower peripheral resistance during exercise (Varnauskas et al. 1961). Our present observations were made in an attempt to decide the relative potencies of chlorthalidone, whose properties are similar to those of the benzothiadiazine diuretics (Douglas et al. 1961), and spironolactone; -to assess their effect when given together; and to determine, so far as possible, whether they act in a similar way. Methods
Observations were made on three women and seven men with moderate arterial hypertension, aged from 43 to 69 years: In none was there any evidence that the hypertension was secondary. Two patients (cases 1 and 7) had previously had hypotensive drugs. Case 7 had in the past been in congestive cardiac failure, which had been relieved by treatment, and at the time of the study the patient was not taking digitalis. Case 4 had sustained a retinal-vein thrombosis. None of the others had retinopathy. All the patients were at work except one (case 10), who had retired. The relevant facts about these cases are shown in the table. Each patient was seen weekly for a total of 27 weeks.
At each attendance the patient was weighed, and the arterial pressure was measured with a sphygmomanometer twice in the lying position and twice in the standing position by the same observer. The figures recorded are the mean of at least six readings. During the first 3 weeks, while they became accustomed to the routine, all the patients were given inert tablets. Thereafter they received, for 6 weeks each, the following four combinations of tablets:
Spironolactone (’Aldactone’, Searle)
500 mg.
daily
with
chlorthalidone (’ Hygroton ’, Geigy) 50 mg. daily. Spironolactone 500 mg. daily with dummy chlorthalidone tablets.
Dummy spironolactone tablets with chlorthalidone 50 mg. daily. Dummy spironolactone and dummy chlorthalidone tablets. The order of administration of the combinations was randomised and unknown to both patients and observers;
1162
All
STUDIES ON TEN CASES are the mean of at least six
blood-pressure figures
the patients were told that they would be given inert tablets at some time. During each 6-week period, three blood samples were taken for estimation of urea and electrolytes: Urea was measured by autoanalyser (’ Technicon ’), sodium
potassium by flame photometry, and chloride by potentioDuring the 4th or 5th week of each 6-week period, the plasma-volume was measured, using 1311 human serumalbumin in a dose of 2-3 {loC. Blood was withdrawn without stasis 15 minutes after the intravenous injection of iodinated albumin and then centrifuged, and the radioactivity of the plasma was counted. An identical amount of radioactive iodinated albumin was made up to 1 litre in alkali, to act as a standard. The plasma and standards were counted, to a total of 1 x 104 counts, in a well-scintillation (’ Panax ’) counter. As the investigation involved patients who were at work, it was not practicable to measure electrolyte balances: No dietary restrictions were issued, and no supplementary potassium was given. So that they would not be influenced by this knowledge, the serum-potassium levels were not made known to the observers. It was arranged that if any patient’s serum-potassium fell below 3 mEq. per litre the observer would be informed, and the patient withdrawn from the trial. In the event, this never happened. and
meter.
Results The effects on arterial pressure are shown in the table: The control level represents the average arterial pressure during the 6-week period when dummy tablets were given. The fall of pressure during the treatment periods is expressed as the difference between the control pressure and the average pressure during the appropriate period. There was much variability of response, and in some patients the difference between the control pressures and the pressure on drugs was not
significant.
Over the entire group, all three treatment regimes did cause -significant falls of arterial pressure (variance ratio 4-57, p < 0-01); these were unrelated to the order in which the drugs were given (variance ratio 1-41, p > 0-2):
Spironolactone caused an average fall in systolic pressure of (s.E.±5-4) mm. Hg, and a fall in diastolic pressure of 5-9 (s.E. ±2-3) mm., measured in the lying position. Chlorthalidone caused an average fall of 16-4 (s.E. ±8) mm. Hg systolic and 9-1 (s.E. ±3-2) diastolic; and the two drugs together produced a fall of 25-8 (s.E. ±3-7) mm. Hg systolic and 9-2 (s.E. ±2-3) 16.7
readings
diastolic. In
general, the standing pressure was reduced a little than the lying pressure. Patients tended to respond in the same way to chlorthalidone and to spironolactone when these were given alone. The fall of diastolic pressure with chlorthalidone was highly correlated with the fall with spironolactone: for the lying pressures r =0-837, P < 0’01; for the standing pressures, r=0.946, P < 0-001. Urea levels are more
represented by the expression Mean
level
urea
during control period/ mean
urea
during period x
level
treatment
100
because, if it is assumed
that
the
nitrogen balance is unchanged, this expression provides an
indication of the
change in
urea-
clearance. This factor is termed the
approximate ureaclearance, and is expressed as a percentage of the control value. In all three treatment periods, the approximate
Fig. 1—The relation between the effects of chlorthalidone and spironolactone on
diastolic arterial pressure, in the
standing position. Each point represents the response of one patient.
urea-clearance
fell significantly. The fall the average was 91.6%
least with chlorthalidone, where (s.E.±2-9%) of the control value. During treatment with spironolactone and with a combination of the two drugs, the average values were respectively 84-9 (s.E.3’1) and 81-4 (s.E.:3’6%) of the control values. The plasma-potassium fell by an average of 0-63 (S.E.±0.13) mEq. per litre when the patients received chlorthalidone. Spironolactone caused a mean rise of 0-40 (S.E.±0.14) mEq. per litre; both changes were significant at the 2% level. When both drugs were given together there was an insignificant rise of 0-17 (s.E.0-16) mEq. per litre. Plasma-chloride levels decreased by an average of 30 (S.E.±0.8) mEq. per litre in patients receiving chlorthalidone; was
1163 relative effects of pharmacologically differing hypotensive agents when given in this way. The combination of spironolactone and chlorthalidone caused a greater fall of arterial pressure than did either agent given alone, but this effect was small. When both were given together, the plasma-potassium levels were satisfactorily maintained, though it is impossible to draw conclusions about the total potassium pool. The dose of chlorthalidone in this trial was relatively small, for it was hoped that the need for potassium supplements would not arise; but larger doses of chlorthalidone seem more potent in reducing arterial pressure: Casual blood-pressure readings have been made on twentytwo clinic patients who were taking chlorthalidone in doses of 50
daily, with potassium supplements: eight patients having daily showed a mean fall of arterial pressure of 21-3+6-4 mm. Hg systolic and 10432 diastolic; fourteen patients taking chlorthalidone 100 mg. daily showed a mean arterial pressure fall of 50056 mm. Hg systolic and or
100 mg.
50 mg.
25-6+7-8 diastolic. We do not know whether spironolactone will maintain the potassium balance in patients taking larger doses of chlorthalidone; if it does so, such a combination might be effective in the treatment of fairly severe hypertension. Evidence from the diuretic response of patients given chlorothiazide and spironolactone suggests that potassium supplements may be needed (Ross 1961). But the present high cost of spironolactone is a valid argument against its long continued use in hypertension, unless the benefits are
unequivocal.
Fig. 2- The effects of spironolactone and chlorthalidone on plasmapotassium, plasma-volume, and approximate urea-clearance (see text). Each point represents the response of one patient.
"
"
1.3 (S.E.±1.1) mEq. per litre in patients receiving spironolactone ; and 1.7 (S.E.±0.7) mEq. per litre in patients receiving both drugs. No significant changes were detected in the
serum-sodium levels.
Plasma-volume, expressed as millilitres per kilogramme, did show significant change during any of the treatment periods. There was a small average fall of 1.2 (S.E.±2.2) ml. per kg. during treatment with spironolactone. Chlorthalidone caused an average rise of 1.4 (S.E.±1.3) ml. per kg.; and both drugs together produced a fall of 1-3 (S.E±1.4) ml. per kg. There was no significant change in the hmmatocrit values. The average weight loss was 1-6 kg. during treatment with spironolactone, 1-2 kg. during treatment with chlorthalidone, and 2-8 kg. with both drugs. not
Only one patient (case 5) had any symptoms during the She noticed slight oedema of the ankles when spironolactone combined with chlorthalidone was replaced by dummy tablets. This was associated with a weight gain of 3-2 kg. The cedema disappeared within a week, and her weight fell by 1 kg. during treatment with dummy
trial.
tablets. Discussion Both
spironolactone and chlorthalidone
are
capable
of
causing reduction of arterial pressure in patients with moderate hypertension. The doses employed were about equally active in this respect. Comparison with results previously obtained in this department (Juel-Jensen and Pears 1960) suggests that chlorthalidone 50 mg. daily has about the same effect on arterial pressure as chlorothiazide 750 mg. daily. The blood-pressure responses to spironolactone and to chlorthalidone were closely related; but we cannot conclude that these drugs act through the same mechanism, because there is no good evidence about the a
Plasma-volume was not significantly reduced in patients receiving either diuretic for 4 or 5 weeks. This agrees with the findings of Conway and Lauwers (1960) in patients taking chlorothiazide. Though a reduced plasma-volume may contribute to the initial fall of arterial pressure when diuretics are given, it does not explain the sustained fall. The fall of diastolic arterial pressure was significantly related to the control level of diastolic pressure, both when spironolactone was given (r= -0743, p < 0.02) and when chlorthalidone was given (r= +0-760, P < 0-02). A similar significant relationship is apparent for chlorothiazide—r=+0-736, P<0.02 from the figures of Hall and Owen (1959), and r=+0-571, p<0.05 according to and The Pears (1960). Juel-Jensen systolic pressure fall was unrelated to the control level of systolic pressure. McQueen and Morrison (1960) found no relation between the arterial pressure fall and the initial level of arterial pressure, but this may have been because they used the mean arterial pressure rather than the diastolic level, or because their patients were only observed for 3 days. The importance of this finding is at present unknown. Blood-urea was increased in all the treatment groups. " We have chosen to express this as a decrease in approximate urea-clearance ", on the assumption that nitrogen balance is unaltered. This cannot be proven, but it seems a reasonable assumption since the trial was conducted in a double-blind fashion. Using this convention, spironolactone caused a slightly greater reduction in approximate clearance than did chlorthalidone, and both drugs together caused a further decrease. When all treatment periods are considered together, there is no correlation between the approximate urea-clearance and the diastolic arterial pressure and plasma-volume, if the latter two are expressed as percentages of the control value (variance ratio 0-64, p > 0-2). This trial was performed on patients with moderate hypertension. Our conclusions may not be valid in the case
1164
of malignant hypertension, where there is some evidence of increased aldosterone production (Laragh et al. 1960).
Summary
Radcliffe Infirmary.
Chlorthalidone 50 mg. daily, and spironolactone 500 mg. daily, were given separately and in combination to ten patients with mild or moderate hypertension, in a doubleblind trial. Both drugs caused small decreases in arterial pressure; there was a significant correlation between the responses to the two agents. In combination, the hypotensive effect was only slightly greater than that of either drug alone. Plasma-volume was not significantly affected by either drug or by the combination. Chlotthalidone caused a significant decrease in plasma-potassium, and spironolactone a significant increase; when both were given together, the plasma-potassium did not differ significantly from the control values. Both drugs, alone and in combination, caused increase of blood-urea. The change of urea-clearance was unrelated to changes in diastolic arterial pressure or plasma-volume.
Preliminary
RETINOPATHY
CHLOROQUINE (7-chloro-4( - 4 - diethylamino-1 - methyl butylamino) quinoline) and its hydroxyl derivative (’ Plaquenil ’), originally developed as antimalarial agents, are now widely used in the treatment of arthritis and in various skin conditions. Often the drug is used in higher dosage than is needed to ensure trypanosomicidal action, and is administered for months, even for years. Several side-effects have been noted.! Ocular disturbances include the appearance of corneal deposits,2 but by far the most Goodman, L. S., Gilman, A. The Pharmacological Basis peutics; p. 1175. New York, 1955. 2. Hobbs, H. E., Calnan, C. D. Lancet, 1958, i, 1207.
Spironolactone was supplied by Dr. G. R. Venning, of G. D. Searle & Co. Ltd., and chlorthalidone by Dr. P. Birkett, of Geigy Pharmaceutical Co. Ltd. Without the willing cooperation of our patients we should have been unable to carry out this trial. REFERENCES
Conway, J., Lauwers, P. (1960) Circulation, 21, 21. Dollery, C. T., Harington, M., Kaufman, G. (1959) Lancet, i, 1215. Douglas, A., Hall, R., Horn, D. B., Kerr, D. N. S., Pearson, D. T., Richardson, H. (1961) Brit. med. J. ii, 206. Dustan, H. P., Cumming, G. R., Corcoran, A. C., Page, I. H. (1959) Circulation, 19, 360. Hall, R., Owen, S. G. (1959) Lancet, i, 129. Juel-Jensen, B. E., Pears, M. A. (1960) Brit. med. J. i, 523. Laragh, J. H. (1960) The Clinical Use of Aldosterone Antagonists; p. 180. Oxford.
Ulick, S., Januszewicz, V., Deming, Q. B., Kelly, W. G., Lieberman, S. (1960) J. clin. Invest. 39, 1091. McQueen, E. G., Morrison, R. B. I. (1960) Lancet, i, 1209. Ross, E. J. (1961) Brit. med. J. i, 1508. Sturvevant, F. M. (1958) Science, 127, 1393. Varnauskas, E., Cramér, G., Malmcrona, R., Werkö, L. (1961) Clin. Sci. 20, 407. Winer, B. M. (1958) Circulation, 18, 800. -
serious of these is the
Communication
ANTICIPATION OF CHLOROQUINE
1.
We are most grateful to Mr. W. Brown for technical assistance; the Nuffield department of clinical biochemistry for estimating blood-urea levels; and to the staff of the pharmaceutical department, to
of Thera-
rare occurrence of a retinopathy.3—7 The onset of retinopathy is sudden. The patient may notice a variety of visual disturbances, and though there may be a slight recovery of function if the drug is withdrawn in the acute stage, very considerable retinal damage Indeed the -condition may occurs and is irreversible. slowly progress: in one of our cases visual function is still slowly declining several years after withdrawal of the drug. The rarity of the complication and the generally accepted value of chloroquine justify its continued use, in spite of the severity of this side-effect. 4 cases of chloroquine retinopathy have been investigated at the electrodiagnostic clinic of the’ Institute of
Ophthalmology. They were characterised by complete absence of the electroretinogram (E.R.G.) and by a grossly abnormal extraoculogram (E.O.G.). The results
are
reported in detail elsewhere 6; they
striking that it seemed worth screening small number of patients who were receiving long-term therapy with chloroquine to determine whether any electrophysiological abnormality could be detected before the onset of visual disturbances. The test employed, the E.o.G., is a new electrodiagnostic method based on the measurement of changes in the comeofundal potential of the eye. The way in which the test is carried out is shown schematically in fig. 1. Electrodes similar to those used in the E.E.G. are placed on the skin on either side of the orbit. As the eye moves, the potential difference between the eye alters, because the globe is electrically polarised, as shown in the figure. The excursion of the recording pen depends upon the angle through which the eye rotates, and upon the size of the comeo-fundal potential. In practice, the subject makes alternating eye movements between two neon fixation lights. Since the eye movements are of constant amplitude, minute-to-minute changes in the measured potential reflect changes in the magnitude of the corneo-fundal potential itself. were so a
Fig. 1-Basis of the extraoculogram. Left: Schematic eye and position of electrodes. The electrical polarisation of the globe and the lines of current flow are shown. When the eye rotates the relative potentials of the two electrodes alter. Right: Graph showing variation of potential in a normal clinical test. Closed circles indicate eye in darkness. Note potential falls to dark trough level (arrow). On subsequent reillumination potential rises to peak (arrow). Inset are sample records.
3.
Hobbs, H. E., Sorsby, A., Freedman; A. ibid. 1959, ii, 478. 4. Hobbs, H. E., Eadie, S. P., Somerville, F. Brit. J. Ophthal. 1961, 45, 284. 5. Ellsworth, R. J., Zeller, R. W. Arch. Ophthal. N.Y. 1961, 66, 269. 6. Arden, G. B., Fojas, M. R. ibid. 1962 (in the press). 7. Ormrod, J. N. Brit. med. J. 1962, i, 918.
obese diabetic patients, who yet excrete large amounts of glucose, makes it unlikely that glycosuria per se is responsible for high pyruvate excretion in insulin-requiring diabetics. This excretion was at first thought to be due to exogenous insulin, since the insulin-requiring diabetics were the only subjects to have received this foreign protein ; but intravenous insulin did not alter pyruvate excretion in either healthy subjects or insulin-requiring obese diabetics. It is also unlikely that the excessive urinary pyruvate is a non-specific result of osmotic diuresis, or is due to altered pH of the urine; the rates of urine-flow and the urinary pH were similar in the three groups. There was no consistent alteration in a-oxoglutarate excretion. Differences like those seen with pyruvate might have been expected if the latter reflected only a non-specific derangement of kidney function. Takanami et al. (1960) found more a-oxoglutarate in the urine of diabetics than in that of healthy subjects; we cannot account for the difference between our results and theirs, although we used different methods. It is now more widely recognised that the clinical syndrome of diabetes mellitus cannot be attributed solely to insulin deficiency, even in those patients whose need for exogenous insulin is absolute. The excessive urinary excretion of pyruvate by many in this category (Lawrence 1951) suggests that they have a defect of carbohydrate metabolism which is not controlled by insulin. Further tests of pyruvate metabolism may lead to other biochemical criteria for differentiating the clinical types of
diabetes.
Summary and Conclusions In healthy, obese diabetic, and insulin-requiring diabetic subjects, pyruvate, a-oxoglutarate, and glucose were measured enzymatically in blood and urine, before and after ingestion of glucose, with and without insulin. Insulin-requiring diabetics, deprived of exogenous insulin, did not show the normal rise in blood-pyruvate concentration after taking glucose. When insulin was given as well, they showed a rise greater than that in healthy subjects and obese diabetics treated similarly. Insulin-requiring diabetics lost, on average, five times more pyruvate in the urine than did healthy or obese diabetic subjects. This loss was unrelated to the bloodpyruvate concentration and could not be corrected by exogenous- insulin. There were no consistent differences in the metabolic behaviour of a-oxoglutarate in the three groups of
subjects studied. suggest that some insulin-requiring diabetics have, besides an abnormality of glucose metabolism, an abnormality of pyruvate metabolism which is not corrected by insulin. This may be important for the biochemical separation of various forms of diabetes. Those results
We are grateful to Sister Betty, Sister Gweneth, and Sister Maureen for valuable help in ensuring the success of these investigations. One of us (J. A.) wishes to thank the Diabetic Association for a grant in support of part of the work. REFERENCES
Anderson, J., Marks, V., Smith, M. J. H. (1961) Lancet, i, 1325. Butterfield, W. J. H., Thompson, R. H. S. (1957) Clin. Sci. 16, 679. Lawrence, R. D. (1951) Brit. med.J. i, 373. Marks, V. (1959) Clin. chim. Acta, 4, 395. (1961) ibid. 6, 724. Miller, M., Craig, J. W., Drucker, W. R., Woodward, J. H. (1956) Yale J. Biol. Med. 29, 335. Moorehouse, J. A. (1959) J. lab. clin. Med. 54, 927. Smith, M. J. H., Taylor, K. W. (1956) Brit. med. J. ii, 1035. Takanami, A., Ohya, S., Goto, Y. (1960) TohokuJ. exp. Med. 72, 163. -
THE EFFECTS OF SPIRONOLACTONE AND CHLORTHALIDONE ON ARTERIAL PRESSURE
W. I. CRANSTON M.D. Aberd., M.R.C.P. FIRST ASSISTANT
B. E. JUEL-JENSEN M.A., B.M. Oxon., Cand. med. Copenhagen ASSISTANT
DEPARTMENT OF THE REGIUS PROFESSOR OF RADCLIFFE INFIRMARY, OXFORD
MEDICINE,
SPIRONOLACTONES may reduce arterial pressure in patients with hypertension (Sturvevant 1958, Laragh 1960), and diuretics of the benzothiadine type clearly do so (Hall and Owen 1959, Juel-Jensen and Pears 1960), though the mechanism responsible is uncertain. The plasma-volume is reduced during the 1st week or so of treatment with chlorothiazide (Dollery et al. 1959, Dustan et al. 1959, Conway and Lauwers 1960); but when chlorothiazide has been given for more than 3 weeks, no significant change in plasma-volume has been found (Winer 1958, Conway and Lauwers 1960), and the cardiac output tends to increase (Conway and Lauwers 1960)., There is thus a probable decrease in peripheral resistance at rest. Even during the early phases of treatment with chlorothiazide and chlorthalidone, hypertensive patients show a lower peripheral resistance during exercise (Varnauskas et al. 1961). Our present observations were made in an attempt to decide the relative potencies of chlorthalidone, whose properties are similar to those of the benzothiadiazine diuretics (Douglas et al. 1961), and spironolactone; -to assess their effect when given together; and to determine, so far as possible, whether they act in a similar way. Methods
Observations were made on three women and seven men with moderate arterial hypertension, aged from 43 to 69 years: In none was there any evidence that the hypertension was secondary. Two patients (cases 1 and 7) had previously had hypotensive drugs. Case 7 had in the past been in congestive cardiac failure, which had been relieved by treatment, and at the time of the study the patient was not taking digitalis. Case 4 had sustained a retinal-vein thrombosis. None of the others had retinopathy. All the patients were at work except one (case 10), who had retired. The relevant facts about these cases are shown in the table. Each patient was seen weekly for a total of 27 weeks.
At each attendance the patient was weighed, and the arterial pressure was measured with a sphygmomanometer twice in the lying position and twice in the standing position by the same observer. The figures recorded are the mean of at least six readings. During the first 3 weeks, while they became accustomed to the routine, all the patients were given inert tablets. Thereafter they received, for 6 weeks each, the following four combinations of tablets:
Spironolactone (’Aldactone’, Searle)
500 mg.
daily
with
chlorthalidone (’ Hygroton ’, Geigy) 50 mg. daily. Spironolactone 500 mg. daily with dummy chlorthalidone tablets.
Dummy spironolactone tablets with chlorthalidone 50 mg. daily. Dummy spironolactone and dummy chlorthalidone tablets. The order of administration of the combinations was randomised and unknown to both patients and observers;
1162
All
STUDIES ON TEN CASES are the mean of at least six
blood-pressure figures
the patients were told that they would be given inert tablets at some time. During each 6-week period, three blood samples were taken for estimation of urea and electrolytes: Urea was measured by autoanalyser (’ Technicon ’), sodium
potassium by flame photometry, and chloride by potentioDuring the 4th or 5th week of each 6-week period, the plasma-volume was measured, using 1311 human serumalbumin in a dose of 2-3 {loC. Blood was withdrawn without stasis 15 minutes after the intravenous injection of iodinated albumin and then centrifuged, and the radioactivity of the plasma was counted. An identical amount of radioactive iodinated albumin was made up to 1 litre in alkali, to act as a standard. The plasma and standards were counted, to a total of 1 x 104 counts, in a well-scintillation (’ Panax ’) counter. As the investigation involved patients who were at work, it was not practicable to measure electrolyte balances: No dietary restrictions were issued, and no supplementary potassium was given. So that they would not be influenced by this knowledge, the serum-potassium levels were not made known to the observers. It was arranged that if any patient’s serum-potassium fell below 3 mEq. per litre the observer would be informed, and the patient withdrawn from the trial. In the event, this never happened. and
meter.
Results The effects on arterial pressure are shown in the table: The control level represents the average arterial pressure during the 6-week period when dummy tablets were given. The fall of pressure during the treatment periods is expressed as the difference between the control pressure and the average pressure during the appropriate period. There was much variability of response, and in some patients the difference between the control pressures and the pressure on drugs was not
significant.
Over the entire group, all three treatment regimes did cause -significant falls of arterial pressure (variance ratio 4-57, p < 0-01); these were unrelated to the order in which the drugs were given (variance ratio 1-41, p > 0-2):
Spironolactone caused an average fall in systolic pressure of (s.E.±5-4) mm. Hg, and a fall in diastolic pressure of 5-9 (s.E. ±2-3) mm., measured in the lying position. Chlorthalidone caused an average fall of 16-4 (s.E. ±8) mm. Hg systolic and 9-1 (s.E. ±3-2) diastolic; and the two drugs together produced a fall of 25-8 (s.E. ±3-7) mm. Hg systolic and 9-2 (s.E. ±2-3) 16.7
readings
diastolic. In
general, the standing pressure was reduced a little than the lying pressure. Patients tended to respond in the same way to chlorthalidone and to spironolactone when these were given alone. The fall of diastolic pressure with chlorthalidone was highly correlated with the fall with spironolactone: for the lying pressures r =0-837, P < 0’01; for the standing pressures, r=0.946, P < 0-001. Urea levels are more
represented by the expression Mean
level
urea
during control period/ mean
urea
during period x
level
treatment
100
because, if it is assumed
that
the
nitrogen balance is unchanged, this expression provides an
indication of the
change in
urea-
clearance. This factor is termed the
approximate ureaclearance, and is expressed as a percentage of the control value. In all three treatment periods, the approximate
Fig. 1—The relation between the effects of chlorthalidone and spironolactone on
diastolic arterial pressure, in the
standing position. Each point represents the response of one patient.
urea-clearance
fell significantly. The fall the average was 91.6%
least with chlorthalidone, where (s.E.±2-9%) of the control value. During treatment with spironolactone and with a combination of the two drugs, the average values were respectively 84-9 (s.E.3’1) and 81-4 (s.E.:3’6%) of the control values. The plasma-potassium fell by an average of 0-63 (S.E.±0.13) mEq. per litre when the patients received chlorthalidone. Spironolactone caused a mean rise of 0-40 (S.E.±0.14) mEq. per litre; both changes were significant at the 2% level. When both drugs were given together there was an insignificant rise of 0-17 (s.E.0-16) mEq. per litre. Plasma-chloride levels decreased by an average of 30 (S.E.±0.8) mEq. per litre in patients receiving chlorthalidone; was
1163 relative effects of pharmacologically differing hypotensive agents when given in this way. The combination of spironolactone and chlorthalidone caused a greater fall of arterial pressure than did either agent given alone, but this effect was small. When both were given together, the plasma-potassium levels were satisfactorily maintained, though it is impossible to draw conclusions about the total potassium pool. The dose of chlorthalidone in this trial was relatively small, for it was hoped that the need for potassium supplements would not arise; but larger doses of chlorthalidone seem more potent in reducing arterial pressure: Casual blood-pressure readings have been made on twentytwo clinic patients who were taking chlorthalidone in doses of 50
daily, with potassium supplements: eight patients having daily showed a mean fall of arterial pressure of 21-3+6-4 mm. Hg systolic and 10432 diastolic; fourteen patients taking chlorthalidone 100 mg. daily showed a mean arterial pressure fall of 50056 mm. Hg systolic and or
100 mg.
50 mg.
25-6+7-8 diastolic. We do not know whether spironolactone will maintain the potassium balance in patients taking larger doses of chlorthalidone; if it does so, such a combination might be effective in the treatment of fairly severe hypertension. Evidence from the diuretic response of patients given chlorothiazide and spironolactone suggests that potassium supplements may be needed (Ross 1961). But the present high cost of spironolactone is a valid argument against its long continued use in hypertension, unless the benefits are
unequivocal.
Fig. 2- The effects of spironolactone and chlorthalidone on plasmapotassium, plasma-volume, and approximate urea-clearance (see text). Each point represents the response of one patient.
"
"
1.3 (S.E.±1.1) mEq. per litre in patients receiving spironolactone ; and 1.7 (S.E.±0.7) mEq. per litre in patients receiving both drugs. No significant changes were detected in the
serum-sodium levels.
Plasma-volume, expressed as millilitres per kilogramme, did show significant change during any of the treatment periods. There was a small average fall of 1.2 (S.E.±2.2) ml. per kg. during treatment with spironolactone. Chlorthalidone caused an average rise of 1.4 (S.E.±1.3) ml. per kg.; and both drugs together produced a fall of 1-3 (S.E±1.4) ml. per kg. There was no significant change in the hmmatocrit values. The average weight loss was 1-6 kg. during treatment with spironolactone, 1-2 kg. during treatment with chlorthalidone, and 2-8 kg. with both drugs. not
Only one patient (case 5) had any symptoms during the She noticed slight oedema of the ankles when spironolactone combined with chlorthalidone was replaced by dummy tablets. This was associated with a weight gain of 3-2 kg. The cedema disappeared within a week, and her weight fell by 1 kg. during treatment with dummy
trial.
tablets. Discussion Both
spironolactone and chlorthalidone
are
capable
of
causing reduction of arterial pressure in patients with moderate hypertension. The doses employed were about equally active in this respect. Comparison with results previously obtained in this department (Juel-Jensen and Pears 1960) suggests that chlorthalidone 50 mg. daily has about the same effect on arterial pressure as chlorothiazide 750 mg. daily. The blood-pressure responses to spironolactone and to chlorthalidone were closely related; but we cannot conclude that these drugs act through the same mechanism, because there is no good evidence about the a
Plasma-volume was not significantly reduced in patients receiving either diuretic for 4 or 5 weeks. This agrees with the findings of Conway and Lauwers (1960) in patients taking chlorothiazide. Though a reduced plasma-volume may contribute to the initial fall of arterial pressure when diuretics are given, it does not explain the sustained fall. The fall of diastolic arterial pressure was significantly related to the control level of diastolic pressure, both when spironolactone was given (r= -0743, p < 0.02) and when chlorthalidone was given (r= +0-760, P < 0-02). A similar significant relationship is apparent for chlorothiazide—r=+0-736, P<0.02 from the figures of Hall and Owen (1959), and r=+0-571, p<0.05 according to and The Pears (1960). Juel-Jensen systolic pressure fall was unrelated to the control level of systolic pressure. McQueen and Morrison (1960) found no relation between the arterial pressure fall and the initial level of arterial pressure, but this may have been because they used the mean arterial pressure rather than the diastolic level, or because their patients were only observed for 3 days. The importance of this finding is at present unknown. Blood-urea was increased in all the treatment groups. " We have chosen to express this as a decrease in approximate urea-clearance ", on the assumption that nitrogen balance is unaltered. This cannot be proven, but it seems a reasonable assumption since the trial was conducted in a double-blind fashion. Using this convention, spironolactone caused a slightly greater reduction in approximate clearance than did chlorthalidone, and both drugs together caused a further decrease. When all treatment periods are considered together, there is no correlation between the approximate urea-clearance and the diastolic arterial pressure and plasma-volume, if the latter two are expressed as percentages of the control value (variance ratio 0-64, p > 0-2). This trial was performed on patients with moderate hypertension. Our conclusions may not be valid in the case
1164
of malignant hypertension, where there is some evidence of increased aldosterone production (Laragh et al. 1960).
Summary
Radcliffe Infirmary.
Chlorthalidone 50 mg. daily, and spironolactone 500 mg. daily, were given separately and in combination to ten patients with mild or moderate hypertension, in a doubleblind trial. Both drugs caused small decreases in arterial pressure; there was a significant correlation between the responses to the two agents. In combination, the hypotensive effect was only slightly greater than that of either drug alone. Plasma-volume was not significantly affected by either drug or by the combination. Chlotthalidone caused a significant decrease in plasma-potassium, and spironolactone a significant increase; when both were given together, the plasma-potassium did not differ significantly from the control values. Both drugs, alone and in combination, caused increase of blood-urea. The change of urea-clearance was unrelated to changes in diastolic arterial pressure or plasma-volume.
Preliminary
RETINOPATHY
CHLOROQUINE (7-chloro-4( - 4 - diethylamino-1 - methyl butylamino) quinoline) and its hydroxyl derivative (’ Plaquenil ’), originally developed as antimalarial agents, are now widely used in the treatment of arthritis and in various skin conditions. Often the drug is used in higher dosage than is needed to ensure trypanosomicidal action, and is administered for months, even for years. Several side-effects have been noted.! Ocular disturbances include the appearance of corneal deposits,2 but by far the most Goodman, L. S., Gilman, A. The Pharmacological Basis peutics; p. 1175. New York, 1955. 2. Hobbs, H. E., Calnan, C. D. Lancet, 1958, i, 1207.
Spironolactone was supplied by Dr. G. R. Venning, of G. D. Searle & Co. Ltd., and chlorthalidone by Dr. P. Birkett, of Geigy Pharmaceutical Co. Ltd. Without the willing cooperation of our patients we should have been unable to carry out this trial. REFERENCES
Conway, J., Lauwers, P. (1960) Circulation, 21, 21. Dollery, C. T., Harington, M., Kaufman, G. (1959) Lancet, i, 1215. Douglas, A., Hall, R., Horn, D. B., Kerr, D. N. S., Pearson, D. T., Richardson, H. (1961) Brit. med. J. ii, 206. Dustan, H. P., Cumming, G. R., Corcoran, A. C., Page, I. H. (1959) Circulation, 19, 360. Hall, R., Owen, S. G. (1959) Lancet, i, 129. Juel-Jensen, B. E., Pears, M. A. (1960) Brit. med. J. i, 523. Laragh, J. H. (1960) The Clinical Use of Aldosterone Antagonists; p. 180. Oxford.
Ulick, S., Januszewicz, V., Deming, Q. B., Kelly, W. G., Lieberman, S. (1960) J. clin. Invest. 39, 1091. McQueen, E. G., Morrison, R. B. I. (1960) Lancet, i, 1209. Ross, E. J. (1961) Brit. med. J. i, 1508. Sturvevant, F. M. (1958) Science, 127, 1393. Varnauskas, E., Cramér, G., Malmcrona, R., Werkö, L. (1961) Clin. Sci. 20, 407. Winer, B. M. (1958) Circulation, 18, 800. -
serious of these is the
Communication
ANTICIPATION OF CHLOROQUINE
1.
We are most grateful to Mr. W. Brown for technical assistance; the Nuffield department of clinical biochemistry for estimating blood-urea levels; and to the staff of the pharmaceutical department, to
of Thera-
rare occurrence of a retinopathy.3—7 The onset of retinopathy is sudden. The patient may notice a variety of visual disturbances, and though there may be a slight recovery of function if the drug is withdrawn in the acute stage, very considerable retinal damage Indeed the -condition may occurs and is irreversible. slowly progress: in one of our cases visual function is still slowly declining several years after withdrawal of the drug. The rarity of the complication and the generally accepted value of chloroquine justify its continued use, in spite of the severity of this side-effect. 4 cases of chloroquine retinopathy have been investigated at the electrodiagnostic clinic of the’ Institute of
Ophthalmology. They were characterised by complete absence of the electroretinogram (E.R.G.) and by a grossly abnormal extraoculogram (E.O.G.). The results
are
reported in detail elsewhere 6; they
striking that it seemed worth screening small number of patients who were receiving long-term therapy with chloroquine to determine whether any electrophysiological abnormality could be detected before the onset of visual disturbances. The test employed, the E.o.G., is a new electrodiagnostic method based on the measurement of changes in the comeofundal potential of the eye. The way in which the test is carried out is shown schematically in fig. 1. Electrodes similar to those used in the E.E.G. are placed on the skin on either side of the orbit. As the eye moves, the potential difference between the eye alters, because the globe is electrically polarised, as shown in the figure. The excursion of the recording pen depends upon the angle through which the eye rotates, and upon the size of the comeo-fundal potential. In practice, the subject makes alternating eye movements between two neon fixation lights. Since the eye movements are of constant amplitude, minute-to-minute changes in the measured potential reflect changes in the magnitude of the corneo-fundal potential itself. were so a
Fig. 1-Basis of the extraoculogram. Left: Schematic eye and position of electrodes. The electrical polarisation of the globe and the lines of current flow are shown. When the eye rotates the relative potentials of the two electrodes alter. Right: Graph showing variation of potential in a normal clinical test. Closed circles indicate eye in darkness. Note potential falls to dark trough level (arrow). On subsequent reillumination potential rises to peak (arrow). Inset are sample records.
3.
Hobbs, H. E., Sorsby, A., Freedman; A. ibid. 1959, ii, 478. 4. Hobbs, H. E., Eadie, S. P., Somerville, F. Brit. J. Ophthal. 1961, 45, 284. 5. Ellsworth, R. J., Zeller, R. W. Arch. Ophthal. N.Y. 1961, 66, 269. 6. Arden, G. B., Fojas, M. R. ibid. 1962 (in the press). 7. Ormrod, J. N. Brit. med. J. 1962, i, 918.