ACTION OF DIURETIC AGENTS
E. G. MCQUEENM.B. Sydney, M.R.C.P., F.R.A.C.P.
SENIOR LECTURER IN CLINICAL PHARMACOLOGY
R. B. 1. MORRISONM.B. N.Z., M.R.A.C.P.
MEDICAL RESEARCH OFFICER
DEPARTMENT OF MEDICINE,- UNIVERSITY OF OTAGO,DUNEDIN, NEW ZEALAND
THE synthesis of chlorothiazide (6-chloro-7-sulphamyl-1,2,4,-benzothiadiazine-l, I-dioxide) provided clinicianswith a powerful oral diuretic agent (Novello and Sprague1957). Its main action appears to be interference withtubular reabsorption of sodium and chloride (Beyer et al.1957), together with mild inhibition of carbonic anhydrase.This results in a marked increase in the urinary excretionof sodium and chloride, and a decrease in the excretion ofpotassium and bicarbonate.The diuretic potency of chlorothiazide was demon-
strated clinically (Ford et al. 1957) and later found tocompare favourably with the activity of the parenteralorganic mercurial diuretics (Ford et al. 1958, Bayliss et al.1958).Almost simultaneous investigations (Hollander and
Wilkins 1957, Freis and Wilson 1957, Tapia et al. 1957)revealed that chlorothiazide was a valuable hypotensiveagent, both alone and in combination with other hypo-tensive drugs. This has been confirmed on a number ofoccasions (Heider et al. 1958, Barnett and Marshall 1958,Wilkins 1958, Hall and Owen 1959). Evidence as to themode of action of chlorothiazide in hypertension is
conflicting. In nonoedematous hypertensive patientslowering of the blood-pressure has been associated witha reduction in the amount of extracellular water andsodium (Wilson and Freis 1958); but this was not con-firmed by Winer (1958), and other investigators think thatthe drug may have an additional specific effect (Wilkins1957, Hollander et al. 1959). A reduction in plasma-volume has also been shown to accompany enhancementof the activity of ganglion-blocking drugs (Dustan et al.1959, Dollery et al. 1959).A more recent analogue-hydrochlorothiazide-has
been found to be between ten and twenty times as
potent a diuretic agent as chlorothiazide (Richterich 1958,Ford 1959, Fleming et al. 1959, Moyer 1959). This
dosage ratio appears to be applicable also to their hypoten-sive actions (Vertes and Sopher 1959, Smirk et al. 1959).The present study was designed to illustrate the relation
between the diuretic and the hypotensive effects of chloro-thiazide and hydrochlorothiazide in noncedematous hyper-tensive patients. The effects of the two drugs werecompared with those of the mercurial diuretic, mersalyl.More detailed observations, including plasma-volume andthiocyanate-" space " estimations, were made in a smallergroup of patients receiving hydrochlorothiazide.
The subjects were hypertensive patients without evi-dence of heart-failure. Most were outpatients and allwere on a free diet with an uncontrolled sodium and fluidintake. Before admission to the trial, each patient wasfamiliarised with the staff and procedures, includingmultiple blood-pressure recordings, employed at the clinic.Five recordings of the blood-pressure were made in the
sitting and standing postures between 9 A.M. and 12 noon.The mean pressure was obtained by summing the systolic anddiastolic readings and dividing the total by 10. The alterationsin blood-pressure are actual changes and not percentages ofthe initial level. The patient had been receiving placebotablets, and when the blood-pressure appeared stable threetwenty-four-hour urine samples were collected and the initialmean blood-pressure recorded. The diuretic was then givenfor three days during which further twenty-four hour urinesamples were collected. Mean blood-pressures were recordedon days 1 and 3.The dosage schedules were: chlorothiazide 0’5 g. twice daily,
hydrochlorothiazide 50 mg. twice daily, mersalyl 2 ml. daily.In 11 patients the plasma-volume, thiocyanate space, packed-
cell volume, serum sodium and potassium, and weight, weremeasured before, and seven days after, the addition of hydro-chlorothiazide.
In a further group of 19 patients comparison was madebetween hydrochlorothiazide and mersalyl.The plasma-volume, and extracellular-fluid estimations
were carried out in the fasting patient at 8.30 A.M. Estimationsof plasma-volume were performed using azovan blue B.P.(Evans blue U.S.P.) according to the method described bySteinbeck (1950), collecting serial blood samples over a periodof sixty minutes and calculating zero time by a mathematicalextrapolation.
Thiocyanate space was estimated on samples withdrawn 120,125, and 130 minutes after administration of approximately20 ml. of a 5% solution of sodium thiocyanate.
Syringes were weighed before and after injection of bothazovan blue and thiocyanate.The creatinine clearance determinations were performed in
duplicate, using Owen’s (1954) method of estimating the trueplasma-creatinine level.The initial heights and weights were recorded and the
surface area calculated from the nomogram of Dubois andDubois. The creatinine clearance, together with alterationin urinary volume and electrolyte excretion, in plasma-volume,and extracellular-fluid space, have all been expressed in unitsper sq. m. surface area. /
The basal blood-pressure was recorded during sedation withpentobarbitone as recommended by Smirk (1957). The supple-mental blood-pressure was derived from the differencebetween the basal pressure and that observed in the clinic.
Observations were made on the hypotensive anddiuretic activity of chlorothiazide in 16 patients, hydro-chlorothiazide in 30, and mersalyl in 16. After treatmentwith any of these drugs for three days, there is a reductionin blood-pressure (shown in table i together with the
average increase in renal elimination of water, sodium,and potassium during three days’ treatment). The blood-pressure changes after one day’s treatment were similarbut smaller.There was no significant difference between the blood-
pressure fall produced by chlorothiazide or hydrochloro-thiazide and that produced by mersalyl. Nor was there a
TABLE I-EFFECT OF THREE DAYS’ TREATMENT WITH CHLOROTHIAZIDE,HYDROCHLOROTHIAZIDE, AND MERSALYL ON BLOOD-PRESSURE ANDAVERAGE INCREASE IN EXCRETION WATER, SODIUM, AND POTASSIUM
* The figure for the potassium excretion is relatively high because of onepatient in whom mersalyl induced an average increase in excretion of28 mEq. per day.
significant dif-ference betweenthe increase inwater and so-dium excretion
produced by anyof these agents.
would be ex-
pected, had a
much smallereffect on potas-sium excretionthan eitherchlorothiazide or
hydrochloro-thiazide. Withthe latter two
drugs no differ-ence in potas-sium loss couldbe detected.
Although a fall in blood-pressure was evident witheach diuretic agent, analysis of regression did not demon-strate a significant relation between this fall and theincrease in fluid, sodium, or potassium excretion, or
between blood-pressure fall and initial blood-pressure.In 13 patients comparison of the effects of hydrochloro-
thiazide and mersalyl at the same blood-pressure level waspossible, 7 receiving hydrochlorothiazide first and 6
mersalyl first. (6 other patients had to be excluded becausethe blood-pressure did not return to its original levelswithin a practicable time. The effects of a three-daycourse may be apparent for as long as three weeks.) Theeffects of the two chemically dissimilar diuretic agentson the fall in blood-pressure and the increase in water andsodium excretion are compared in figs. 1-3. With both
drugs a high degree of correlation between these twoeffects is seen in every case. It seems that, for the indivi-dual patient, a characteristic diuretic response is accom-panied by a characteristic blood-pressure response.The relation of the blood-pressure response to altera-
tions in plasma-volume and extracellular fluid (measuredby the thiocyanate space) was studied in a further 11
patients before and after a week’s treatment with hydro-chlorothiazide. (One thiocyanate reading was discardedfor technical reasons.) Except for 1 patient in whom theplasma-volume increased slightly, all showed a reductionin plasma-volume. However, the fall in blood-pressure
Fig. 2-Comparison of the average daily diuresis (ml. per sq. m.surface area) following 3 days’ treatment with mersalyl (2 ml.daily) and with hydrochlorothiazide (100 mg. daily). r=080.
Fig. 1-Comparlson of falls in blood-pres-sure after 3 days’ treatment with mersalyl(2 ml. intramuscularly daily) and with
hydrochlorothiazide (100 mg. daily).r=0-69.
did not correlate significantly with the plasma-volumecontraction.
All patients showed a reduction in thiocyanate space.When the fall in blood-pressure was plotted against thisdecrease (fig. 4), a probably significant relationship wasapparent. The individual values for initial blood-pressureand blood-pressure fall, reduction of plasma-volume andof thiocyanate space, fall in body-weight and reduction ofsurface area, are shown in table 11. The correlationsbetween (a) the reduction in plasma-volume and thio-cyanate space (r==0’72, p=0-02) and (b) the reduction inthiocyanate space and body-weight (r=0’84, 0.01 >p >
0’001) seem to confirm the validity of the methods
employed.The serum-sodium level, although varying in some
cases, did not show the overall reduction seen with the
serum-potassium. Some haemoconcentration can beinferred from the increase in packed-cell volume (table in).
Fig. 5 shows the alteration in the blood-pressure in 5patients following infusion of 6% salt-free dextran in a
Fig. 3-Comparison of the average daily increase in sodiumexcretion (mEq. per sq. m. surface area) following 3 days’ treat-ment with mersalyl (2 ml. daily) and with hydrochlorothiazide(100 mg. daily). r=O’81.
quantity the same as the estimated reduction in plasma-volume. Immediately after this infusion, the blood-
pressure returned to approximately its pretreatment value.As the three diuretic agents in the dosage given
appeared to have comparable hypotensive activity, thewhole group was considered together, and the relation ofblood-pressure fall to various other factors was examined.There was no correlation between blood-pressure fall and
either initial blood-pressure, or basal blood-pressure. However,there was a quite significant (0’05 > P > 0’02) correlationbetween the fall and the " supplemental " blood-pressure.Blood-pressure fall was not significantly related to age orweight.There was no correlation between the blood-pressure fall
and the creatinine clearance. But, somewhat surprisingly,there was a highly significant negative correlation between thecreatinine clearance and the increase in fluid excretion(p < O’OOl). This was contributed to mainly by’ the mersalylgroup (P< O’OOl), the hydrochlorothiazide and chlorothiazidegroups having non-significant negative regression coefficients.The urine pH rose both with chlorothiazide and with hydro-
chlorothiazide-more with the former-but did not altersignificantly with mersalyl. As there is no concise method ofgrouping these results, the values have not been included.
Chlorothiazide has established itself as a potent oraldiuretic agent of very low toxicity. When used for
TABLE II-RELATION BETWEEN BLOOD-PRESSURE DROP FOLLOWING ONE WEEK’S TREATMENT WITH HYDROCHLOROTHIAZIDE (50MG. TWICE DAILY) AND DIMINUTION IN PLASMA-VOLUME, EXTRACELLULAR-FLUID VOLUME, AND BODY-WEIGHT
removing oedema fluid from patients with hypertensive’ heart-failure, it was found also to lower the blood-pressure.
Considerable hypotensive activity was then demonstratedin nonoedematous hypertensive patients; and chloro-
thiazide, together with its recently synthesised and morepowerful analogue hydrochlorothiazide, has since provedTABLE III-EFFECT OF ONE WEEK’S TREATMENT WITH HYDROCHLORO-THIAZIDE (100 MG. DAILY) ON THE SERUM SODIUM AND POTASSIUMAND THE PACKED-CELL VOLUME (11 PATIENTS)
i i I
very useful in the management of high blood-pressure(Smirk et al. 1959).The relation between the diuretic and hypotensive
effects of these drugs has a possible bearing on thepathogenesis of hypertension. The present study showsthat their reduction of blood-pressure is not significantlyrelated to the increase in excretion of water, of sodium,or of potassium. This might suggest that they have aspecific hypotensive action in addition to their diureticaction. However, the organic mercurial mersalyl can beseen to have an entirely comparable effect. When thehypotensive responses of the individual patient to hydro-chlorothiazide and to mersalyl were compared, theyresembled each other closely and were associated withvery similar increases in excretion of water and sodium.
Though different people seem to differ widely in theirresponse to diuretic agents, the same person respondsin much the same way to different agents.
Fig. 4-Correlation between blood-pressure fall (mm. Hg) anddecrease in the extracellular fluid (thiocyanate space: litres persq. m.) following 7 days’ treatment with hydrochlorothiazide(100 mg. daily). r=O.72.
Wilkins et al. (1958) demonstrated the hypotensiveaction of intravenous mercaptomerin, and the same grouphave published (Hollander et al. 1959) data which agreewith our own observations-namely, that in hypotensivepatients whose blood-pressure fell with mercurial diureticsit also fell with chlorothiazide.
A sharp diminution of plasma-volume (Dustan et al.1959, Dollery et al. 1959) and of plasma-volume and extra-cellular-fluid volume (Wilson and Freis 1958) has beenrecorded after administration of chlorothiazide. But areturn to pretreatment values was noted after long-continued therapy (Wilson and Freis 1958): indeed aftersix to eight weeks Winer (1958) could find no significantchanges either in the plasma and extracellular-fluid
volumes, or in the total exchangeable sodium and totalbody-water. Similarly Murphy (1950) found no relationbetween the fall in blood-pressure and the reduction inplasma-volume caused by a low-salt diet.
After seven days’ treatment with hydrochlorothiazidewe found a reduction in plasma-volume in 10 out of 11hypertensive patients. However the regression of blood-pressure fall on decrease in plasma-volume was not
statistically significant.On the other hand relating blood-pressure fall to reduc-
tion in thiocyanate space (10 cases) gave a regressioncoefficient (r=0-63-8 d.f.-0-1 >p> 0-05) indicating aprobably significant relationship. The modification ofsuch additional factors as tissue turgidity might perhapsaccount for this result.
In 4 patients restoration of pretreatment blood-volumeby infusion of dextran also restored the blood-pressure tonear pretreatment levels.
It seems likely, then, that in an individual hypertensivepatient reduction in plasma-volume may produce a
Fig. 5-Fall in blood-pressure in five patients after 7 days’ treatmentwith hydrochlorothiazide (100 mg. daily), and response to infusionof salt-free dextran to replace the measured reduction in plasma-volume.
characteristic fall in blood-pressure, but that when agroup of patients are examined the reduction in plasma-volume is not strictly related to the hypotensive response.That restoration of blood-volume with dextran infusions
can abolish the sensitising effect of chlorothiazide onganglion-blocking agents has been shown in both hyper-tensive (Dollery et al. 1959) and normotensive subjects(Wanko and Freis 1958).The validity of the plasma-volume and thiocyanate-space
estimations was attested by the significant relations between thereduction of each and between fall in total body-weight and thereduction in thiocyanate space.Taking all three diuretic groups together, no significant
correlation was observed between the hypotensiveresponses and the severity of the hypertension as suggestedby the basal blood-pressure or the height of the initialpressures. There did appear, however, to be a correlationbetween the hypotensive response and the " supple-mental" blood-pressures-i.e., the difference betweenthe " casual " (in this case the initial) and the " basal "
blood-pressures. This suggests that the fraction of the
blood-pressure affected by diuretic agents is that super-added by the patients’ reaction to the environment at thetime the pressure is measured (Smirk 1957) ratherthan the fundamental or basal hypertensive state.
There was no correlation with the patients’ age or
weight.To sum up, it seems likely that chlorothiazide and
hydrochlorothiazide reduce the blood-pressure in hyper-tensive patients by their diuretic action, and that thereduction of blood-pressure is a characteristic response ofthe individual to diuresis rather than to a particular drug.The fall in blood-pressure induced by diuresis is broughtabout, at least in part, by reduction in plasma-volume,supplemented perhaps by concomitant diminution intissue fluids.
Additional evidence against a specific hypotensive effect ofchlorothiazide is provided by animal experiments (E. G. M.,unpublished) which did not show any vasodepressor effect inperfused rat hindquarter or isolated arterial strip preparations.Much interest is being taken in the comparative potency
of chlorothiazide and hydrochlorothiazide. Our resultssuggest that with the dosage used (chlorothiazide 1 ’0 g.per day, hydrochlorothiazide 0-1 g. per day) there is nopractical difference in their efficacy either in reducing theblood-pressure or in increasing the renal excretion ofwater, sodium, or potassium in the nonoedematous hyper-tensive patient. Other investigators have pointed out thathydrochlorothiazide has less effect on pH and bicarbonateexcretion. The action of mersalyl (2 ml. daily) is similarexcept that it has little effect on potassium excretion.However the considerable loss of potassium in one patientconfirms the observations of Cort and Matthews (1954)that serious depletion may occasionally be induced by theorganic mercurial diuretics. After three days’ treatmentwith any of three powerful diuretic agents the blood-pressure may take one to three weeks to return to pre-treatment levels.
It is of interest that, within the considerable range ofrenal function in our patients, the hypotensive responseswere not related to the creatinine clearance. Evenmore surprising, perhaps, was the significant inverserelation of creatinine clearance to fluid excretion, seenparticularly in the mersalyl group. No similar relationwas evident between creatinine clearance and sodiumexcretion.
SummaryChlorothiazide, hydrochlorothiazide, and mersalyl were
found to produce equivalent hypotensive responses ina group of nonoedematous patients.
In the group as a whole there was no significant relationbetween the fall in blood-pressure and the increase in therenal excretion of water, sodium, and potassium. In theindividual patient, however, the fall in pressure corre-
sponded to the increase in the renal excretion of waterand sodium, whether this was produced by mersalyl orhydrochlorothiazide.There appeared to be a significant relation between the
fall in blood-pressure and the reduction in the extra-
Lowering of blood-pressure was also associated witha reduction in plasma-volume, and in individual patientsrestoration of plasma-volume with salt-free dextranrestored the blood-pressure approximately to the pre-treatment levels for that patient.
In doses of 1 g. and 100 mg. per day respectively,chlorothiazide and hydrochlorothiazide had closelyequivalent effects on electrolyte excretion.We wish to acknowledge the encouragement and advice of Sir
Horace Smirk. One of us (R. B. 1. M.) receives a grant from theMedical Research Council, New Zealand.The chlorothiazide used was supplied by Messrs. Merck Sharp
& Dohme and the hydrochlorothiazide by Ciba Ltd., Basle.
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"... It is not for disease or diseases in the abstract thatprovision has to be made; but for persons liable to or sufferingfrom disease. The first essential for the proper and efficienttreatment of individual persons is, therefore, not institutionalbut personal service, such as can be rendered to the people intheir own homes only by a family doctor who has the con-tinuous care of their health, to whom they will naturally turnfor advice and help in all matters pertaining tlfereto; who willafford them such professional services as he can render per-sonally ; and who will make it his duty to see that they obtainfull advantage of all the further auxiliary services that may beotherwise provided."-Report to Scottish Board of Healthfrom its Consultative Council on Medical and Allied Services.1920.