Chlorothiazide as an adjunct in the treatment of essential hypertension

Chlorothiazide Treatment

as an Adiunct

of Essential

MARVIN MOSER,

T

I;ypertension*

F.A.C.C. and ALICE I. MA~UJLAY,

M.D.,

Valhalla,

New York

HE recent synthesis of an orally effective, potent diuretic agent, chlorothiazide’ (Di-

specific

uril),

presented

an opportunity

effect of prolonged

to judge

“salt depletion”

of employing

drastic

Preliminary

without

dietary

firmed

re-

alone

and

in combination

whether

continuous

diuretic

pressure control

can be achieved

to results obtained

retic agent2 Pharmacologic have

revealed

diuretic

therapy

and whether

agent

crease in the urinary sium, and chloride.3,4 to drug action ministration

produces excretion

on a long-

of this agent

when

sures of hypertensive diet (Table

an antihypertensive more specific

in-

conjunction

of sodium, potasad-

administered

to that

was added

of 91 hypertensive

four years.

to other presently Preliminary alone

and

Side

and

oral diuretic

on the

in combination

with

have

have been

(Inversine),

is

All of these patients

specific

been

minimal

of es-

and

who had

a

new

of

drugs,

mecamylamine ganglionic blocking

methosulfate,

desig-

as foilows with regard hypertensive

ing

severity

to

of their

I or IA; to IIIA;

previously takes

THE

disease:

34, Grade II or IIA; 34, and 16, Grade IV, accordpublished into

AMERICAN

criteria.’

consideration

* From the Cardiac Clinic, Department of Medicine, Grasslands Hospital, Valhalla, N. Y. ported by a grant-in-aid from the Merck Sharp & Dohme Laboratories, West Point, Pa. 214

rauwolfia

to the

classification

no

had been on

nated WY 1395.’ Patients were classified 22, Grade Grade III

encouraging.ss6

(Apresoline), or

trimethidinium

agent,

effect agents.

more

to the treatment

individuals

therapy with one or a combination

hydralazine

use of this agent

drugs in the treatment

hypertension effects

mercurials

available

reports

antihypertensive sential

inhibitors

in its sodium-depleting

or in

been followed for periods of from six months to

(Diamox) 1. The potency of compares favorably with that of

superior

agents,

with a low sodium diet.

two or more of the following:

parenterally

blood pres-

used with the

blocking

ics such as the

generally

chloro-

a minimal

who had pre-

drug when

continuous

[acetazolamide chlorothiazide

had

and were on a normal

autonomic

Chlorothiazide regimen

of tolerance

anhydrase

individ-

I).

which is noted after other orally effective diuretcarbonic

conchlo-

For this reason it was believed that chlorothiazide would be most effective as

is a potent

as compared

alone,

individuals

viously been untreated

a diu-

on continued

that

alone in doses of be-

effect on both systolic and diastolic

blood

a marked

reports

series of 15 patients utilized

in this manner

No evidence

has developed

utilized

without

chlorothiazide

which

when

In an additional thiazide,

studies in animals and humans that

in our clinic

published

uals, has little or no effect upon blood pressure.

specific

better

observations

tween 0.5 to 1.5 g a day in normotensive

drugs in an effort to determine

term basis is feasible as compared

with

has thus far been reported.

previously

rothiazide,

During the past year 106 patients have been studied and treated with chlorothiaantihypertensive

M.D

CASE MATERIAL AND METHOD

striction. zide

“toxicity”

the

on the course

of the patient with essential hypertension the necessity

in the

This fundu-

This study was sup-

JOURNAL

OF CARDIOLOGY

Moser

and

Macaulay

TABLE Blood Pressure Response Number of cases

215

I to Chlorothiazide .%veragr blood pressure change

Average blood pressure before addition of ~ chlorothiazide”

Average blood pressure after addition of chlorothiazidet

15

174/108

159/100

~

-15i-8

plus chlorothiazidc

39

184/112

166/98

~

-18-14

Hydralazine Reserpinc plus chlorothiazide

17

170/102

156/94

-14;

154/85

-2O/-16

.__..._~~~~ Chlorothiazide Rauwolfia

alone

Mecamylamine Hydralazine Reserpint plus chlorothiazide

~

35

I

174/101

-8

Total * Represents blood pressure after prolonged therapy with drugs other than chlorothiazide. t Average duration of therapy, 7 months.

scopic findings, renal

disease,

and duration Thirty-five

as well as evidence progression

of the disease. patients were \-aried between

given in two divided doses. given

initially

with

nitrogen

retention

(reserpine

or Raudixin)

a gan-

already

of dosage

after

if blood pres-

In patients

chlorothiazide

with

was started

been lowered

addition

in

be reduced

after chlorothiazide

factory

chloride

revealed

that most patients were

approximately

3 to 4 g of sodium

daily on this regimen.

OK BLOOD

reserpine

Results

of average

hypertensive

drugs

after chlorothiazide

blood alone

pressures

and

blood

on antipressures

was added to the treatment

regimen

are given in Table

reported

were maintained

I.

Most

patients

on chlorothiazide for Some blood presfrom six months to one year. sure reduction degree patients FEBRUARY,

occurred

of lowering

in all groups,

was significant

\vho had previously 1959

alone,

(0.25

but the

only in those

been on rauwolfia

to withdraw ganglionic In 3 patients a satis-

it was necessary

or in combination

to 0.50

were permanently

mg daily)

and the more

to continue

or Raudixin potent

ganglionic

patients

when

sodium

intakes

daily).

Results

be reported CASE

agent

they

maintained

1 g of sodium

in this group

who

as a blood

was greater

were

(under

in com-

intensive therap)

with more potent drugs. The potency of chlorothiazide lowering

blocking

drugs in patients

might have required

pressure

drugs

blood pressure con-

with chlorothiazide

with rauwolfia

b) with

In two cases

discontinued.

In several instances

drugs.

ordinarily

PRESSURE

hypotension

blood pressure level was maintained

bination

EFFECTS

agents had to

to avoid

drugs was made.

trol was achieved

RESULTS

to the

was added.

(100 mg per day),

dium excretion

blocking

In 5 cases an attempt blocking

prior

In many cases the

significantly

normal

diet with the exception that no salt was Intermittent evaluation of soto food.

by therapy

dosage of the ganglionic

chlorothiazide

ingesting

with other drugs.

of chlorothiazide.

doses of 0.25 g twice daily and reduced if azoPatients were maintained on a temia increased. added

or on ganglionic

blocking agents in combination

0.5 and 1.5 g daily Larger doses were

reduction

\vas achieved.

alone

It should be noted that blood pressure levels had receiving

the first week or two of treatment sure control

or

if any,

Dosage of chlorothiazide

glionic blocking agent. administered

of cardiac

of symptoms,

in several on low chloride

of patients

will

elsewhere.*

HISTORIES

The following cases illustrate the use of chlorothiazide in combination with other drugs.

216

Chlorothiazide

in Hypertension

Fig. 1. Case 1. A 43-year-old man with severe essential hypertension. Excellent response of blood pressure to addition of chlorothiazide to mecamylamineRaudixin regimen. Note prompt rise in blood pressure when chlorothiazide is withdrawn.

CASE 1. A 43.year-old white male who had been treated for severe essential hypertension for three years with ganglionic blocking drugs in combination with Raudixin had experienced a satisfactory drop in blood pressure, although normotensive levels had never been achieved. Figure 1 illustrates the results of the addition of chlorothiazide, 0.5 g twice daily, to treatment. Dosage of mecamylamine (Inversine) has been reduced from 32 mg daily to 17.5 mg since the addition of chloroSide effects have decreased following this thiazide. reduction of dosage. Note the rise in blood pressure within 36 hours after chlorothiazide is withdrawn and the fall in pressure within 24 to 36 hours after the drug is readministered (Fig. 1). Normotensive blood pressure levels have persisted on combination chlorothiazidemecamylamine-rauwolfia therapy. CASE 2. A 4%year-old white male with progressive hypertension had noted dyspnea on exertion for several weeks. Blood pressures varied between 220/140 and ‘25O/lGO. On combination therapy with chlorothiazide, reserpine, and mecamylamine an excellent blood pressure and symptomatic response was noted within two to three days (Fig. 2). An attempt to control blood pressure without mecamylamine failed and combination therapy has now been continued with good results for six months. OTHER EFFECTS

OF CHLOROTHIAZIDE

A marked diuresis and weight loss of between

two and three pounds were noted in all patients with few exceptions

during the first three days of

therapy

with chlorothiazide.

urinary

output

Six patients

and

After that

weight

complained

usually

of nausea

time,

stabilized. and a bitter

taste in the mouth during the first month or so of treatment. tinuation

Nausea of the

was accentuated to the regimen ing agents.

disappeared

drug.

after

Postural

after chlorothiazide of patients

was added

on ganglionic

agent was reduced. In

Serum Electrolyte Changes:

two

with renal failure and a “salt losing” before the use of chlorothiazide, was

noted

block-

This, however, tended to disappear

as the dosage of the blocking

potassium

discon-

hypotension

and after

progressive the

excessive loss of

nitrogen

drug

patients syndrome

was

retention

administered.

In contrast, patients with normal or only slightly impaired renal function showed little change in serum sodium, potassium, prolonged

chlorothiazide

and chloride administration.

decrease in serum electrolytes

levels on Some

was noted initially

but these stabilized on continued therapy. For this reason, in patients who were able to maintain a reasonably good diet, supplemental potasTHE AMERICANJOURNAL OF CARDIOLOGY

217

Moser and Macaulay

190 I85 I80 /75 170 I65 I60

I50 145 140 155

7

/25 I.?0 115 110 105 100 95 90 I234567

6

9

IO

II

/z

13

14

‘5

16

17

18

I9

PO

21

Fig. 2. Case 2. A 48-year-old man with grade III essential hypertension. Blood pressure contro1 achieved only by combination of mecamylamine,reserpine, and chlorothiazide. Note blood pressure rise again after withdrawal of mecamylamine. sium

was not added to treatment

experience. rich

after our initial

Extra orange juice and other foods

in potassium

In patients

were

advised

in all cases.

who were on poor diets 1 to 3 g of

extra potassium

were administered

daily in the

form of potassium chloride or Potassium Triplex. It may be assumed that a decrease lar potassium longed

could

occur

chlorothiazide

in intracellu-

in patients

therapy

despite

serum levels and/or lack of clinical electrolyte depletion

depletion.

Possible

upon renal tubular

on pronormal

symptoms

effects

of

of this

cells, especially

Complete

blood

hematologic skin

reactions

“allergic”

could

necessary. In the

Urinary

retention

occurred

in several

in the 45 to 60 age group.

of

these patients presented obvious evidence of prostatic hypertrophy. No definite arrythmias the use of chlorothiazide Skin Rash: or

Three

petechial

E‘ERRTTARY. 1959

rashes

could be attributed

to

in our group of patients.

patients developed while

on

macular

chlorothiazide.

represent

these

a “toxic”

or

three

who received

diabetic

hypertensive

chlorothiazide

no definite

hyperglycemic

this association

change

are

patients

for long periods was noted.

of

Possible

effects of this agent are presently

under investigation.

in

male

None

any

to reveal

Although

or disprove

kCUSSION

patients with renal disease, must be watched for. patients

failed

response to the drug, further observa-

tions to prove

time

studies

abnormalities.

It

is apparent

chlorothiazide

from

these observations

possesses a significant

that

blood pres-

sure lowering effect when combined with more specific antihypertensive agents. This effect occurs ance date.

in a high percentage to drug effect The

following

absence

of cases and toler-

has not been of significant

observed

to

side effects

the use of this drug and the fact that

in Hypertension

Chlorothiazide

218 other

more

potent

agents

with

result when chlorothiazide ment

regimen

in the moderately Marked

to be necessary

of hypertensive of salt would

when chlorothiazide restriction

is used conwhen mod-

is continued, allowThis allows for a pal-

ing 2-4 g sodium daily. atable

not appear

Best results are obtained

sodium

patients

severe to severe group.

restriction

tinuously. erate

is added to the treat-

suggest that this drug will be of

value in the treatment

diet.

Dosage

of chlorothiazide

is standardized

does not require the persistent changing justments

necessary

agents

and

used.

It would

servations

when

other,

from

blocking drugs

are

preliminary

ob-

that 0.75 to 1 g a day is a satisfactory

dose in most hypertensive higher

and

and ad-

ganglionic

antihypertensive

appear

doses

(1.5

individuals,

g a day)

may

although

be necessary

during the first week of treatment. The antihypertensive would

appear

and the resultant though

other

result

changes

more

actions

may exist quite apart

effect.

Although

been

reported

chlorothiazide,

low

from its saluretic

potassium

levels

the continued

especially

in patients

been our experience

al-

antihypertensive

following

disease and congestive of hypertensive

of loss of salt

in blood volume,

specific

heart

failure,

have use of

with renal it has not

to observe this in most cases

renal failure.

cardiovascular disease without Potassium levels should be care-

fully observed

in all patients

and should be intermittently

with renal disease checked during the

first two to three weeks of chlorothiazide ment this

in all patients. time,

therapy means,

that

the

We

at

of potassium

to

is necessary, in most

other than by dietary Hypertensive patients cases.

on therapy pills and,

are already taking a large number of if possible, additional medication If weakness occurs, or if should be avoided. potassium levels are noted to fall, the addition of potassium

chloride

in 4 divided

by mouth

(2 to 4 g daily

doses) or Potassium

Triplex

(4 cc

four times daily) will usually control symptoms or signs. Patients receiving digitalis and chlorothiazide

should

supplements.

always

be

given

is a potent, orally efwhich produces a

Chlorothiazide

diuretic

continuous

effect

side

diuretic

effects.

pressure been

in

with

not

in the

noted when

with other

sive drugs, such as the rauwolfia

blood

has

alone

of cases, but is frequently

zine, and the ganglionic

in

individuals

chlorothiazide

the drug is combined

significant

reduction

hypertensive

noted

majority

without

Significant

antihypertendrugs, hydralaOptiagents.

blocking

mal doses range from 0.5 to 1.5 g daily in two divided doses. (2)

Nausea,

weakness,

and skin rashes these

are

Severe

electrolyte

present

only

ever,

following

renal

failure

electrolyte

and

depletion,

the only side effects;

occasionally

of

disturbances

are noted,

chlorothiazide those

significance. how-

in patients

on low sodium

with diets.

The drug should be used with care in patients The mode of action

(3)

hypertension ability

potassium

of chlorothiazide

most probably

to increase

depends

sodium excretion

in

upon

its

and reduce

blood volume. (4)

It

represents treatment

would

appear

an important of the

that

advance

hypertensive

chlorothiazide in the modern patient.

This

drug would appear to potentiate the effects of In many cases of severe disease it other drugs. may be possible aged” compound blockers

to substitute

this “easily

man-

for the more potent ganglionic

without loss of blood pressure lowering

effect.

treat-

do not believe,

addition

(1)

fective nonmercurial

with renal failure.

action of chlorothiazide

to be the

SUMMARY

side reactions

may be reduced in dosage without loss of clinical

REFERENCES H. F., and HAIMBACH, A. S. : Chlorothiazide (6-chloro-7 sulfamyl1,2,4-benzothiadiazine-l,l dioxide) : The enhancement of sodium chloride excretion. Fed. PIOG.16 : 282, 1957.

1. BEYER, K. H., BAER, J. E., Russo,

2. MOSER, M.,

MACAULAY, A.

TROUT, K. W.

: Drug

I.,

GRANZEN, R.,

therapy of hypertension.

and II.

Xew York J. Med. 56: 2487, 1956. 3. BEYER, K. H.: The mechanism of action of chlorothiazide. Ann. New York Acad. SC. 71: 363, 1958. 4. FORD, R. V., ROCHELLE, J. B., HANDLEY, C. A., MOYER, J. H., and SPURR, C. L.: Choice of a diuretic agent based on pharmacological principles. J.A.M.A. 166: 129, 1958. 5. FREIS, E. D., WANKO, A., WILSON, I. M., and PARRISH, A. E.:

Treatment

of essential hypertension

THE AMERICAN JOURNAL OF CARDIOLOGY

Moser and Macaulay with chlorothiazide (Diuril). J.A.M.A. 166: 137, 1958. 6. WILKINS, R. W.: New drugs for hypertension with special reference to chlorothiazide. New England J. Mfd. 257: 1026, 1957. 7. JORDAN. .4., MACAULAY, A. I., and MOSER, M. : Pre-

FEBRUARY, 1959

219

liminary observations on a new ganglionic blocking agent: Trimethidinium methosulfatc (WU 1395). In preparation. 8. MACAULAY, .4. I., JORDAN, A., and MOSER, M.: Exprrience with chlorothiazide in hypertension. To be published.