Drugs 30: 469-474 ( 1985)
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How Dangerous Are Diuretics?
Edward D. Freis and Vasilios Papademetriou
Veterans Administration and Georgetown University Medical Center, Washington

Two major concerns that have been raised
against the use of diuretics are: (a) diuretic-induced
hypokalaemia may predispose to dangerous ar-
rhythmias including sudden death (Kolata, 1982);
and (b) long term diuretic use may cause an in-
crease in serum cholesterol and thus an increased
risk of arteriosclerosis, including coronary artery
disease (Grimm et al., 1981).

Diuretics have provided the basic regimen for
treating hypertension for many years and have
served as the primary treatment in most of the
controlled trials demonstrating the effectiveness of
treatment. Although most physicians still believe
that treatment for hypertension usually should be-
gin with a thiazide diuretic, others are apt to try
alternative regimens, This is due primarily to an
increased concern with the potential risks of di-
uretic-induced hypokalaemia. These concerns re-
sulted initially in a dramatic increase in the admin-
istration of potassium supplements or potassium-
sparing diuretics, the cost of which in the USA to-
talled $250 million in 1981 alone (Harrington et
al.. 1982). Recently, because of fear of toxicity some
physicians. especially in Scandinavia, have re-
duced the doses of hydrochlorothiazide to as low
as 6.25 or 12.5 mg/day (e.g. Andrew et al., 1983;
Berglund and Anderson, 1976).

Diuretics are the only known antihypertensive
agents which lower blood pressure by reducing salt,
water and extracellular fluid volume (Freis, 1976).
Recent controlled trials indicate that when given
as the sole treatment thiazide diuretics control

blood pressure in approximately half of the pa-
tients treated (Veterans Administration Coopera-
tive Study Group, 1982a,b,c, 1983), and in 85% of
those given a diuretic plus a step-two drug (Edi-
torial, 1977; Freis, 1976). Because they are effec-
tive, and certainly the least expensive of the anti-
hypertensive agents, the validity of the charges
against them needs to be carefully examined.

1. Diuretics and Hypokalaemia
1.1 Relationship Between Dose, Volume
Depletion and the Antihypertensive Effects of
Diuretics

There is a close association between volume re-
duction and the antihypertensive response to the
diuretics. It has been known for many years that
diuretics cause a moderate reduction in extracel-
lular fluid volume and plasma volume, approxi-
mating 10 to 15% (Dustan et al., 1959; Wilson and
Freis, 1959). This effect, although moderate, ap-
pears to play a major role in the reduction of blood
pressure (Dustan et al., 1959; Freis, 1976). Volume
loss occurs during the first 3 or 4 days of contin-
uous treatment with diuretics after which no fur-
ther volume depletion occurs (Freis, 1976; Papa-
demetriou et al., 1984a). The net reductions in fluid
volume are reflected in loss of bodyweight which
approximates 1 to 2kg (Papademetriou et al., 1984a;
Wilson and Freis, 1959). With respect to hydroch-
lorothiazide, doses of 50 mgJday were required to
produce weight loss in most patients whereas lower


How Dangerous are Diuretics?                                                 470

doses of 25 or 12Smg did not result in significant
weight loss (McGregor et al., 1983). Thus, in many
patients, doses smaller than 50 mg/day would not
be sufficient to lower volume effectively and prob-
ably blood pressure as well.

The antihypertensive effectiveness of long term
drug therapy is often difficult to assess. Because of
spontaneous decreases in blood pressure such stud-
ies need to be carefully controlled. Following re-
peated visits to the clinic, blood pressure often re-
verts back to normal levels without any drug
treatment (Carey et al., 1976; Management Com-
mittee Australian Therapeutic Trial in M'ild Hy-
pertension, 1982), and without proper controls it
may be impossible to differentiate spontaneous and
drug-induced reductions in blood pressure.

A few studies have suggested that when low
doses of hydrochlorothiazide are given with a @-
blocker the dose-response curve becomes flat after
6.25 or 12.5 mgfday of hydrochlorothiazide (An-
drew et al., 1983; Berglund and Anderson, 1976).
However, it is difficult to judge the effectiveness
of one drug when it is combined with another, es-
pecially when there is no control evaluation of
either drug used alone (Andrew et al., 1983).

On the other hand there is considerable evi-
dence to indicate that the antihypertensive re-
sponse to hydrochlorothiazide alone does not be-
come flat at low levels but rather continues to
increase to quite high doses of the diuretic. For ex-
ample, in the Veterans Administration Coopera-
tive Study, propranolol alone was compared with
hydrochlorothiazide alone in patients with mild
hypertension. Doses of hydrochlorothiazide were
titrated as needed from 25mg twice daily to 50mg
twice daily and finally to IOOmg twice daily until
the diastolic blood pressure was controlled to
<90mm Hg (Veterans Administration Cooperative
Study Group, 1982a,b). Of the patients controlled
on hydrochlorothiazide alone, 50% attained the goal
diastolic pressure with the 25mg twice daily dose.
However, 30% required the 50mg twice daily dose
and 20% needed 1OOmg of the diuretic twice daily
before their diastolic blood pressure fell to
<90mm Hg. These doses are far in excess of the
6.25 or 25mg recommended by others.

Studies other than the Veterans Administration
trial have found that the dose-response curve of
hydrochlorothiazide also does not remain flat after
small doses, and that doses as high as 100 mg/day
are required in many patients (Anderson et al.,
1984; Henning et al., 1980). It would appear from
these results that different patients vary in their
responsiveness to the diuretics and that while small
doses are satisfactory in some patients they are in-
adequate in others. As with most antihypertensive
agents, the optimal dose of a diuretic is probably
best found by individual titration.

1.2 Diuretic-Induced Hypokalaemia and
Ventricular Arrhythmias

Reluctance to employ standard doses of diuret-
ics in treating patients with uncomplicated essen-
tial hypertension derives primarily from the pos-
sibility that diuretic-induced hypokalaemia may
predispose to the development of life-threatening
or even fatal ventricular arrhythmias (Kolata, 1982;
Multiple Risk Factor Intervention Group, 1982).

Contrary to popular opinion, diuretic-induced
hypokalaemia is not associated with a major loss
of total body potassium. The hypokalaemia is lim-
ited almost exclusively to the extracellular com-
partment. Review of various studies indicates that
during continuous thiazide treatment, losses of body
potassium approximate only a biologically unim-
portant 5 to 7% of the total body content (Kassirer
and Harrington, 1977). These small losses are in
contrast to changes in extracellular potassium.
which is reduced by about 20%. Because potassium
concentrations within the cells are much greater
than in extracellular fluid, large changes in extra-
cellular potassium may exert only a small influence
on total body potassium. The large difference be-
tween extra- and intracellular potassium levels is
maintained by sodium-potassium metabolic pump
activity (Haddy and Pamnami, 1984).

Whether selective extracellular hypokalaemia
without significant change in intracellular potas-
sium, such as occurs with diuretic-induced hypo-
kalaemia, predisposes to increased risk of ventric-
ular arrhythmias is not known. Although adequate


How Dangerous are Diuretics?                                                   471

studies in experimental animals have not been per-
formed (Harrington et al., 1982) the electrophys-
lological changes associated with selective extra-
cellular hypokalaemia point towards a decreased
rather than increased incidence of cardiac arrhyth-
mias. According to the Nemst equation (Dyckner
and Wester. 1979: Papademetriou, 1983) an in-
crease in the intracellular/extracellular ratio which
occurs in diuretic-induced hypokalaemia causes
hyperpolarisation of the cell membrane. This raises
rhe depoiarisation threshold of the myocardium re-
sulting in decreased rather than increased suscep-
tibility of the heart to the development of arrhyth-
mias. Hyperpolarisation of the cell membrane,
however, may also raise conduction velocity which
under special circumstances such as ischaemia,
heart blocks or myocardial scars may either pro-
mote or retard re-entry phenomena. Regardless of
these theoretical considerations. an increase in the
ratio of intracellular/extracellular potassium of the
type associated with thiazide diuretics has not been
reported to produce life-threatening arrhythmias.

Diuretic-induced hypokalaemia may have dif-
fering physiological or pathological effects depend-
ing on the presence or absence of heart disease. For
example. in the presence of congestive heart failure
there may be a reduction in the intracellular con-
centration of potassium (Editorial, 1977). Local-
lsed changes in potassium may occur such as in
acute myocardial infarction where high concentra-
tions of potassium have been measured in the is-
chaemic zone (Hydegger et al., 1984). The elevated
concentrations of potassium are thought to be the
result of leakage of potassium from the injured cells.
The role of whether diuretic-induced hypokalae-
mia in these special situations has not yet been
clarified. This article, however, is not concerned
with these forms of heart disease, but rather with
the great majority of hypertensive patients who do
not have overt heart disease and whose intracell-
ular potassium content is apparently normal.

1.3 Hypokalaemia and Frequency of
Ventricular Arrhythmias

The most practical and direct way of determin-

ing whether diuretic-induced hypokalaemia pro-
duces disturbances in cardiac rhythm is to carry
out electrocardiographic monitoring. Using 48-hour
continuous ambulatory monitoring, no association
between hypokalaemia and the incidence of ven-
tricular arrhythmias was found by Papademetriou
et al. (1984b). Continuous electrocardiographic
monitoring was carried out in patients with mild
hypertension prior to any therapy and following
hydrochlorothiazide treatment for 4 weeks. Pa-
tients were separated into those who developed hy-
pokalaemia with thiazide therapy and those in
whom serum potassium concentrations remained
within the normal range. Following thiazide ther-
apy no change was noted in either the frequency
or severity of the arrhythmias in the patients who
became hypokalaemic or those who remained nor-
mokalaemic. Other investigators using continuous
electrocardiographic monitoring have confirmed the
above findings (Leif et al., 1984; Madias et al.,
1984). Further, in patients with overt hypokalae-
mia on long term diuretic therapy, administration
of potassium supplements and potassium-sparing
diuretics in amounts sufficient to raise serum po-
tassium levels to normal had no effect on ventric-
ular arrhythmias (Papademetriou et al., 1983).

A previous study by Holland et al. (I 98 1) using
electrocardiographic monitoring indicated that hy-
pokalaemia secondary to the thiazides did increase
the frequency and severity of ventricular arrhyth-
mias. The difference between Holland's results and
the more recent studies probably can be explained
by differences in methodology. Holland excluded
all patients who exhibited 6 or more ventricular
premature beats/hour during the control period
prior to thiazide administration. However, because
of the great day-to-day spontaneous fluctuation in
ectopic activity (Michelson and Morgenroth, 1980)
the chances of these selected patients showing
greater ectopic activity on the second (hypoka-
laemic) monitoring would be greatly enhanced
simply by chance alone. Other investigators who
did not select their patients on this basis found no
increase in arrhythmias associated with the devel-
opment of hypokalaemia (Leif et al., 1984, Madias
et al., 1984; Papademetriou et aL, 1984b).


How Dangerous are Diuretics?

472

Another previous study found an association  cause for an increase in cardiac deaths in a subgroup
between hypokalaemia and exercise-induced pre-   of patients with minor electrocardiographic abnor-
mature ventricular beats (Hollilield and Staton,   malities. However, there are several problems with
1981). The results are diflicult to interpret, how-   the interpretation of these data. The study was not
ever, for a number of reasons: (a) the correlations   designed to determine the relationship of cardiac
were based on only 2- to 5-minute monito~ng of  deaths with respect to treatment with thiazide di-
arrhythmias which may be insufficient to distin-   uretics. The relationship between thiazide diuretics
guish chance occurrence of ectopic beats from those   and sudden death was found after a retrospective
due to hypokaiaemia; (b) the clinical significance   search for correlations between many variables,
of exercise-induced premature beats and their   This kind of retrospective procedure often leads to
prognostic value is essentially unknown; and (c) the   positive correlations by chance alone. Therefore,
reproducibility of this method of assessing arrhyth-   evidence so derived must be confirmed by inde-
mias is very poor. This work has not been repeated   pendent studies. The results of other studies, how-
and remains unconfirmed.             ever, have not been confirmatory.

Additional concern with respect to diuretic-
induced hypokalaemia has been generated by the
recent observation that catecholamines which in-
crease entry of potassium into cells may further
aggravate the hypokalaemia resulting from treat-
ment with thiazides (Struthers et al., 1983). How-
ever, these studies have not demonstrated that the
hypokalaemia resulting from the combined effects
of the diuretic and ~t~holamines has any effect
on ventricular ectopic activity or that it increases
either the frequency or severity of ventricular ar-
rhythmias. As a result of catecholamine excess, po-
tassium moves mostly into skeletal muscle cells
with only minimal changes in potassium content
of myocardial cells. The catecholamine-induced
changes increase the ratio of intra- to extracellular
potassium and theoretically at least should make
the ventricle less rather than more susceptible to
development of arrhythmias. Although catechol-
amines are known to increase ventricular arrhyth-
mias they probably do so by other mechanisms than
reduction in extracellular potassium.

Available data from similar trials such as The
Hypertension Detection and Follow-up Program
(HDFP) failed to confirm the findings of MRFIT.
Thus, in HDFP no subgroup correlations were
found between thiazide treatment and cardiovas-
cular deaths (The Hypertension Detection and Fol-
low-up Program, 1984). The HDFP investigators
concluded that their results offered no support for
the hy~thesis raised in MRFIT that diuretics in-
crease the mortality rates of patients with resting
ECG abnormalities. The recently published mor-
bidity-mortality results of the Medical Research
Council Working Party (MRC Trial, 198.5) indi-
cated no significant differences between the effects
of bendrofluazide in the prevention of all-cause
mortality compared with propranolol (p = 0.24 and
0.71, respectively; cigarette smokers and non-
smokers combined). Furthermore, in none of the
studies (including MRFIT) has there been any cor-
relation between diuretic dosage, serum potassium
Ievels and deaths due to heart disease (Medical Re-
search Council Working Party on Mild to Mod-
erate Hy~~ension, 1983; MRFIT Trial, 1985).

1.4 Evidence from Clinical Trials

Most of the concern regarding the possible re-
lationship between thiazide-induced hypokalaemia
and sudden death has been generated by the results
of the Multiple Risk Factor Intervention Trial
(MRFIT) [Kolata, 1982; Multiple Risk Factor In-
tervention Trial, 19821. It was suggested that data
from MRFIT implicated thiazide diuretics as the

The Medical Research Council Working Party
on Mild to Moderate Hypertension (1983) re-
ported 2 substudies with electrocardiographic
monitoring. In one study without pretreatment
baseline monitoring an increased incidence of ven-
tricular ectopy occurred in hypertensive patients
during long term treatment with thiazides com-
pared to a group receiving only placebos. In this
subgroup, however, there was no correlation be-


How Dangerous are Diuretics?

473

tween arrhythmias and serum potassium level, al-   other studies which made only long term obser-
though there was a weak correlation with serum   vations on changes in plasma cholesterol. When
uric acid concentration. A second trial, better con-   serum cholesterol levels were measured 1 or 2 years
trolled, failed to confirm the first in that there was   after beginning treatment they were not elevated
no increase in arrhythmias during treatment with   in 2 studies (Amery et al., 1982; Kannel et al., 19771,
thiazide diuretics for a period of 8 to 10 weeks.    but were elevated in 1 (Goldman et al., 1980).

The available evidence, therefore, fails to sup-
port the view that in patients without heart disease
diuretic-induced hypokalaemia causes increased
ventricular arrhythmias. But, because of the undue
concern that has been generated, potassium re-
placement therapy has become widespread (Har-
rington et al., 1982), which if overdone could be-
come potentially dangerous (Lawson, 1974).

Thus, elevated serum cholesterol concentration
is not a risk during long term treatment with di-
uretics because the almost unanimous experience
has been that elevation is not persistent aRer 6
months or 1 year of treatment.

3. Summary and Conclusions

2. Diuretics and Serum Cholesterol

Serum cholesterol usually increases slightly when
thiazide diuretics are administered (Grimm et al.,
I98 1). Some investigators have expressed concern
that the elevation, even though slight, would over
a period of many years aggravate and accelerate
the development of coronary heart disease (Grimm
et al., 1981). This fear would have some justifi-
cation if it could be shown that the elevation of
serum cholesterol is indeed persistent. The avail-
able evidence, however, indicates that it is not.

Three studies have shown that expected initial
Increases in serum cholesterol levels were followed
later by reduction to or below the pretreatment lev-
els. One of these trials was carried out in a Vet-
erans Administration cooperative study in which
343 patients with mild hypertension received hy-
drochlorothiazide and no other drugs or dietary
treatment (Veterans Administration Cooperative
Study, 1982b). Plasma cholesterol rose during the
first 3 months of treatment but at 12 months the
cholesterol level fell to below baseline. Similarly,
Ucazar et al. (1982) also found that plasma cho-
fester01 only rose initialiy, and after 3 months re-
turned toward the pretreatment baseline, remain-
ing there for the next several years of observation.
Data taken from the HDFP also indicated that the
short term rise in plasma cholesterol was followed
by a long term return to baseline (Williams et al.,
1983). These observations are further supported by

The proposal that thiazide diuretics may in-
crease cardiovascular risk receives no support from
recent data. Current evidence does not indicate that
diuretic-induced hypokalaemia is associated with
increased ventricular ~hythmias. This evidence
includes continuous electrocardiographic monitor-
ing - which is the most sensitive technique for
quantitating cardiac arrhythmias. In contrast to
earlier reports, more recent studies found no evi-
dence for increased arrhythmias during the period
of hypokalaemia, or for decreased arrhythmic ac-
tivity after correction of hypokalaemia. Similarly,
studies claiming increased sudden death in pa-
tients on diuretic treatment have not been sub-
stantiated by the results of other large-scale trials.
Elevation of serum cholesterol concentrations
with thiazide appears to be a short term phenom-
enon since most studies indicate the elevation re-
verts to baseline during long term treatment.
Thiazide diuretics remain as one of our most
effective antihypertensive agents. Fears of their in-
creasing the incidence of ventricular arrhythmias
due to hypokalaemia, or constituting a risk factor
for atherosclerosis by elevating serum cholesterol
concentrations, appear largely unsubstantiated.

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Address for correspondence and reprinls: Dr .!Z&~ii D. F'~~`~~~
Hypertension Research, VA Medical Center. Washington. Dr.
20422 (USA).