Diuretics and Their Side Effects

Dilemma in the Treatment of Hypertension

MYRON H. WEINBERGER

SUMMARY Diuretics have traditionally been the keystone of antihypertensive therapy. A variety of
clinical trials, designed to examine the benefit of blood pressure reduction in decreasing morbidity and
mortality from hypertension-related cardiovascular disease, have surprisingly failed to show a de-
crease in coronary artery disease death rate, although other forms of vascular disease were impres-
sively reduced. These trials have consistently used diuretics as the initial therapeutic choice. Such
observations have stimulated a reevaluation of the "stepped-care" approach and a critical appraisal of
diuretic effects. This review examines the efficacy of diuretics in reducing blood pressure and attempts
to identify individuals most likely to respond to these agents. The side effects of diuretic therapy are
reviewed in hemodynamic, cardiac, metabolic, and symptomatic terms, but because some of these
aspects of diuretic or antihypertensive therapy are detailed elsewhere in this monograph, the present
discussion focuses on cardiac, metabolic, hemodynamic, and symptomatic effects. Finally, alternative
therapeutic options and guidelines for therapy are outlined.
(Hypertension 11 [Suppl UJ: H-16-II-20, 1988)

KEY WORDS • diuretics • potassium • lipids • glucose • arrhythmias

Background examine this question.2 Patients were randomly as-

signed to receive either placebo or a sequential thera-

U NTIL the late 1950s, the only therapeutic in-

tervention in hypertension directed toward
peutic approach beginning with a diuretic and then
adding antihypertensive agents (reserpine, hydrala-
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sodium excess was the Kempner "rice diet"1
or some modification thereof. This diet, which was
very low in sodium and protein and high in potassium,
was lifesaving in many patients with severe, acceler-
ated, or malignant hypertension, but it was impractical
for the majority of hypertensive patients to achieve or
maintain. The availability of diuretics,firstin the form
of organomercurials and then the sulfonamide-derived
chlorothiazide in the late 1950s, made it possible to
reduce extracellular fluid volume and sodium in hyper-
tensive patients without marked changes in dietary
habits and life-style or, indeed, much interruption of
their daily routine. With the advent of diuretics, the
treatment of hypertension became routine, and the next
challenge became the demonstration that blood pres-
sure reduction was beneficial to health.
Trials of Blood Pressure Reduction
A cooperative study based at several Veterans Ad-
ministration hospitals was organized and conducted to
From the Hypertension Research Center, Indiana University
School of Medicine, Indianapolis, Indiana.
Address for reprints: Myron H. Weinberger, M.D., Director,
Hypertension Research Center, 541 Clinical Drive, Room 409,
Indianapolis, IN 46223.
H-16
zine, and guanethidine) until a predetermined level of
blood pressure reduction was achieved. Both groups
were followed for several years to compare morbidity
and mortality of hypertension treated by placebo with
the active treatment. This study demonstrated a signifi-
cant reduction in both morbid and fatal events among
severe2 and moderate3 hypertensive patients receiving
active drug therapy compared with the placebo-treated
group. However, when the causes for morbidity and
mortality were compared between the groups, no dif-
ference in coronary artery disease was identifiable.
Longitudinal studies at Framingham, Massachusetts,
indicated that coronary artery disease has multiple
antecedents.4 In addition to hypertension, elevation of
cholesterol and glucose and cigarette smoking, as well
as increases in uric acid5 and left ventricular hyper-
trophy,6 were shown to increase the risk of cardiovas-
cular death in an additive or synergistic fashion. 456
More recently, this long-term study has suggested that
diuretic treatment of hypertension may itself be associ-
ated with sudden death in hypertensive patients.7
In the United States, Europe, and Australia, studies
were designed and conducted to examine the benefit of
intervention upon one or more of these cardiovascular
disease risk factors to determine whether their associ-
ated cardiovascular disease morbidity and mortality
 SIDE EFFECTS OF DRmETlCS/Weinberger
could be modified. One of the largest such trials, the
Multiple Risk Factor Intervention Trial (MRFTT),
compared a special intervention program attacking one
or more of three major risk factors to less-structured
community health care resources.8 The subjects were
selected because of the presence of one or more risk
factors: elevated blood pressure, cholesterol, or ciga-
rette smoking habit. Qualifying men were randomly
assigned to each group at multiple participating sites.
The special intervention group received behavior
modification designed to decrease cigarette smoking,
dietary counseling to reduce consumption of saturated
fats and, thus, lower their blood cholesterol levels, and
a stepped-care antihypertensive regimen modeled on
the VA Cooperative Study algorithm.2 Individuals in
the comparison group were referred to their usual care
resources and were followed in parallel for outcome
comparisons. Significant reductions in all three risk
factor levels were accomplished in the special inter-
vention group compared with those receiving usual
care. However, a reduction in death rate from coronary
artery disease was not discernible among the special
intervention group when compared to usual care. 8
These observations were confirmed by an Australian
trial that also failed to demonstrate a decrease in myo-
cardial infarction among diuretic-treated hypertensive
patients compared to those receiving placebo.9 An-
other large trial, the Hypertension Detection and Fol-
low-up Program (HDFP), which also used a diuretic-
first, stepped-care approach, appeared to have been
associated with a decrease in myocardial infarction.10
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However, when the high risk individuals in that study
were examined, rates similar to that of the MRFTT
study were reported." The failure to observe a de-
crease in heart attack rate in several trials has focused
attention on the impact of antihypertensive agents on
cardiovascular disease risk.
Diuretics constitute the most frequently prescribed
single class of drugs in the United States. The popular-
ity of diuretic therapy for hypertension in this country
has both a scientific and practical basis. The first large-
scale trial of the benefit of antihypertensive therapy,
the VA Cooperative Study,2 began treatment with
these agents and demonstrated an overall reduction in
morbidity and mortality in comparison with placebo. It
is important to recognize that the population participat-
ing in that study was not representative of the general
American hypertensive population. The VA patients
were almost exclusively men; the majority were over
age 40 and included a substantial proportion of black
individuals. These demographic characteristics often
favor sodium sensitivity13 and, hence, diuretic respon-
siveness of blood pressure. In contrast, studies have
shown that /9-blockers are equal or greater in efficacy
to diuretics among European hypertensive patients,12
an observation not observed among VA patients.14 The
practical advantage of diuretic therapy resides in its
cheap financial cost in comparison with other antihy-
pertensive agents. However, diuretics may have other
costs that are currently receiving considerable atten-
tion and scrutiny.
n-17
General Effects of Diuretics
Diuretics reduce blood pressure primarily by reduc-
ing extracellular fluid volume, although they may have
secondary effects of reducing pressor responsiveness
to vasoconstrictor agents and reducing sodium and
water content of vascular smooth muscle. When used
to excess or in individuals susceptible to volume deple-
tion, such as the elderly or those with impaired sympa-
thetic reflexes, or in conjunction with sodium restric-
tion, diuretics can cause orthostatic hypotension or
even cardiovascular collapse.15 The reduction in renal
blood flow secondary to volume depletion can pro-
duce oliguria and azotemia.13 Other consequences of
volume depletion may include lethargy and mental
confusion.
Metabolic Effects of Diuretics
Diuretics regularly induce a variety of metabolic
side effects. Hypokalemia is a consistent, dose-
dependent consequence of diuretic therapy that is di-
rectly related to volume-induced stimulation of the
renin-aldosterone system and the level of sodium in-
take. Diuretic-induced hypokalemia has been associat-
ed with a variety of undesirable consequences. Digital-
is toxicity is more frequent in the presence of
hypokalemia.16 Gastrointestinal disorders, including
constipation and paralytic ileus, are more apt to be
observed in hypokalemic subjects. Diuretic-induced
magnesium depletion also occurs in parallel with po-
tassium loss and exacerbates potassium loss in cardiac
muscle. This can modify the action potential of cardiac
myocytes and influence the threshold for arrhythmias.
Hypokalemia suppresses pancreatic insulin release
and, thus, predisposes to hyperglycemia or worsening
of existent diabetes mellitus. 1719 Diuretic-induced hy-
perglycemia does not appear to be a transient phenom-
enon since it persists with treatment for a year or
more.20 Hyperuricemia occurs secondary to a reduc-
tion in glomerular filtration rate and inhibition of uric
acid secretion because of competition from organic
acid-diuretic at the renal tubule. Volume depletion also
enhances proximal tubular uric acid reabsorption.
Thiazides and loop diuretics may produce hyponatre-
mia, particularly in the presence of dietary sodium
restriction, because of their actions to decrease free
water clearance. Enhanced proximal tubular calcium
reabsorption may lead to hypercalcemia. Diuretics can
reduce lithium clearance, thus increasing serum lith-
ium concentration and increasing the likelihood of lith-
ium toxicity. The MRFIT, 8 HDFP, 24 and VA Cooper-
ative Studies21 have demonstrated adverse effects on
serum lipids that persist for the duration of therapy up
to 6 years. 2 3 ' a These effects included increases in total
cholesterol, triglycerides, and low-density lipopro-
teins. Some have argued that these changes are transi-
tory since they return to baseline levels with continued
therapy. However, parallel placebo control groups
have demonstrated progressive declines in lipid levels
with long-term surveillance, 21 ' n and in other studies,
withdrawal of diuretic therapy after several years was
 11-18 ANTIHYPERTENSIVE DRUG EFFECTS SUPPL II HYPERTENSION, VOL 11, No 3, MARCH 1988
associated with a significant fall in serum lipids.23"25
Other studies suggest that significant changes in lipids
may only be seen in men.22
Potassium and Arrhythmias
The most worrisome effects of diuretic therapy have
revolved around hypokalemia and its relationship to
cardiac arrhythmias and sudden death. This interrela-
tionship is a complex one and may also involve chang-
es in magnesium content of plasma or cells. It has been
recognized that potassium can reverse digitalis-
induced arrhythmias.16 In one study of this problem
among hypokalemic patients, arrhythmias were ob-
served in 50%, and 25% were receiving digitalis.26
This is not surprising in view of the fact that extracellu-
lar potassium concentration is the primary determinant
of the cardiac action potential.16 In the Oslo Study,
diuretic treatment lowered blood pressure 17/10 mm
Hg compared with placebo, yet there was no difference
in the mortality rate between the two groups.n Among
Australian hypertensive patients, the mortality rate
among those treated with thiazide, presumably from
fatal myocardial infarction and sudden death, was
twice that of any other treatment group (placebo, di-
etary sodium restriction, and propranolol).27 The large
Medical Research Council trial reported an increased
frequency of ventricular ectopy among hypertensive
patients receiving thiazides when compared with pla-
cebo-treated patients.28 They also observed an inverse
relationship between ventricular ectopy and serum po-
tassium concentration and a direct relationship with
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age, inferring that older hypertensive patients were
more susceptible to thiazide-associated cardiac
arrhythmias.28
Diuretic treatment increases catecholamines.29
Some studies have suggested a relationship between
arrhythmias and such increases. Certainly pathological
states associated with increased catecholamine release,
such as some forms of essential or accelerated hyper-
tension, acute myocardial infarction, asthmatic at-
tacks, and alcohol or narcotic withdrawal symptoms,
have demonstrated increased susceptibility to cardiac
arrhythmias and sudden death in the presence of hypo-
kalemia and diuretic therapy. Indeed, catecholamines
themselves, acting by the /32-adrenergic receptor, are
capable of rapidly lowering serum potassium.30'3I Pre-
sumably the cardiac protective effects of nonselective
/3,- and /32-blockade are due, at least in part, to their
ability to preserve potassium levels.
Recent studies have demonstrated ventricular ec-
topy in 33% of asymptomatic hypokalemic hyperten-
sive patients that was reversed by increasing the serum
potassium concentration.32 Other investigators have
shown an increase in cardiac arrhythmias in hypokale-
mic patients during exercise33 or in the presence of
known coronary artery disease.34 Curry et al.33 have
reported an association between "torsade de pointes,"
a hypokalemia-related ventricular tachycardia, and
quinidine. It must, however, be emphasized that not all
investigators have confirmed an increased incidence of
arrhythmias with diuretic therapy.36"38 Studies in ani-
mals have also been conflicting. One study demon-
strated an increase in malignant arrhythmias after myo-
cardial infarction in diuretic-treated dogs given a low
potassium diet compared with dogs not receiving di-
uretic treatment.39 Another study did not observe in-
creased myocardial irritability in response to electrical
pacing in diuretic-treated dogs that were not subjected
to coronary artery ligation.40
In the presence of an acute myocardial infarction,
cardiac arrhythmias and sudden death appear to be
more frequent in hypokalemic, diuretic-treated pa-
tients.41 Solomon and Cole42 demonstrated a dose-re-
sponse relationship between serum potassium concen-
tration and ventricular tachycardia among patients
with myocardial infarction. Only 20% of patients with
potassium levels above 3.5 mEq/L demonstrated such
arrhythmias in comparison with 40% of those with
levels 3.1 to 3.5 mEq/L and 67% of those with levels
below 3.1 mEq/L.42 This observation was confirmed
by Nordrehaug43 who reported that 17% of patients
with acute myocardial infarction having serum potas-
sium levels greater than 3.5 mEq/L demonstrated ven-
tricular tachycardia or ventricular fibrillation as com-
pared with 29% of those with potassium levels below
3.5 mEq/L. An explanation for this frighteningly high
rate of ventricular arrhythmias during myocardial in-
farction in thiazide-treated patients may be derived
from other recent studies. Struthers et al.44 observed
that thiazide treatment was associated with a greater
fall in serum potassium after epinephrine administra-
tion than had been observed in untreated subjects.31
Further evidence linking diuretics and arrhythmias is
provided by a European study demonstrating a direct
relationship between serum potassium levels and all
cardiac arrhythmias observed after acute myocardial
infarction.45
Acute myocardial infarction does not provide the
only setting in which increased risks of cardiac ar-
rhythmias and sudden death have been reported to be
associated with diuretic treatment. The MRFIT study
identified a 3.5-fold increase in risk for coronary artery
disease death for men with baseline electrocardio-
graphic abnormalities receiving diuretic therapy when
compared with those without electrocardiographic ab-
normalities.8 This was also observed in the HDFP
study." Other investigators have reported an increased
likelihood of an abnormal electrocardiogram among
hypertensive blacks (when compared with whites) and
among Japanese.45 While the explanation for this ob-
servation is not clear, it may represent an increased
frequency of electrocardiographic manifestations of
left ventricular hypertrophy in blacks and Japanese.
Messerli and colleagues47 identified left ventricular hy-
pertrophy as ariskfactor for sudden death. They noted
a marked increase in ventricular arrhythmias and a six-
fold increase in sudden death among subjects with left
ventricular hypertrophy.47 Recent observations from
the Framingham Study confirm the risk of left ventric-
ular hypertrophy.6 A recent study has demonstrated the
risk of arrhythmias associated with diuretic-induced
hypokalemia in hypertensive patients with left ventric-
 SIDE EFFECTS OF DIURETICS/Weinberger
ular hypertrophy but without evidence of coronary ar-
tery disease.48 Diuretic treatment could affect this risk
in another way. Tarazi49 and Drayer50 have reported
that not all agents producing blood pressure reduction
in hypertensive subjects are associated with regression
of left ventricular hypertrophy when present. Diuretics
have been reported to be associated with no change, or
progression, of cardiac enlargement rather than regres-
sion. 4 ' 30 In addition, diuretic-induced sympathetic
nervous system stimulation in the presence of de-
creased potassium levels, cardiac hypertrophy, or
coronary artery disease could increase myocardial irri-
tability and, thus, provoke arrhythmias and sudden
death. Recent observations from the Framingham
Study appear to link diuretic treatment directly to sud-
den death in humans. 7
Symptomatic Side Effects
Side effects of diuretics have also been identified as
a significant problem in recent large-scale trials. In the
HDFP, among 5485 patients receiving stepped-care
treatment, drug discontinuation because of side effects
occurred in 33%. 5I Diuretics were frequently discon-
tinued because of side effects. With chlorthalidone,
the rate was 20.6% and with spironolactone, 16.9%.31
Specific side effects observed in more than 1% of
study participants included gastrointestinal distress,
weakness, dizziness, lethargy, skin rash, sexual dys-
function and impotence, and muscle cramps.51 The
Medical Research Council of Great Britain studying
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7229 patients reported similar side effects, including
impotence at a frequency of 19.6 per 1000 patient-
years in diuretic-treated men.22 Other idiosyncratic re-
actions include ototoxicity with loop diuretics. This
appears to be more common with ethacrynic acid than
with furosemide, which in turn appears to cause hear-
ing impairment more frequently than bumetanide.
Many diuretics can provoke nausea, vomiting, hemo-
lytic anemia in subjects with glucose-6-phosphate de-
hydrogenase deficiency, decreased platelet count, pan-
creatitis, and photosensitivity.
All of these concerns about the adverse effects of
diuretic therapy have forced a reevaluation of the tradi-
tional, diuretic-first, stepped-care treatment of hyper-
tension. Indeed, the Joint National Committee on De-
tection, Evaluation and Treatment of High Blood
Pressure in its 1984 Report, for the first time, proposed
the use of /3-blocking drugs as an alternative to diure-
tics as the first step in the treatment of elevated blood
pressure.52 Further, the Committee recommended a
trial of dietary sodium reduction and weight loss (for
those overweight) with mild blood pressure elevation
(diastolic 90-95 mm Hg) as well as those with high-
normal pressure (85-89 mm Hg). /3-Adrenergic block-
ing drugs, however, may not be ideal alternatives to
diuretics for the treatment of mild hypertension since
they also induce some of the adverse effects on glucose
and lipids seen with diuretics. In addition, they may
exacerbate pulmonary disease, provoke asthma, pro-
voke congestive heart failure, or worsen peripheral
vascular disease. They also may not be effective in
11-19
cigarette smokers33 or in hypertensive blacks.14 The
use of other agents such as angiotensin converting en-
zyme inhibitors, a-blockers, or calcium channel
blockers may provide an effective alternative to initial
therapy of mild hypertension without many of the ad-
verse effects of diuretics and /3-blocking drugs, al-
though their beneficial effect in reducing cardiovascu-
lar morbidity and mortality awaits confirmation.
Acknowledgments
I am grateful for the expert secretarial assistance provided by
Mrs. Uma Richmond and Mrs. Cassandra Brown.
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