Current Concepts o f
Phar macotherapy i n H y p e r t e n s i o n
Domenic A. Sica, MD, Senior Editor
Diuretic-Related Side Effects:
Development and Treatment
Diuretics are important therapeutic tools. First,
they effectively reduce blood pressure and have
been shown in numerous hypertension clinical
trials to reduce both cardiovascular and cerebro-
vascular morbidity and mortality. In addition,
their use has been equally effective in controlling
cardiovascular events as angiotensin-converting
enzyme inhibitors or calcium channel block-
ers. Diuretics are currently recommended by the
Seventh Report of the Joint National Commission
on Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure report as first-
line therapy for the treatment of hypertension.
In addition, they remain an important aspect of
congestive heart failure treatment in that they
improve the congestive symptomatology, which
typifies the more advanced stages of congestive
heart failure. This article reviews the commonly
encountered side effects with the various diuretic
classes. Where indicated, the mechanistic basis
and treatment of such side effects is further dis-
cussed. (J Clin Hypertens. 2004;6:532–540)
©
2004 Le Jacq Communications, Inc.
From the Departments of Medicine and Pharmacology,
Section of Clinical Pharmacology and Hypertension,
Division of Nephrology, Virginia Commonwealth
University, Richmond, VA
Address for correspondence:
Domenic A. Sica, MD, Professor of Medicine and
Pharmacology, Chairman, Clinical Pharmacology
and Hypertension, Division of Nephrology, Virginia
Commonwealth University, MCV Station Box 980160,
Richmond, VA 23298-0160
E-mail: dsica@hsc.vcu.edu
www.lejacq.com
532 THE JOURNAL OF CLINICAL HYPERTENSION
The Journal of Clinical Hypertension (ISSN 1524-6175) is published monthly by Le Jacq Communications, Inc., Three Parklands Drive, Darien, CT 06820-3652. Copyright ©2004 by Le Jacq Communications, Inc., All rights reserved. No
part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing
from the publishers. The opinions and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please
contact Sarah Howell at showell@lejacq.com or 203.656.1711 x106.
Domenic A. Sica, MD
T he dose-response relationship for the antihy-
pertensive effect of diuretics has been more
fully characterized over the past 20 years. In the
process, many of the supposed negative attributes
of diuretics are less common than was first thought.
In the early days of diuretic use, doses were unnec-
essarily high, with dosing driven by the belief that
“If a little is good, more is better”; however, it was
quickly recognized that the blood pressure (BP)
lowering effect for a thiazide-type diuretic, such as
hydrochlorothiazide (HCTZ), was relatively flat
beyond a daily dose of 25 mg, and that at the high-
er dosages (100–200 mg/d), more negative meta-
bolic experiences would occur.2–3 At lower doses
(HCTZ, 12.5–25.0 mg), the metabolic mischief
seen with high-dose thiazide-type diuretic therapy
was much less concerning, with the possible excep-
tion of new-onset diabetes.3 Recent observations
suggest that becoming a new-onset diabetic as a
consequence of diuretic therapy carries a similar
negative cardiovascular (CVR) risk as exists for
the diabetic population in general.4 This obser-
vation varies from that of the Antihypertensive
and Lipid-Lowering Treatment to Prevent Heart
Attack Trial,5 where the CVR outcomes in either
new-onset or already present diabetics were not
worsened by diuretic therapy.
ADVERSE EFFECTS OF DIURETICS
Diuretic-related side effects can be separated into
several categories, including those with well–
worked-out mechanisms such as electrolyte defects
and/or metabolic abnormalities and occurrences,
such as impotence, which are mechanistically less
well understood. In addition, various drug-drug
ID: 3789 interactions are recognized to occur with diuretics.
VOL. VI NO. IX SEPTEMBER 2004
 Diuretic-related side effects are more common and risks of ongoing hyponatremia must be weighed
of a greater intensity with loop diuretics. Thiazide- against those of too hasty a correction, and cur-
related side effects are somewhat more common rent recommendations are that plasma Na+ should
with longer-acting compounds, such as chlortha- be corrected by no more than 0.5 mmol/h during
lidone and metolazone. Among the thiazide-type the first 24 hours of treatment.11–12 The pace at
diuretics, indapamide has been touted by some which hyponatremia is corrected should be slowed
as distinctive in not causing significant metabolic once a mildly hyponatremic serum Na+ range has
derangements; however, when it is given in equiva- been reached (approximately 125–130 mmol/L).
lent doses to HCTZ, there is little that separates The acuity (≤48 hours) of the hyponatremia also
these two drugs relative to side effects. influences the speed with which hyponatremia is
corrected. Controversy still surrounds a number of
HYPONATREMIA aspects of the therapy of hyponatremia.
Hyponatremia is an uncommon, but serious, com-
plication of diuretic therapy.6–7 Thiazide diuretics HYPOKALEMIA AND HYPERKALEMIA
are more likely than loop diuretics to cause hypo- A serum K+ value of ≤3.5 mmol/L, which is the
natremia. Loop diuretics inhibit sodium (Na+) most common definitional criterion for a diagnosis
transport in the renal medulla and prevent the of hypokalemia, is a common finding in patients
generation of a maximal osmotic gradient. Thus, treated with loop and/or high-dose thiazide diuret-
urinary concentrating ability is impaired with ics.12 During the first several days of thiazide-
loop diuretics. Alternatively, thiazide-type diuretics diuretic therapy, plasma K+ falls an average of 0.6
increase Na+ excretion and preclude maximal urine mmol/L (in a dose-dependent manner) in subjects
dilution, while preserving the kidney’s innate con- not taking K+ supplements, as compared with a
centrating capacity. When diuretic-related hypona- 0.3 mmol/L drop in those taking furosemide.13
tremia occurs, it is typically in elderly females and However, it is unusual for serum K+ values to
is usual seen shortly after therapy begins (within settle <3.0 mmol/L in diuretic-treated outpatients,
the first 2 weeks).8 However, diuretic-related hypo- apart from a high dietary Na+ intake and/or when
natremia can occur on a delayed basis even after a long-acting diuretic is being given (as is the case
several years of therapy.7 Multiple factors contrib- with chlorthalidone). Mechanisms that contribute
ute to the penchant of females to diuretic-related to the onset of hypokalemia during diuretic use
hyponatremia, including age, reduced body mass, include: increased flow-dependent distal nephron
exaggerated natriuretic response to a thiazide K+ secretion (more commonly observed with a high
diuretic, diminished capacity to excrete free water, Na+ intake), a fall in distal tubule luminal chloride
and self-imposed low-solute intake. Independent (Cl–) metabolic alkalosis, and/or secondary hyper-
of this constellation of risk factors, it has been aldosteronism.14–15
suggested that the apparent female preponderance The cardiac implications of diuretic-induced
of thiazide-induced hyponatremic adverse events hypokalemia remain controversial. It would seem
is related to overrepresentation of females in thia- logical to infer that arrhythmia-related event rates
zide-treated cohorts, rather than intrinsic suscepti- are connected to the degree of hypokalemia, but this
bility to the electrolyte disturbance.7 is in no way an unambiguous relationship (at least
Mild asymptomatic diuretic-related hyponatre- in an outpatient setting). This theme is confused by
mia (typically between 125–135 mmol/L) can be several factors including: the inconstant relationship
managed in a number of ways (which are not nec- between serum K+ concentrations and total body
essarily mutually exclusive), including: restricting K+ deficits in the face of diuretic therapy; the fact
free-water intake, replacing potassium (K+) losses, that in most clinical trials evaluating arrhythmia
withholding diuretics, or switching to loop diuretic risk (and/or sudden cardiac death [SCD]), serum K+
therapy if diuretic therapy remains necessary.9–10 values have not been measured frequently enough
Severe, symptomatic hyponatremia (generally <125 or under sufficiently standardized conditions to
mmol/L), complicated by seizures or other active allow for anything more than an educated guess as
neurologic sequelae, represents a true medical to the “average” K+ value at the time of an event;
emergency. A fall in serum Na+ to this degree calls that the range of serum K+ values most commonly
for intensive therapy; however, this level of symp- associated with increased ventricular ectopy is very
tomatic hyponatremia should not be corrected too small typically between 3.0–3.5 mmol/L and finally
rapidly because the osmotic demyelinating syn- the issue of whether hypokalemia produced by tran-
drome has occurred under these circumstances. The scellular shifts of K+ manufactures a similar risk as

VOL. VI NO. IX SEPTEMBER 2004 THE JOURNAL OF CLINICAL HYPERTENSION 533

The Journal of Clinical Hypertension (ISSN 1524-6175) is published monthly by Le Jacq Communications, Inc., Three Parklands Drive, Darien, CT 06820-3652. Copyright ©2004 by Le Jacq Communications, Inc., All rights reserved. No
part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing
from the publishers. The opinions and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please
contact Sarah Howell at showell@lejacq.com or 203.656.1711 x106.
 that generated by a reduced serum K+ on the basis Those subjects who developed hypokalemia did
of total body losses. not secure the treatment benefits on CVR and
It has been observed that even mild degrees of coronary events as well as stroke recognized in
diuretic-induced hypokalemia can be coupled with similarly-treated, but normokalemic patients, with
ventricular ectopy.16–17 For example, the Multiple isolated systolic hypertension.
Risk Factor Intervention Trial16 observed a sig- Two additional issues are considerations in
nificant inverse relationship between the serum K+ the milieu of diuretic-related hypokalemia: first,
concentration and the frequency of premature the hemodynamic benefit of normalizing serum
ventricular contractions (PVCs); however, in this K+ 29 and second, the consequences of different
trial patients on chlorthalidone with the greatest doses, combinations of diuretics and/or K+-sparing
decrease in serum K+ levels had the best outcomes. diuretics on SCD.30–31 To the former, K+ supple-
However, this relationship has not been detected in mentation (average increase in serum K+ of 0.56
all studies, possibly because of the brief duration mmol/L) in hypokalemic (serum K+ values <3.5
of many of these trials.18–19 For example, in the mmol/L), diuretic-treated patients have been fol-
Medical Research Council (MRC) study, 287/324 lowed by a 5.5 mm Hg average fall in mean arterial
patients with mild hypertension underwent ambula- pressure.29 As to the latter, the risk of SCD among
tory electrocardiographic (ECG) monitoring. In the patients receiving combined thiazide and K+-spar-
short-term (8 weeks), there was no increase in the ing diuretic therapy has been shown to be lower
frequency of PVCs; however, after 24 months of than that found in patients treated with thiazides
therapy, a significant difference, which correlated alone, with odds ratios for an event increasing
with serum K+ concentrations, emerged in the PVC significantly as the monotherapy dose of HCTZ
rate (20% [diuretic treated] vs. 9% [placebo]).19 increased from 25–100 mg/d.30 Of note in these
The hazards central to diuretic-related hypo- studies, the addition of K+ supplements to thiazide
kalemia are most apparent in patients with left therapy had little effect on the risk of SCD, sug-
ventricular hypertrophy, congestive heart failure gesting that other properties of K+-sparing diuret-
(CHF), and/or myocardial ischemia; particularly ics (such as decreasing urinary losses of magnesium
when they become acutely ill and have need [Mg2+]) may have been at play.30
of hospitalization.20–23 As mentioned previously, K+-sparing diuretics (such as triamterene and
outpatient forms of diuretic-related hypokalemia amiloride) and aldosterone-receptor antagonists
are seldom of a severe enough nature to demand (such as spironolactone and eplerenone) are often
urgent attention; however, these mildly lowered used for their ability to conserve K+ when it might
serum K+ values create a basis for more significant otherwise be lost with thiazide and loop diuretic
degrees of hypokalemia when transcellular shifts therapy. In certain instances, significant enough K+
of K+ are interposed, as occurs during stressful cir- retention occurs so as to result in hyperkalemia.
cumstances marked by high endogenous epineph- Hyperkalemia with K+-sparing diuretics is usually
rine levels24; therein lies one of the major at-risk encountered in patients with an existing reduction
scenarios of diuretic-related hypokalemia. in their glomerular filtration rate (when also given
Despite a sometimes monotonous level of con- K+ supplements or salt substitutes), individuals
cern about CVR risk (rather than benefit) with who develop acute-on-chronic renal failure, those
diuretic therapy, in part, due to associated electro- on an angiotensin-converting enzyme (ACE) inhib-
lyte abnormalities, several clinical trials, including itor/angiotensin receptor blocker (ARB) and/or a
the Systolic Hypertension in the Elderly Program, nonsteroidal anti-inflammatory drug, or in other
Swedish Trial in Old Patients with Hypertension, situations that predispose to hyperkalemia, such
and MRC have shown that low-dose diuretic ther- as metabolic acidosis, hyporeninemic hypoaldoste-
apy reduces CVR event rates by 20%–25%.25–28 ronism, or heparin therapy (including subcutane-
Perhaps the use of lower doses of thiazides or their ous heparin regimens).32
combination with a K+-sparing diuretic explains
these favorable results as compared with earlier tri- HYPOMAGNESEMIA
als, such as the Multiple Risk Factor Intervention Both thiazide and loop diuretics increase urinary
Trial, in which higher doses of diuretics were Mg2+ excretion. All K+-sparing diuretics diminish the
employed (and PVCs were more frequent). In magnesuria that accompanies thiazide or loop diuretic
the Systolic Hypertension in the Elderly Program use.33 Prolonged therapy with thiazide and loop diuret-
(SHEP),28 7.2% of those actively treated developed ics, on average, reduces plasma Mg2+ concentration by
hypokalemia (serum K+ <3.5 mmol/L at year 1). 5%–10%, although patients can develop more severe

534 THE JOURNAL OF CLINICAL HYPERTENSION VOL. VI NO. IX SEPTEMBER 2004

The Journal of Clinical Hypertension (ISSN 1524-6175) is published monthly by Le Jacq Communications, Inc., Three Parklands Drive, Darien, CT 06820-3652. Copyright ©2004 by Le Jacq Communications, Inc., All rights reserved. No
part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing
from the publishers. The opinions and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please
contact Sarah Howell at showell@lejacq.com or 203.656.1711 x106.
 hypomagnesemia in association with similarly-sized cally normalizing a laboratory value. These include
total body deficits.34 Cellular Mg2+ depletion occurs possible favorable effects on BP control, arrhyth-
in up to 50% of patients receiving thiazide diuretics mia development, and/or coexisting electrolyte or
and can be present despite normal serum Mg2+ con- neuromuscular symptoms. In the instance of BP
centrations. Hypomagnesemia occurs more frequently control, there appears to be little additional reduc-
in the elderly, and in those receiving high-dose loop tion in BP when Mg2+ deficiency is corrected; this
diuretic therapy for extended periods of time (such circumstance differs from the BP reduction occa-
as heart failure patients).35 Hypomagnesemia often sionally seen when Mg2+ supplementation takes
coexists with hyponatremia and hypokalemia, with place in a nondeficient state. In the presence of
one study finding 41% of patients with hypokale- refractory tachyarrhythmias or torsade de pointe,
mia to also have low serum Mg2+ concentrations.36 hypomagnesemia should be rapidly treated. Finally,
Hypocalcemia and/or hypokalemia found in associa- when quantifiable measures, such as the electrolyte
tion with low serum Mg2+ concentrations can prove abnormalities of hypokalemia and/or hypocalcemia
refractory to all treatment measures until the underly- are present, the value of treating diuretic-related
ing Mg2+ deficit is corrected.37 hypomagnesemia is readily apparent.
The measurement of serum Mg2+ concentra- It is worthwhile for Mg2+ deficiency to be identi-
tion continues as the everyday test for uncovering fied in all patients in whom a high index of suspi-
hypomagnesemia38–39; however, the presence of cion for hypomagnesemia exists, but particularly in
hypomagnesemia can be suspected from charac- those with ischemic heart disease or known cardiac
teristic ECG, neurologic and/or neuromuscular arrhythmias. In mild deficiency states, Mg2+ balance
findings. On ECG, hypomagnesemia can present as can often be reestablished by attention to the origi-
prolongation of the Q-T and P-R intervals, widen- nal causes (e.g., limiting diuretic and Na+ intake)
ing of the QRS complex, ST segment depression, and allowing dietary Mg2+ to correct the deficit.
and low T waves, as well as supraventricular and Parenteral Mg2+ administration, however, is the most
ventricular tachyarrhythmias.40 The neurological effective way to correct a hypomagnesemic state, and
changes with hypomagnesemia are nonspecific and should be the route used when replacement is of a
include mental status changes and/or neuromuscu- more emergent nature. In the depleted patient, total
lar irritability. Tetany, one of the most striking and body deficits of Mg2+ are typically in the order of
better known manifestations of Mg2+ deficiency, is 1–2 mEq/kg/BW. One commonly employed regimen,
only rarely seen; instead, less specific neurologic albeit empiric, gives 2 g of magnesium sulfate (16.3
signs such as tremor, muscle twitching, bizarre mEq) IV over 30 minutes, followed by a constant
movements, focal and/or generalized seizures, and infusion providing between 32–64 mEq/d until the
delirium/coma are more common findings.41 deficit is presumed corrected.
While a low serum Mg2+ level is helpful and A variety of oral Mg2+ salts are available for
is typically indicative of low intracellular stores, the treatment of hypomagnesemia. Mg2+ oxide is
normal serum Mg2+ values can still be observed in one commonly employed, but this salt is poorly
the face of a significant body deficiency of Mg2+; soluble and acts as a cathartic, which can limit its
thus, serum Mg2+ determinations are an unreliable effect. Mg2+ gluconate is the preferred salt for oral
measure of total body Mg2+ balance.42 Intracellular therapy, as this agent is very soluble and is mini-
Mg2+ measurements, as well as other technologies, mally cathartic. Mg2+ carbonate is poorly soluble
are available to assess Mg2+ balance, but are not and does not appear to be as effective in reversing
readily available. A more practical measure of Mg2+ hypomagnesemia as is the gluconate salt. Oral
balance is the “magnesium loading test,” which at Mg2+ is not recommended for therapy during acute
the same time is both therapeutic and diagnostic. situations, since the high doses needed almost
This test consists of the parenteral administration always cause significant diarrhea. The IM route
of magnesium sulfate and a time-wise assessment of for Mg2+ administration is another route of deliv-
urinary Mg2+ retention. This can be accomplished ery, albeit a potentially painful one, and should be
on an outpatient basis with the Mg2+ load being avoided as long as IV access is readily available.37
given in as short a time interval as 1 hour with sub-
sequent urine collection over 24 hours. Individuals ACID-BASE CHANGES
in a state of normal Mg2+ balance eliminate at least Mild metabolic alkalosis is a common feature of
75% of an administered load.43 thiazide diuretic therapy, particularly at higher
Several issues arise concerning the treatment of doses. Severe metabolic alkalosis is much less fre-
diuretic-related hypomagnesemia beyond empiri- quent and, when it occurs, it is in association with

VOL. VI NO. IX SEPTEMBER 2004 THE JOURNAL OF CLINICAL HYPERTENSION 535

The Journal of Clinical Hypertension (ISSN 1524-6175) is published monthly by Le Jacq Communications, Inc., Three Parklands Drive, Darien, CT 06820-3652. Copyright ©2004 by Le Jacq Communications, Inc., All rights reserved. No
part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing
from the publishers. The opinions and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please
contact Sarah Howell at showell@lejacq.com or 203.656.1711 x106.
 loop diuretic use. The generation of a metabolic be restarted at a lower and sometimes still effective
alkalosis with diuretic therapy is primarily due to dose. In the process, careful attention should be
contraction of the extracellular fluid space caused paid to avoidance of excessive volume contrac-
by urinary losses of a relatively HCO3-free fluid.44 tion. In the patient with preexisting gout and with
Diuretic-induced metabolic alkalosis is best man- a need for diuretic therapy, the xanthine oxidase
aged by administration of K+ and/or Na+ chloride, inhibitor, allopurinol, can be considered. However,
although Na+ chloride administration may be allopurinol (a renally-cleared compound) should
impractical in already volume-expanded patients be used cautiously (dose-adjusted according to
(such as those with CHF). In such cases, a K+-spar- level of renal function) in patients receiving a thia-
ing diuretic or a carbonic anhydrase inhibitor, such zide-type diuretic, since allopurinol hypersensitiv-
as acetazolamide, may be considered. Metabolic ity reactions are more common with this combina-
alkalosis also impairs the natriuretic response to tion.52 A final consideration is what steps to take
loop diuretics and may play a role in the diuretic in a patient with diuretic-related hyperuricemia
resistance occasionally found in the CHF patient.45 who is intolerant of allopurinol. In such subjects,
All K+-sparing diuretics can cause hyperkalemic the ARB losartan, which is a uricosuric compound,
metabolic acidosis, which in elderly patients, or in can be safely given with a reduction in serum uric
those with renal impairment or CHF, can reach a acid and no risk of acute urate nephropathy and/or
life-threatening level.46 uric acid stones.53

HYPERURICEMIA METABOLIC ABNORMALITIES

Thiazide diuretic therapy increases serum urate Hyperglycemia
concentrations by as much as 35%; an effect Prolonged thiazide diuretic therapy can lead to glu-
related to decreased renal clearance of urate, and cose intolerance and may occasionally precipitate
one that is most prominent in those with the high- diabetes mellitus.4,5,54,55 Short-term metabolic stud-
est pretherapy urate clearance values.47 Decreased ies, epidemiologic studies, and a variety of clinical
urate clearance may be linked to increased reab- trials suggest a connection between ongoing thiazide
sorption secondary to diuretic-related extracellular diuretic use and the development of type 2 diabetes.
fluid volume depletion and/or competition for However, it should be noted that interpretation
tubular secretion, since both thiazide diuretics and of these studies is confounded by multiple factors
urate undergo tubular secretion by the same organ- including: differing definitions of new-onset diabe-
ic anion transporter pathway.48–49 Diuretic-related tes, small numbers of patients, inadequate compari-
hyperuricemia is dose-dependent and is pertinent son groups, relatively limited periods of follow-up,
for two reasons: first, as a precipitant of gout and selection criteria that limited the generalizability of
second, relative to its effect on CVR event rate. the findings, and study designs that prohibited valid
First, diuretic-related hyperuricemia does not comparisons among antihypertensive drug classes.56
typically precipitate a gouty attack unless the Moreover, in a review of all the placebo-controlled
patient has an underlying gouty tendency or serum hypertension trials with diuretics, there was only
urate concentrations routinely exceed 12 mg/dL.48 an approximate 1% increase in new-onset diabetes
To this end, in the MRC trial, patients receiving compared with placebo.57
high-dose thiazide diuretics had significantly more Hyperglycemia and carbohydrate intolerance
withdrawals for gout than did placebo-treated have been linked to diuretic-induced hypokalemia.
patients (4.4 vs. 0.1/1000 patient years).50 Second, K+ deficiency is known to inhibit insulin secretion
in the SHEP,51 those with a serum uric acid increase by β cells; however, diuretic-induced changes in
≥0.06 mmol/L (median change) in the active treat- glucose metabolism are not conclusively related
ment group had a similar risk of coronary events as to altered K+ homeostasis, and impaired glucose
the placebo group, suggesting that diuretic-related tolerance occurs even when thiazide-type diuret-
hyperuricemia offsets the positive CVR benefits ics in relatively low doses are combined with
otherwise seen with diuretic therapy. This differ- K+-sparing agents. The glucose intolerance seen
ence was not explained by BP effects. with diuretic therapy can deteriorate further with
Allopurinol should not be routinely started (as an increase in sympathetic nervous system activity,
often is the case) for asymptomatic diuretic-related which also decreases peripheral glucose utilization.
hyperuricemia. If a gouty attack occurs in a diuret- Diuretic-associated glucose intolerance appears to
ic-treated patient, the diuretic in use should be tem- be dose-related, less common with loop diuretics,
porarily discontinued. Oftentimes, a diuretic can not present with spironolactone, and reversible

536 THE JOURNAL OF CLINICAL HYPERTENSION VOL. VI NO. IX SEPTEMBER 2004

The Journal of Clinical Hypertension (ISSN 1524-6175) is published monthly by Le Jacq Communications, Inc., Three Parklands Drive, Darien, CT 06820-3652. Copyright ©2004 by Le Jacq Communications, Inc., All rights reserved. No
part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing
from the publishers. The opinions and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please
contact Sarah Howell at showell@lejacq.com or 203.656.1711 x106.
 on withdrawal of the agent, although the data on Moreover, data from the Hypertension Detection
reversibility in HCTZ-treated patients is somewhat and Follow-up Program indicate that diuretic-treated
conflicting.55 Of note, an overview of this issue hypertensive subjects with baseline cholesterol values
found that glucose homeostasis was unpredictably of >250 mg/dL experience a decline in cholesterol
affected by low-dose HCTZ (12.5–50 mg/d).58 levels from the second to the fifth year of treatment.65
Recently, a large, prospective, cohort study Finally, in the diuretic-based SHEP, CVR outcome was
(12,550 nondiabetic adults [45- to 64- years old] similar in patients with cholesterol levels <200 mg/dL
who did not have diabetes) concluded (after appro- and >280 mg/dL. Thus, whatever lipid changes that
priate adjustment for confounders) that hyperten- do occur with diuretics are not only short-term, but
sive patients taking thiazide diuretics were not at also are probably of limited clinical importance.
greater risk for subsequent diabetes development
than patients who were not receiving antihyperten- OTHER ADVERSE EFFECTS
sive therapy. The diuretic doses were not reported Impotence
in this cohort study; thus, because of the perceived Adverse effects of thiazide and thiazide-like diuretics
variability of this effect, blood glucose should be on male sexual function, including decreased libido,
monitored during thiazide therapy, particularly in erectile dysfunction, and difficult ejaculation have
those with either the metabolic syndrome or existing been reported in several studies with an incidence
diabetes.59 This is particularly so since the CVR risk that varies from 3%–32%.5,66–69 As an example, in
with new-onset diuretic-related diabetes parallels the MRC trial, in which 15,000 hypertensive subjects
that which accompanies existing diabetes.4 Other received either placebo, thiazide (bendrofluazide), or
drug classes such as ACE inhibitors and ARBs are a β blocker (propranolol) for 5 years, impotence was
associated with a lesser incidence of new-onset 22-fold and four-fold higher in those receiving ben-
diabetes. It remains to be determined the extent to drofluazide, compared with placebo or a β blocker,
which either of these drug classes reduces the diabe- respectively.5 In this trial, impotence was the most
togenic potential of thiazide-type diuretics. frequent principal reason for withdrawal from anti-
hypertensive therapy. Another smaller trial reported
HYPERLIPIDEMIA on by Chang et al.70 also found a higher frequency of
Short-term thiazide diuretic therapy can dose- decreased libido, difficulty in gaining and sustaining
dependently elevate serum total cholesterol levels, an erection, and trouble in ejaculating in thiazide-
modestly increase low-density lipoprotein choles- treated patients. Multivariate analysis suggested that
terol levels and raise triglyceride levels, while mini- these findings were not mediated by either low-serum
mally changing high-density lipoprotein cholesterol K+ or by the observed fall in BP.
concentrations.60–63 These lipid effects have been In a study by Wassertheil-Smoller et al.69 prob-
reported to be more apparent in blacks, males, dia- lems with sexual interest, erection, and orgasm
betics, and nonresponders to diuretic therapy.62–63 were greater among men receiving chlorthalidone
In nonresponders to diuretic therapy, the observed compared with those given placebo or atenolol. Of
increase in lipid values likely relates to the higher note, in this trial, weight loss corrected the problem
diuretic doses used (or required) in such patients.64 of chlorthalidone-induced sexual dysfunction. Also,
All diuretics, including loop diuretics, cause these use of a diuretic in combination with other antihy-
lipid changes, with the possible exception of inda- pertensive agents has been associated with a higher
pamide.61 The mechanisms of diuretic-induced dys- incidence of sexual dysfunction symptoms than with
lipidemia remain uncertain, but have been related to the use of a diuretic alone. The mechanism by which
worsened insulin sensitivity and/or reflex activation thiazides effect erectile function or libido is unclear,
of the renin-angiotensin-aldosterone system (RAAS) although it has been suggested that these drugs wield
and sympathetic nervous system in response to vol- a direct effect on vascular smooth muscle cells and/or
ume depletion. Supporting this latter notion is the decrease the response to catecholamines; however,
fact that doses of diuretics, which are low enough patients with diuretic-related impotence can respond
so as not to activate the sympathetic nervous sys- to sildenafil without any additional drop in BP.71
tem, do not increase lipid values; in contrast, higher Impotence and decreased libido are the more frequent
diuretic doses are more apt to be associated with sexual side effects with spironolactone.66 Gynecomastia,
reflex sympathetic nervous system activation. another fairly frequent complication of spironolactone
Long-term clinical trials differ from short-term therapy, may be associated with mastodynia and is typi-
studies in that cholesterol levels are little changed cally bilateral. One study reported that 91 (13%) of 699
from baseline after 1 year of diuretic therapy.61–62 men prescribed spironolactone, alone or in association

VOL. VI NO. IX SEPTEMBER 2004 THE JOURNAL OF CLINICAL HYPERTENSION 537

The Journal of Clinical Hypertension (ISSN 1524-6175) is published monthly by Le Jacq Communications, Inc., Three Parklands Drive, Darien, CT 06820-3652. Copyright ©2004 by Le Jacq Communications, Inc., All rights reserved. No
part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing
from the publishers. The opinions and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please
contact Sarah Howell at showell@lejacq.com or 203.656.1711 x106.
 with another antihypertensive treatment, developed dose-
related gynecomastia that was reversible. At daily doses
of <50 mg, the incidence of gynecomastia was 6.9%; at
daily doses of >150 mg, the incidence was 52.2%.72 The
sexual side effects of spironolactone have been attributed
to endocrine dysfunction; spironolactone is structurally
similar to the sex hormones and inhibits the binding of
dihydrotestosterone to androgen receptors, thus produc-
ing an increased clearance of testosterone.73 Eplerenone
is another aldosterone-receptor antagonist which is more
selective than spironolactone and is devoid of the sexual
side effects seen with spironolactone.74
DRUG ALLERGY
Photosensitivity dermatitis rarely occurs secondary
to thiazide or furosemide therapy.75 HCTZ more
commonly causes photosensitivity than do the other
thiazides.76 Diuretics may rarely cause a more serious
generalized dermatitis and, at times, even a necrotiz-
ing vasculitis. Cross-sensitivity with sulfonamide
drugs may occur with all diuretics, with the excep-
tion of ethacrynic acid; however, the frequency with
which cross-sensitivity occurs is much less common
than was first thought and appears to be due to a pre-
disposition to allergic reactions, rather than to spe-
cific cross-reactivity with sulfonamide-based drugs;
thus, patients with a sulfonamide allergy that was not
“extreme” (such as Stevens-Johnson syndrome or a
necrotizing vasculitis) in its original presentation can
cautiously receive a thiazide or a loop diuretic.77
Severe necrotizing pancreatitis is a rare, but serious
and potentially life-threatening, complication of thia-
zide therapy. Acute allergic interstitial nephritis with
fever, rash, and eosinophilia, although an uncommon
complication of diuretics, is one that may result in
permanent renal failure if the drug exposure is pro-
longed.78 Allergic interstitial nephritis may develop
abruptly or some months after therapy is begun with
a thiazide diuretic or, less commonly, it can occur
with furosemide.79 Ethacrynic acid is chemically dis-
similar to the other loop diuretics and can be safely
substituted in diuretic-treated patients who experi-
ence any of these allergic complications.
CARCINOGENESIS
Twelve clinical studies, three cohort (1,226,229 patients
with 802 cases of renal cell carcinoma) and nine case-
controlled studies (4185 cases of renal cell carcinoma and
6010 controls), have evaluated the association between
the use of diuretics and renal cell carcinoma. In all case-
controlled studies, the odds were greater for patients
being treated with diuretics to develop renal cell carci-
noma (average odds ratio of 1.55). The risk of renal cell
carcinoma appeared to be related not to the average daily
538 THE JOURNAL OF CLINICAL HYPERTENSION
The Journal of Clinical Hypertension (ISSN 1524-6175) is published monthly by Le Jacq Communications, Inc., Three Parklands Drive, Darien, CT 06820-3652. Copyright ©2004 by Le Jacq Communications, Inc., All rights reserved. No
part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing
from the publishers. The opinions and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please
contact Sarah Howell at showell@lejacq.com or 203.656.1711 x106.
diuretic dose, but rather to the duration of the diuretic
treatment. Unlike the association between diuretics and
renal cell carcinoma, no association has been found
between diuretic therapy and breast cancer. The issue of
renal cell carcinoma occurring with diuretic therapy at
the current time remains one incompletely resolved.80–82
ADVERSE DRUG INTERACTIONS
Loop diuretics can potentiate aminoglycoside nephro-
toxicity.83 By causing hypokalemia, diuretics increase the
risk of digitalis toxicity.84 Plasma lithium (Li+) concen-
trations can increase with thiazide therapy with signifi-
cant volume contraction due to the associated increase
in Li+ absorption.85 However, some diuretics, such as
chlorothiazide or furosemide, with significant carbonic
anhydrase inhibitory, can increase Li+ clearance, thus
leading to a fall in blood levels.86–87 Whole-blood Li+
should be closely monitored in patients administered Li+
in conjunction with diuretics. Nonsteroidal anti-inflam-
matory drugs can both antagonize the effects of diuret-
ics and predispose diuretic-treated patients to a form
of functional renal insufficiency. The combination of
indomethacin and triamterene may be particularly dan-
gerous, in that acute renal failure can be precipitated.88
CONCLUSIONS
Diuretic-related side effects occur more commonly
with loop and/or K+-sparing agents and are less so
with thiazide-type diuretics, as they are currently used
in the treatment of hypertension. Diuretic-related
side effects, particularly with loop and/or K+-sparing
agents, are not uncommon causes for hospitalization
due to hypotension, renal impairment, electrolyte
disturbances, and gout in the context of hospital
admissions prompted by adverse drug reactions.89
Many diuretic-related side effects can be avoided or
effectively tempered by selection of the lowest dose
necessary for effective BP and/or volume control.
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