Download Use of Diuretics in Patients with Hypertension

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m e dic i n e
review article
Drug Therapy
Use of Diuretics in Patients
with Hypertension
Michael E. Ernst, Pharm.D., and Marvin Moser, M.D.
T
hiazide diuretics became available in the late 1950s and were
the first effective oral antihypertensive agents with an acceptable side-effect
profile.1,2 A half-century later, thiazides remain important medications for the
treatment of hypertension. These agents reduce blood pressure when administered
as monotherapy, enhance the efficacy of other antihypertensive agents, and reduce
hypertension-related morbidity and mortality. This review focuses on thiazides, the
diuretics most often indicated for long-term therapy for hypertension; loop diuretics and potassium-sparing agents are briefly considered.
Cl inic a l Ph a r m ac ol o gy of Thi a zide s
Chemistry and Mechanism of Action
Diuretic therapy for hypertension originated in 1937 with the discovery that sulfonamides caused acidemia and mild diuresis by inhibiting carbonic anhydrase in the
proximal tubule.3,4 Chlorothiazide, a benzothiadiazine derivative, was isolated during a search for more potent inhibitors of carbonic anhydrase5; chlorothiazide was
found to be a more effective diuretic and also to unexpectedly increase the excretion
of chloride, rather than bicarbonate.6 This effect on excretion eventually led to identification of the upstream portion of the distal convoluted tubule as the major site
of action of the thiazides, where they interfere with sodium reabsorption by inhibiting the electroneutral sodium–chloride symporter (Fig. 1).7 Activity against carbonic anhydrase, although maintained by some thiazides, is considered irrelevant
to their mechanism of action, since sodium that is rejected proximally is reabsorbed
downstream in the renal tubule in the thick ascending limb. Despite structural variation among the different congeners, the term thiazide diuretic includes all diuretics
believed to have a primary action in the distal tubule.
From the Department of Pharmacy Practice and Science, College of Pharmacy,
and Department of Family Medicine,
Carver College of Medicine, University of
Iowa, Iowa City (M.E.E.); and the Section
of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT
(M.M.). Address reprint requests to Dr.
Ernst at the Department of Family Medicine, University of Iowa Hospitals and
Clinics, 200 Hawkins Dr., 01291-A PFP,
Iowa City, IA 52242, or at michael-ernst@
uiowa.edu.
This article (10.1056/NEJMra0907219) was
updated on November 3, 2010, at NEJM
.org.
N Engl J Med 2009;361:2153-64.
Copyright © 2009 Massachusetts Medical Society.
Pharmacokinetics
The pharmacokinetic activities of thiazides are not uniform. All are absorbed orally and have volumes of distribution equal to or greater than body weight (Table
1).8-10 Thiazides are extensively bound to plasma proteins, which helps limit their
filtration by the glomeruli, in effect trapping the diuretic in the vascular space and
allowing for its delivery to secretory sites of the renal proximal tubular cells. Organic anion transporters may also assist by concentrating thiazides in the tubular
lumen.11
The onset of action occurs after approximately 2 to 3 hours for most thiazides,
with little natriuretic effect beyond 6 hours.12 Their metabolism, bioavailability,
and plasma half-lives are variable. The latter two pharmacokinetic features are the
most clinically relevant, as they determine the dose and frequency of administra-
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2153
The
Proximal
convoluted tubule
(65–70%)
n e w e ng l a n d j o u r na l
Distal convoluted
tubule (5%)
Na+
Filtered blood out
(efferent arteriole)
Glomerulus
Cl−
Na+
Thiazides
Collecting
duct
(1–2%)
Unfiltered
blood in
(afferent arteriole)
NaHCO3
Aldosterone
Carbonic
anhydrase
inhibitors
K+
K+-sparing diuretics and
mineralocorticoid-receptor
antagonists
Thick descending
limb
Renal
artery
Na+
Na+/K+
2Cl−
Loop
diuretics
Cortex
Medulla
Thick ascending
limb
Kidney
of
m e dic i n e
intake enhances absorption.8,9 Some thiazides undergo extensive metabolism, whereas others are
excreted nearly intact in urine. A 50% reduction
in hydrochlorothiazide absorption is observed in
patients with heart failure. Relatively little else is
known about the influence of disease on the pharmacokinetics of thiazides.8
Most thiazides have a half-life of approximately
8 to 12 hours, just permitting effective oncedaily dosing.9 Among thiazides, chlorthalidone
is uniquely long-acting, with an elimination halflife of 50 to 60 hours, owing to its large volume
of distribution.13 Nearly 99% of chlorthalidone
is bound to erythrocyte carbonic anhydrase, and
the drug has a stronger inhibitory effect than
other thiazides against several catalytically active
mammalian isoforms.14,15 The substantial partitioning of chlorthalidone into erythrocytes creates
a tissue reservoir that allows the constant seeping of chlorthalidone back into plasma, through
which it exerts its therapeutic effect.14 This depot
effect of chlorthalidone may be advantageous in
patients who occasionally miss doses, and the
agent appears to retain measurable efficacy when
given less frequently than once daily.16,17
Pharmacodynamics
Hemodynamic Effects
Renal
vein
Urine
Cortex
Medulla
Loop of Henle
(25%)
Figure 1. Sites of Diuretic Action in the Nephron.
The percentage of sodium reabsorbed in a given region is indicated in parentheses. “K+ -sparing agents” collectively refers to the epithelial sodiumchannel inhibitors (e.g., amiloride and triamterene) and mineralocorticoidreceptor antagonists (e.g., spironolactone and eplerenone). Sodium is
reabsorbed in the distal tubule and collecting ducts through an aldosterone-sensitive sodium channel and by activation of an ATP-dependent sodium–potassium pump. Through both mechanisms, potassium is secreted
into the lumen to preserve electroneutrality. Sodium-channel inhibitors
preserve potassium by interfering with the sodium–potassium pump,
whereas mineralocorticoid-receptor antagonists spare potassium through
their inhibitory effect on aldosterone. NaHCO3 denotes sodium bicarbonate.
tion. Chlorothiazide is relatively insoluble in lipids, and large doses are required to achieve levels
sufficient to reach the site of action. Hydrochlorothiazide has relatively greater bioavailability;
approximately 60 to 70% is absorbed, and food
2154
n engl j med 361;22
The hemodynamic effects of thiazides can be separated into short-term and long-term phases (Table 2).18 Initial decreases in blood pressure are
attributed to the reductions in extracellular fluid
and plasma volumes, leading to depressed cardiac
preload and output.19 Dextran administration during this short-term phase will restore plasma volume and blood pressure to pretreatment levels.
Counterregulatory activation of the sympathetic
nervous system and the renin–angiotensin–aldosterone system induces a transient rise in peripheral vascular resistance, although this is not
usually sufficient to negate the blood-pressure
reduction.20 Combining a thiazide with an angiotensin-converting–enzyme (ACE) inhibitor or an
angiotensin II–receptor blocker (ARB) can oppose
this transient rise in resistance and increase the
antihypertensive response.
The long-term antihypertensive response to
thiazides cannot be reliably predicted by the degree of initial reduction in plasma volume, which
eventually returns to near-normal levels. Volume
expansion due to the use of dextran at this stage
no longer
restores the
blood pressure to pretreatVersion 7
11/06/09
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COLOR FIGURE
Author
Ernst
Fig #
1
Title
Diuretic Use in Hyper.
november
26, 2009
ME
JL
JRI
DE
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drug ther apy
Table 1. Pharmacokinetic Characteristics of the Thiazide Diuretics Approved for Use in the United States.*
Diuretic†
Thiazide-type
Chlorothiazide
Hydrochlorothiazide
Methychlothiazide
Polythiazide
Bendroflumethiazide
Thiazide-like
Chlorthalidone
Metolazone
Indapamide
Relative Carbonic
Anhydrase
Inhibition‡
Oral Bioavailability
Volume of
Distribution
Protein Binding
percent
liters per kilogram
percent
++
+
—
+
0
15–30
60–70
—
—
90
1
2.5
—
—
1.0–1.5
70
40
—
—
94
100% Renal
95% Renal
Hepatically metabolized
25% Renal
30% Renal
1.5–2.5
9–10
—
26
9
+++
+
++
65
65
93
3–13
113 (total)§
25 (total)§
99
95
75
65% Renal
80% Renal
Hepatically metabolized
50–60
8–14
14
Route of Elimination
Elimination
Half-Life
hr
*All the diuretics listed are available in generic form in the United States as monotherapy, except polythiazide (not currently available) and
bendroflumethiazide (available only in combination with nadolol). Dashes indicate an absence of data.
†The terms thiazide-type and thiazide-like are used to group thiazides on the basis of the presence of a benzothiadiazine molecular structure.
Thiazide-like diuretics lack the benzothiadiazine structure but have a mechanism of action similar to that of thiazide-type diuretics, which
have the benzothiadiazine structure.
‡Plus signs indicate inhibition, with greater numbers of plus signs reflecting increased inhibition (lower inhibition constants); the zero indicates an inhibition constant of 0.
§ The volumes of distribution of metolozone and indapamide are given for the total volume, in liters; data on liters per kilogram were not
available.
ment levels.21-23 A more likely explanation for the
persistent antihypertensive effects of most thia­
zides is an overall reduction in systemic resistance,
although the exact mechanisms are unclear.24 Evidence suggests that chlorthalidone may not lower
systemic resistance, even after 8 to 12 months of
therapy, indicating that other mechanisms may
be responsible.17 It is not yet clear whether thiazides have direct vasodilatory properties or induce a reverse autoregulation phenomenon; they
have also been proposed to cause structural membrane changes or altered ion gradients.24 A simpler possibility is that a low level of prolonged
diuresis produced by long-term thiazide administration may maintain a nominal state of volume
contraction, thereby promoting a downward shift
in vascular resistance.12
Thiazides have substantial residual effects after
discontinuation. Rapid volume expansion, weight
gain, and decreased renin levels occur after stopping thiazides, but blood pressure rises slowly
and does not immediately reach pretreatment levels.18,25 With adherence to lifestyle modifications
(e.g., weight loss, reduction in sodium and alcohol intake), nearly 70% of patients may not require
antihypertensive medications for up to 1 year after
long-term thiazide-based therapy is withdrawn.26
Tolerance to Diuretics
The use of diuretics elicits both short- and longterm adaptations intended to protect intravascular volume. Short-term tolerance may result from
a period of post-dose antinatriuresis triggered by
the initial reduction in extracellular fluid volume,
corresponding to a decline in the drug level in
plasma and tubular fluid to below the diuretic
threshold.27 Activation of the renin–angiotensin–
aldosterone system and the sympathetic nervous
system, as well as suppression of the secretion of
atrial natriuretic peptide and renal prostaglandin,
also contribute to short-term tolerance.27 Post-dose
sodium retention is significantly influenced by dietary sodium intake. Sodium restriction promotes
an overall negative sodium balance and enhances
the therapeutic response to thiazides, whereas persistently high dietary sodium offsets this effect.28
Long-term diuretic adaptation, or the braking
effect, refers to a gradual return of the sodium–
chloride balance to an electroneutral level. Persistent volume removal appears to trigger long-term
activation of the renin–angiotensin–aldosterone
system, increasing circulating angiotensin II levels,
which in turn promotes increased proximal sodium reabsorption and limits the overall delivery
of sodium to the distal site. Other volume-inde-
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2155
The
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of
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Table 2. Hemodynamic and Physiological Effects after Initiation and Cessation of Diuretic Therapy.
Variable
Short-Term Phase
(first 2–4 wk)
Long-Term Phase (mo)
Cardiac output
Decrease
Increase (return to pretreatment
level)
No change
Plasma volume
Decrease
Increase (near-return to pretreatment level)
Increase (possibly exceeding pretreatment level)
Plasma renin activity
Increase
Increase
Peripheral resistance
Transient increase
Gradual decrease
Decrease
Decrease
Blood pressure
pendent mechanisms may be involved, including
the up-regulation of sodium transporters downstream from the primary site of diuretic action
and structural hypertrophy of distal nephron
segments.29-31
Tolerance to diuretics can be overcome by administering higher doses or combinations of diuretics. For example, synergistic diuresis occurs
when a thiazide is added to loop-diuretic monotherapy in patients with edema.32 Occult volume
expansion can be present in patients with resistant hypertension, despite existing diuretic therapy; increasing the dose of diuretics may improve
the blood pressure.33 High doses and combinations of diuretics must be used carefully to avoid
renal injury and marked electrolyte disturbances.
Diur e t ic Ther a py
for H y per tensi v e Pat ien t s
Many physicians consider thiazides the diuretics
of choice for long-term therapy. On average, after
adjustment for reductions seen with the use of placebo, thiazides induce a reduction in the systolic
and diastolic blood pressures of 10 to 15 mm Hg
and 5 to 10 mm Hg, respectively. Hypertension
responding preferentially to thiazides is considered
to be low-renin or salt-sensitive hypertension. The
elderly, blacks, and patients with characteristics
associated with high cardiac output (e.g., obesity)
tend to have this type of hypertension. Thiazides
also correct the hypertension and electrolyte abnormalities associated with pseudohypoaldosteronism type 2 (Gordon’s syndrome), a rare
mendelian form of hypertension in which the sodium–chloride symporter is excessively active. Thiazides potentiate other antihypertensive agents
2156
Post-Therapy Period
Decrease (return to pretreatment
level)
Increase (gradual return to pretreatment level)
Gradual increase
when they are used in combination, often producing an additive decrease in blood pressure. The addition of a thiazide minimizes racial differences
usually observed in response to monotherapy with
inhibitors of the renin–angiotensin–aldosterone
system, and the use of such an inhibitor can lessen
the degree of the hypokalemia and the metabolic
perturbations that may be evoked by thiazides.
The dosing of thiazides has evolved in parallel
to our progressive understanding of their mechanism of action and dose–response relationships.
Earlier use of high doses was based on the belief
that efficacy was directly linked to the amount of
renal sodium excretion and reduction in plasma
volume; the larger the dose, the greater the assumed reduction in blood pressure. However, thiazides are now used in substantially smaller doses,
and the term low-dose thiazide has become synonymous with hydrochlorothiazide at a dose of
12.5 to 25 mg per day (or the equivalent dose of
another thiazide). Approximately 50% of patients
will respond initially to these low doses. In the
Systolic Hypertension in the Elderly Program
(SHEP),34 chlorthalidone given at a dose of 12.5 mg
per day controlled blood pressure, for several
years, in more than 50% of patients. Increasing the
dose of hydrochlorothiazide from 12.5 to 25 mg
per day may result in a response in an additional
20% (approximately) of patients; at 50 mg per day,
80 to 90% of patients should have measurable decreases in blood pressure.35 Increased electrolyte
losses at the higher doses of diuretics may preclude their routine use.
For many hypertensive patients, several agents
will be needed to achieve desired blood-pressure
targets. Combination regimens that include a thiazide can achieve therapeutic synergy while min-
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drug ther apy
imizing adverse effects.36 The lack of appropriate per minute per 1.73 m2 of body-surface area) or
diuretic use is often identified as the primary drug- by volume overload (e.g., in congestive heart failrelated cause of resistance to treatment.37
ure or the nephrotic syndrome); in patients with
such complications, loop diuretics provide consisDiuretics in Renal Impairment
tent natriuresis and diuresis. Furosemide should
Thiazides are typically considered ineffective when be administered twice daily, whereas torsemide is
the glomerular filtration rate decreases below 30 a longer-acting alternative that may be administo 40 ml per minute per 1.73 m2 of body-surface tered once daily.
area, although direct evidence is lacking. Small
studies have shown that thiazides can elicit an an- Potassium-Sparing Agents and
tihypertensive response in patients with chronic Mineralocorticoid-Receptor Antagonists
kidney disease38,39; however, their use in patients Potassium-sparing agents induce only minimal
with severe renal impairment remains impracti- natriuresis and are relatively ineffective in lowercal, for two reasons: first, the reduced glomeru- ing blood pressure (Fig. 1). Their primary value is
lar filtration rate limits the overall filtered sodi- their ability to reduce the loss of potassium when
um load reaching the distal tubule; and second, they are used with thiazides. They also avert the
reabsorption in the distal tubule is only modestly urinary loss of magnesium, which is important,
effective as compared with that in the large-capac- since restoration of magnesium balance is necesity, thick ascending limb.12 These features under- sary for optimal correction of diuretic-induced
score the rationale for substituting so-called high- hypokalemia. Triamterene is commonly adminceiling diuretics that act more proximally, in the istered with hydrochlorothiazide, although other
loop of Henle, in hypertensive patients with renal fixed-dose combinations of thiazides and potasimpairment.
sium-sparing agents are available. Amiloride, an
Metolazone, a quinazoline derivative, is an ex- epithelial sodium-channel blocker, is reportedly
ception among thiazides because it retains its ef- more effective than spironolactone as therapy in
ficacy in patients who have renal insufficiency or blacks who have resistance to treatment.42
other diuretic-resistance states.40 Its effect is limThe phenomenon of aldosterone escape, whereited by slow, erratic absorption; the more predict- by aldosterone activity is incompletely suppressed
able bioavailability of other thiazides makes them in hypertensive patients who are receiving inhibibetter suited as long-term therapy of hypertension. tors of the renin–angiotensin–aldosterone system,
Metolazone should be reserved for use in combi- can lead to increased salt and water retention.
nation with loop diuretics in patients with volume Agents that block the effect of aldosterone are useoverload whose fluid and electrolyte balance are ful for treating this retention. Spironolactone,
being closely monitored. It is administered daily a nonselective mineralocorticoid-receptor antagofor a short period (3 to 5 days), with administra- nist, is well absorbed and has a long half-life (aption reduced to thrice weekly after this period or proximately 20 hours), attributable to its active
after euvolemia is achieved.27
metabolites.43 Spironolactone not only corrects
thiazide-induced potassium and magnesium lossLoop Diuretics
es, but also, in low doses (12.5 to 50 mg per day),
Diuretics that act in the loop of Henle can lower provides additive hypotensive effects in patients
blood pressure but are less effective in the long who have resistance to treatment.44 Spironolactone
term than thiazides.41 Most loop diuretics have a remains effective when renal function is impaired,
short duration of action (approximately 6 hours), but patients must be monitored carefully for the
resulting in an initial diuresis that is followed development of hyperkalemia. Eplerenone, a newer
closely by a period of antinatriuresis lasting up to agent that is more selective for aldosterone than
18 hours per day when the drug is administered for androgen and progesterone receptors, is assoonce daily. A net neutral sodium balance, or even ciated with less gynecomastia and breast tendera positive balance, can occur with the use of loop ness than is found with spironolactone. However,
diuretics. These agents are most appropriate for direct comparisons of the efficacies of eplerenone
the treatment of hypertension that is complicated and spironolactone in patients with treatmentby a reduced glomerular filtration rate (<30 to 40 ml resistant hypertension are lacking.
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2157
The
n e w e ng l a n d j o u r na l
Diur e t ic s in T r i a l s w i th
C a r diova scul a r End P oin t s
The efficacy of thiazides in reducing the risk of
major cardiovascular events was first established
in 1967, in the landmark Veterans Affairs Cooperative Study.45 In the ensuing years, thiazide regimens have proved highly effective in the prevention of stroke, coronary heart disease, and heart
failure (see the Supplementary Appendix, available
with the full text of this article at NEJM.org).
Combined meta-analyses and systematic reviews report that, as compared with placebo, thiazide-based therapy reduces relative rates of heart
failure (by 41 to 49%), stroke (by 29 to 38%), coronary heart disease (by 14 to 21%), and death from
any cause (by 10 to 11%).46-48 These and other
analyses also show that the benefit from thia­
zides is broadly similar to that from other antihypertensive drugs, with results consistent across
age and sex strata.46-51 The largest randomized,
blinded study performed to date, the Antihypertensive and Lipid-Lowering Treatment to Prevent
Heart Attack Trial (ALLHAT),52 compared initial
treatment consisting of chlorthalidone, at a dose
of 12.5 mg per day, with treatment consisting of
amlodipine, lisinopril, or doxazosin. The 42,418
high-risk study participants were 55 years of age
or older, and 35% were black. The doxazosin treatment was stopped prematurely owing to a significantly greater incidence of heart failure events than
with chlorthalidone. At the end of the study, no
significant differences were found between the
chlorthalidone group and any other treatment
group in the rate of the composite primary end
point of fatal coronary heart disease or nonfatal
myocardial infarction; however, chlorthalidone
was superior with respect to several predefined
secondary end points, including heart failure (vs.
amlodipine and lisinopril) and stroke (vs. lisinopril). The explanation for these findings may be
related to the improved blood-pressure control
maintained throughout the study in the patients
receiving chlorthalidone as compared with those
receiving another treatment. Analyses of data
stratified on the basis of race and metabolic status
consistently indicate that chlorthalidone, used as
initial therapy, was not surpassed by any of the
three comparison drugs with regard to antihypertensive efficacy or event-rate reduction.53-57
Although chlorthalidone and hydrochlorothiazide have been commonly used in the United
2158
of
m e dic i n e
States, other thiazides, such as bendroflumethia­
zide and indapamide, have also been studied. Recently, the use of a sustained-release indapamidebased regimen as initial therapy led to relative
reductions of 39%, 64%, and 21% in the rates of
fatal stroke, heart failure, and death, respectively,
in patients older than 80 years of age.58
Ther a peu t ic C on t rov er sie s
The concept of a class effect among thiazides has
been promulgated in the absence of comparative
studies. In the United States, this debate largely
centers on whether to use hydrochlorothiazide or
chlorthalidone.59 Chlorthalidone is frequently suggested for use, since the rate of cardiovascular
events has been reduced in every study in which
it was used, including at the low doses in the
SHEP study and ALLHAT, whereas the effects of
other thiazide regimens have been less consistent.60 Trials in which hydrochlorothiazide was
associated with favorable reductions in the rate
of cardiovascular events have typically used higher
doses (between 25 and 50 mg per day) than currently advocated. These dose-based differences are
underappreciated, and the perception that thia­
zides are interchangeable is reinforced by the abundance of fixed-dose combinations containing lowdose hydrochlorothiazide. Two trials of low-dose
hydrochlorothiazide in combination with other
medications showed less effectiveness as compared with the nonthiazide regimen.61,62
Hydrochlorothiazide and chlorthalidone are often incorrectly described as equipotent.10 However, early trials comparing the two drugs often
involved the administration of hydrochlorothia­
zide twice daily to achieve reductions in blood
pressure similar to those effected by chlorthali­
done.63,64 When evaluated on the basis of the
dose required to achieve equivalent reductions in
the systolic blood pressure, 24-hour ambulatory
blood-pressure monitoring confirmed that chlor­
thalidone is approximately twice as potent as
hydrochlorothiazide.65 These findings may be attributable to the ability, with chlorthalidone therapy, to maintain efficacy throughout the night and
reduce the gradual rise in blood pressure that may
occur during the interval between daily doses.
Whether hydrochlorothiazide and chlorthalidone are interchangeable in reducing the risk of
cardiovascular events is questionable. An analysis in the Multiple Risk Factor Intervention Trial
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drug ther apy
(MRFIT) suggested a lower mortality rate in the
group randomly assigned to undergo a “special
intervention” in clinics predominantly using
chlorthalidone than in those predominantly using hydrochlorothiazide, but the assignment to a
specific diuretic was not randomized, and the
study design precluded an ability to reliably separate diuretic effects from those of the other concurrent interventions.66 Conversely, a meta-analysis that did not include the MRFIT findings has
suggested no significant differences between the
two agents.67
Optimal Role of Diuretics — Initial or Add-On
Therapy?
Despite a long, well-established record of efficacy,
the role of thiazides in hypertension therapy continues to provoke debate.68 Based on the benefits
observed in studies in which thiazides were used
as initial therapy in a stepped-care approach, with
agents added sequentially, guidelines for hypertension therapy in the United States have advocated
thiazides as initial treatment since 1977, when
the first Joint National Committee report was issued.69 In contrast, British guidelines recommend
diuretics more selectively, such as for use in the
elderly and blacks.70 European guidelines endorse
several antihypertensive agents, including diuretics, as initial therapy.71 An update from the Joint
National Committee is anticipated in the near
future.
Slightly more than one third of the patients in
the United States who are eligible for thiazide therapy actually receive it.72 The reasons for this low
rate of use may include the absence of corporate
promotion of diuretics and the heavy marketing of
newer medications.73 Pleiotropic effects in addition
to the blood-pressure–lowering effect have been
hypothesized for ACE inhibitors and ARBs but
not for thiazides.74 In addition, there is discussion
about the importance of adverse electrolyte and
metabolic changes in association with thiazides
and whether these changes abrogate the overall
blood-pressure–lowering benefits of the drugs.75,76
Cumulative evidence from trials suggests that
the magnitude of blood-pressure lowering is the
most important determinant in reducing the cardiovascular risks associated with hypertension.49
As diuretics are eventually required in many hypertensive patients to achieve blood-pressure goals,
debate about their role as initial or add-on therapy may be predominantly academic.
S a fe t y a nd A dv er se Effec t s
of Thi a zide s
Much of the criticism against thiazides is directed
toward their adverse-effect profile, but low doses
are usually well tolerated and have been shown to
improve quality-of-life measures.77 Most complications of thiazide therapy are related to the dose
and duration of use (Fig. 2).
Thiazides can reduce the excretion of calcium
and uric acid and thereby increase their plasma
levels, and the drugs increase potassium and
magnesium excretion, potentially leading to hypokalemia and hypomagnesemia. On average,
measured plasma potassium levels decrease by
about 0.3 to 0.4 mmol per liter with typical dosing of thiazide monotherapy,78 but coadministration of an ACE inhibitor or an ARB can reduce the
incidence of clinically relevant hypokalemia. In
ALLHAT, the average potassium level among patients receiving chlorthalidone decreased from
4.3 mmol per liter to 4.1 mmol per liter over a
4-year period.52 The plasma potassium level should
be measured at baseline, before the initiation of
thiazide monotherapy; a potassium-sparing agent
may be considered if the baseline level is less
than 3.8 mmol per liter.
Maintaining potassium homeostasis is essential, since epidemiologic evidence implicates hypokalemia in the pathogenesis of thiazide-induced
dysglycemia.79 The importance of potassium balance is also emphasized by findings from the
SHEP study, in which the rate of coronary events
among patients with potassium levels below 3.5
mmol per liter was reduced to a lesser degree than
among patients with higher potassium levels.80
Hypokalemia can be managed with the use of a
potassium-sparing agent or supplemental potassium chloride. Potassium-sparing agents are preferred because they correct the underlying cause.
Dietary salt restriction can also minimize thia­
zide-induced potassium losses.28
New-onset diabetes has been reported in patients receiving thiazides; however, newly diagnosed diabetes occurs over time in many hypertensive patients, regardless of which class of
antihypertensive agent is used. Data suggest that
receipt of thiazides, as compared with other antihypertensive agents, over several years may lead to
an excess of 3 to 4% of new cases of diabetes.79
In ALLHAT, the rates of fatal and nonfatal myocardial infarction were similar among patients re-
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2159
n e w e ng l a n d j o u r na l
The
of
m e dic i n e
Increased proximal Na+ reabsorption
Increased arterial resistance
Possible limitation of blood-pressure lowering
Increased proximal Ca++ reabsorption
Decreased plasma volume
Diuretic
Adaptations to diuretics
Decreased cardiac output
Diuresis
Orthostasis
Decreased Ca++ clearance
Hypomagnesemia
Increased distal Ca++ reabsorption
Decreased uric acid clearance
Hyperuricemia
Impaired renal H2O excretion
Hyponatremia
Decreased renal blood flow
Prerenal azotemia
Increased activation of RAAS
Kaliuresis
Hypokalemia
?
Impaired insulin resistance
Dysglycemia
Figure 2. Potential Complications of Diuretics and Their Associated Mechanisms.
RAAS denotes the renin–angiotensin–aldosterone system.
ceiving chlorthalidone, despite the fact that newly
diagnosed diabetes was more frequent in the
chlorthalidone group (seen in 11.6% of patients)
than in the amlodipine group (9.8%) or the
lisinopril group (8.1%).54 To date, no analyses of
ALLHAT data have indicated that the development of diabetes obviates the benefit of the
thiazide.53-57 Similar findings have been reported in a large meta-analysis and in long-term
follow-up data of the SHEP cohort.81-83 Despite
these reassurances, newly diagnosed diabetes in
patients receiving thiazides remains a potential
concern, since the period of monitoring for long-
term diabetes-related adverse effects on cardiovascular outcomes may have been too short.
Few clinically relevant drug interactions occur with the use of thiazides; most notably, nonsteroidal antiinflammatory drugs diminish the
therapeutic effect of thiazides by causing sodium
retention. Thiazides can increase serum lipid levels, primarily total cholesterol and low-density lipoprotein cholesterol levels, by approximately 5 to
7% in the first year of therapy.84 A summary of
common clinical problems encountered with thiazides, and potential solutions, are detailed in
Table 3.
COLOR FIGURE
Version 4
Author
Fig #
Title
ME
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Artist
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Ernst
2
Diuretic Use in Hyper.
JL
JRI
LAM
AUTHOR PLEASE NOTE:
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Table 3. Common Clinical Problems Encountered with Thiazides, and Possible Solutions.*
Clinical Problem
Possible Solution
Attack of acute gouty arthritis
Obtain uric acid level, and discontinue thiazide if level is elevated. Recheck
level after resolution of the attack, and assess the need for prophylaxis.
Use another antihypertensive agent if uricosuric prophylaxis is not
tolerated or indicated.
Hypokalemia (serum potassium ≤3.5 mmol/liter)
Correct hypomagnesemia if present. Add potassium-sparing agent or supplemental potassium chloride. Advise salt restriction. If blood pressure is not
controlled, consider adding a RAAS inhibitor.†
Increase in serum creatinine from baseline level
Assess hydration status and discontinue any concurrent and unnecessary
nephrotoxic drugs (e.g., NSAIDs). Recognize that a slight elevation in creatinine may be the result of improved blood-pressure control in patients
with microvascular disease, in whom renal function is dependent on
blood pressure for adequate perfusion.
No apparent response to hydrochlorothiazide at a dose
of 25 mg/day
Assess lifestyle and advise salt restriction if needed. Consider increase in diuretic dose, switch to longer-acting thiazide such as chlorthalidone, or
addition of RAAS inhibitor.†
Report of dizziness on standing
Check for orthostasis. Reduce diuretic dose if necessary. Assess hydration
status, and insure diuretic is administered in the morning. Instruct the
patient to stand up slowly.
Discovery of asymptomatic hyponatremia
Assess concurrent medications (e.g., SSRIs) and determine risks and benefits
of continuing thiazide. Evaluate patient for excessive water intake.
Thiazide therapy recommended for patient with documented history of allergy to a sulfa antibiotic
Sulfa antibiotic allergy is not a contraindication to receiving a thiazide. The
risk for cross-sensitivity appears to be more dependent on an underlying
propensity for atopy than on any specific cross-reactivity among the
classes. If true allergy to thiazide is documented, ethacrynic acid
(a non–sulfa-containing loop diuretic) can be used.
Report of muscle cramps
Check serum potassium level and normalize if low. Consider another diuretic
if electrolyte levels are normal.
Impaired fasting glucose level or diabetes at baseline
Institute appropriate management of cardiovascular risk factors. Thiazide use
is not precluded.
Development of diabetes during thiazide therapy
Institute appropriate management of diabetes and related cardiovascular risk
factors. The average excess increase in glucose attributed to thiazide use
is approximately 3–5 mg/dl (0.2–0.3 mmol/liter). Thiazides will probably
be necessary for achieving blood-pressure targets. The addition of a RAAS
inhibitor† should be considered, especially if blood pressure is not controlled.
Nocturia or incontinence
Avoid thiazide dosing in the afternoon or evening. Limit evening fluid intake.
Consider discontinuing thiazide if symptoms are intolerable.
Baseline GFR <30–40 ml/min/1.73 m2 of body-surface
area
Substitute furosemide or torsemide. A practical formula for determining the
dose of furosemide, in milligrams to be given twice daily, is as follows:
(patient age + blood urea nitrogen level) ÷ 2. Torsemide can be given
once daily.
Development of sun sensitivity
Encourage sunscreen use.
* GFR denotes glomerular filtration rate, NSAID nonsteroidal antiinflammatory drug, and SSRI selective serotonin-reuptake inhibitor.
† Examples of renin–angiotensin–aldosterone system (RAAS) inhibitors are angiotensin-converting–enzyme inhibitors and angiotensin
II–receptor blockers.
pharmacologic discoveries have advanced the treatment of any disease in such a profound and enDiuretics are a heterogeneous class of antihyper- during manner.
tensive medications that have long demonstrated
Dr. Ernst reports receiving advisory fees and consulting fees
effectiveness in reducing blood pressure and the from Takeda Pharmaceuticals; and Dr. Moser, advisory fees
risk of cardiovascular events. With proper atten- from Takeda Pharmaceuticals and GlaxoSmithKline and lecture
fees from Kaiser and the Consortium for Southeastern Hypertion to appropriate selection, dosing, and moni- tension Control. No other potential conflict of interest relevant
toring, diuretic-based regimens can greatly improve to this article was reported.
the ability to achieve blood-pressure goals. Few
C onclusions
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n e w e ng l a n d j o u r na l
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Coyote Bluffs, Arizona
2164
Howie Garber, M.D.
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