Journal of Cardiovascular Pharmacology and

Therapeutics
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Diuretics: A Review and Update

George C. Roush, Ramdeep Kaur and Michael E. Ernst
J CARDIOVASC PHARMACOL THER published online 15 November 2013
DOI: 10.1177/1074248413497257

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Article
Journal of Cardiovascular
Pharmacology and Therapeutics
Diuretics: A Review and Update 00(0) 1-9
The Author(s) 2013
Reprints and permission:
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DOI: 10.1177/1074248413497257
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George C. Roush1, Ramdeep Kaur1, and Michael E. Ernst2

Abstract
Diuretics have been recommended as first-line treatment of hypertension and are also valuable in the management of hypervolemia
and electrolyte disorders. This review summarizes the key features of the most commonly used diuretics. We then provide an
update of clinical trials for diuretics during the past 5 years. Compared to other classes of medications, thiazide diuretics are atleast
as effective in reducing cardiovascular events (CVEs) in patients with hypertension and are more effective than b-blockers and
angiotensin-converting enzyme inhibitors in reducing stroke. Observational cohort data and a network analysis have shown that
CVEs are lowered by one-fifth from chlorthalidone when compared to the commonly used thiazide, hydrochlorothiazide. Relative
to placebo, chlorthalidone increases life expectancy. In those aged 80 years and older, the diuretic, indapamide, lowers CVEs relative
to placebo. The aldosterone antagonist, eplerenone, lowers total mortality in early congestive heart failure. The benefit of eplere-
none following acute myocardial infarction (MI) is limited to administration within 3 to 6 days post-MI. Aldosterone antagonists have
been shown to lower the incidence of sudden cardiac death and to reduce proteinuria. In the setting of heart failure, long acting loop
diuretics azosemide and torasemide are more effective in improving heart failure outcomes that the far more commonly used short
acting furosemide. Evening dosing of diuretics appears to lower CVEs relative to morning dosing. In conclusion, diuretics are a
diverse class of drugs that remain extremely important in the management of hypertension and hypervolemic states.

Keywords
cardiac pharmacology, cardiovascular disease, cerebrovascular disease, congestive heart failure, hypertension, diuretics

Introduction Henle, where 20% to 30% of filtered NaCl is reabsorbed. Loop

Diuretics are an invaluable and heterogeneous class of agents
commonly used in the treatment of hypertension, heart failure,
and electrolyte disorders. This review summarizes the basic
features of diuretics, including their mechanism of action, indi-
cations, adverse effects, and duration of action, followed by a
review of recent findings from randomized trials. For the latter,
we conducted a systematic review from PubMed covering the
last 5 years.
Mechanisms of Action
Diuretics are a heterogenous group of medications, but a few
generalizations are possible. With the exception of mannitol
and vasopressin receptor antagonists, all diuretics function ini-
tially by blocking sodium reabsorption in various sites within
the renal tubules. The organic acid secretory pathway delivers
carbonic anhydrase inhibitors, loop diuretics, thiazide diuretics,
and thiazide-like diuretics into the tubular lumen and thereby
arrives at their sites of action. In contrast, aldosterone antago-
nists reach their site of action, the principal cells of the cortical
collecting duct, via the blood stream.
The carbonic anhydrase inhibitor, acetazolamide, impairs
reabsorption of Na, HCO3, and water, increasing distal
delivery of Na to the distal collecting duct and K loss.
Loop diuretics such as furosemide, torasemide, azosemide,
and bumetanide act at the thick ascending limb of the loop of
diuretics bind to the Na-K-2Cl transport protein and inhibit its
action, impairing reabsorption of Na, K, and Cl and deli-
vering an increase in Na to the distal tubule. There it increases
exchange of Na for K and promotes K secretion into the
distal tubule. These changes decrease the osmotic driving force
and concentrating ability of the kidney.
Thiazide and related diuretics act mainly at the distal convo-
luted tubule, where the NaCl cotransporter is blocked, resulting
in impaired Na and Cl reabsorption, increased delivery of
Na to collecting ducts, enhanced exchange of Na and K, and
K wasting. Thiazides impair the kidneys diluting capacity and
impair Mg reabsorption but stimulate Ca2 reabsorption. This
last effect accounts for their role in treating calcium-containing
renal stones.
1
UCONN School of Medicine and St Vincents Medical Center, Bridgeport,
CT, USA
2
Department of Family Medicine, University of Iowa Hospitals and Clinics,
Iowa City, IA, USA
Manuscript submitted: May 4, 2013; accepted: June 18, 2013.
Corresponding Author:
George C. Roush, UCONN School of Medicine and St. Vincents Medical
Center, 2800 Main Street, Bridgeport, CT 06606, USA.
Email: groush@gcr0.com

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2 Journal of Cardiovascular Pharmacology and Therapeutics 00(0)
Thiazides decrease peripheral resistance by an unknown
mechanism and thereby lower blood pressure (BP). Initially,
thiazides decrease extracellular volume (ECF) and cardiac out-
put, but the ECF gradually returns to near normal over the
course of several weeks to months.
Potassium sparing diuretics act at the cortical collecting
duct and can be divided into 2 subcategories; Pteridine analogs
(that is triamterene and amiloride) inhibit reabsorption by the
epithelial Na channel (ENaC) of the collecting duct. Because
only 3% of the filtered Na is reabsorbed at the collecting duct,
these drugs do not result in appreciable diuresis and minimal
antihypertensive efficacy as monotherapies. Instead, they are
often used with other agents to correct K deficiency. The
aldosterone receptor blocker acts in the cytoplasm of principal
cells to downregulate the basolateral Na/K pump and the
aldosterone-sensitive ENaC. The final effect of both subcate-
gories is impairment of Na reabsorption, coupled with dec-
reased H and K secretion that would otherwise occur as a
result of voltage changes across the membrane.
The osmotic diuretic, mannitol, exerts its osmotic effect
throughout the length of renal tubule regardless of hydration
status and impairs normal tubular water reabsorption. Ulti-
mately, mannitol washes out the medullary solute gradient and
thereby impairs the kidneys concentrating ability. As with
thiazide and loop diuretics, there is increased Na delivery to
the distal nephron increasing K loss.
Vasopressin receptor antagonists block vasopressin at V2
receptors and prevent free water reabsorption at the collecting
ducts, leading to increased free water excretion.
Indications, Adverse Effects, and
Pharmacokinetics
Tables 1 and 2 present the key clinical and pharmacokinetic
aspects of each subclass of diuretics. The most important
adverse effects are derangements in electrolytes, particularly
serum potassium, which may be lowered by thiazides and loop
diuretics and elevated by aldosterone antagonists. The longer
duration of action of chlorthalidone, torasemide, and azose-
mide may be partly responsible for their greater efficacy in
reducing CVEs relative to their alternatives (see below).
It should be noted that the diuretic-induced reduction in salt
and water activates hormonal systems such as vasopressin, the
reninangiotensinaldosterone system, and the sympathetic
nervous system.1 This may lead to a relatively flat doseBP
response curve in patients with hypertension. However, in the
case of chlorthalidone, these effects can be eradicated by the
coadministration of spironolactone.2,3
Thiazide and Thiazide-Like Diuretics
Thiazides are Prominent in the Reduction of CVEs
In 2003, Psaty and colleagues, using both direct and indirect
(network) comparisons, demonstrated that low-dose diuretics
were superior to other major antihypertensive drug classes for
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reducing CVEs.4 Two recent meta-analyses exclude indirect
comparisons and limit comparisons of each drug class with
placebo or usual care.5,6 (In these analyses, reference to thia-
zides includes both true thiazides, such as hydrochlorothia-
zide, and thiazide-like diuretics, such as chlorthalidone and
indapamide.)
In one meta-analysis, data were limited to studies in which
70% or more of the patients had a BP >140/90, and low-dose
thiazides had, by far, the most evidence for a benefit in reduc-
ing CVEs.5 In a second meta-analysis,6 wherein data also
included trials in patients with primarily normal BP, thiazide
and thiazide-like diuretics were at least as effective as other
antihypertensives in reducing CVEs (see Figures 1 and 2). For
stroke outcomes, based on data in Figure 2, it can be calculated
that the relative risk from thiazides and thiazide-like diuretics
gave a point estimate significantly lower than that for b-block-
ers and angiotensin-converting enzyme inhibitors, P .013
and P .046, respectively.
Chlorthalidone is Superior to Hydrochlorothiazide in
Reducing CVEs
Hydrochlorothiazide (HCTZ) is the 10th most commonly pre-
scribed drug in the United States9 and is 20 times more fre-
quently prescribed than chlorthalidone (CTDN).10,11 In the
last 5 years, a number of studies have demonstrated the impro-
priety of these prescribing practices. CTDN has been shown
to be superior to HCTZ by 5 to 6 mm Hg in lowering systolic
BP,12,13 and, with its longer duration of action, has a relatively
greater impact on nighttime BP12 and trough levels.13 Com-
pared to HCTZ, CTDN was associated with a lower develop-
ment of left ventricular hypertrophy in a post hoc analysis of
the data of the multiple risk factor intervention (MRFIT)
trial.14
In a further retrospective cohort analysis of MRFIT partici-
pants, the relative risk (RR) (95% confidence interval [CI]) for
CVEs of CTDN versus HCTZ was 0.79 (0.68, 0.92).7 In a more
recent observational cohort study from the Ontario Drug
Benefit database, the RR for the primary health outcome was
0.93 (0.81, 1.06).15 However, this latter study had methodolo-
gical problems biasing the results toward finding no difference
between the 2 diuretics, including no standardization of cardi-
ovascular outcomes, the use of total mortality as a component
of the primary outcome, a duration of follow-up for patients on
CTDN of only 8.3 months, and the use of additional nondiure-
tic drugs on initiation of the diuretics. In a network analysis, the
RR for CVEs for CTDN versus HCTZ was 0.79 (0.88, 0.72),
P<.0001.8 Two other network analyses suggesting equivalence
of the 2 drugs suffer from the inclusion of other medications
at step 1 of the HCTZ arm16,17 and the omission of 3 large
trials, Antihypertensive and Lipid-Lowering treatment to pre-
vent Heart Attack (ALLHAT), Avoiding Cardiovascular
events in Combination therapy in Patients Living with Systo-
lic Hypertension (ACCOMPLISH), and Australian National
Blood Pressure 2 (ANBP2),16 all strongly favoring CTDN
in network analysis.
Roush et al 3

Table 1. Indications, Contraindications, and Adverse Effects of Diuretics.

Diuretic Clinical Uses Contraindication Adverse Effects

Loop Diuretic Edematous disorders (congestive heart Hypersensitivity to sulfa Volume depletion, decreased serum
failure, hepatic cirrhosis, agents, gout, pregnancy, K, Na, Mg2, and H. Increased
and nephrotic syndrome), nonreversible anuria uric acid, glucose, cholesterol, LDL,
hypertension with glomerular and triglycerides. Nausea,
filtration rate <30 mL/min, ototoxicity, and allergic interstitial
hypercalcemia, SIADH given with nephritis
NaCl, and renal tubular acidosis
Thiazides Nephrogenic diabetes insipidus, Hypersensitivity to sulfa agents, Orthostatic hypotension. Decreased
mild edema, and renal gout, hepatic failure, serum Na, K, Mg, and H.
calcium stones. and renal failure Modest increases in Ca2. Increases
in serum uric acid, glucose,
cholesterol, LDL, and triglycerides.
Erectile dysfunction, impotence, and
lithium accumulation
Thiazide-like agents Hypertension and resistant Ditto Ditto
(eg, chlorthalidone and hypertension
indapamide)a
Potassium Sparing Pteridine derivatives: Hyperkalemia, concomitant use Increase serum K+, Cl-, & H+. Nausea,
Pteridines: Hypertension with K+ &/or Mg+ loss, of ACEIs or ARBs, & renal flatulence & skin rash with amiloride
Triameterene & amiloride. Liddles syndrome failure, hepatic failure, or triamterene, nephrolithiasis with
pregnancy (particularly triamterene. Gynecomastia &
Aldosterone antagonists: Aldosterone antagonists: triamterene) decreased libido in men with
Spironolactone & Hypertension with K &/or Mg loss, spironolactone
Eplerenone. resistant hypertension, Primary
aldosteronism and other mineral
corticoid excess,b CHFc
Carbonic Glaucoma, metabolic alkalosis, altitude Hypersensitivity to Volume depletion, hypokalemia,
anhydrase inhibitors sickness, and diuretic resistance sulfonamides, metabolic hyperchloremic metabolic acidosis,
acidosis, pregnancy, light-headedness, circumoral par-
hepatic failure, and esthesias, weakness, and confusion
renal failure
Osmotic agents Cerebral edema CHF, volume depletion, Low volume, K, and H. CHF,
and nonreversible headache, nausea, vomit, fever,
anuria confusion, and lethargic state
Arginine vasopressin Short-term use in euvolemic or Increased thirst, dry mouth,
antagonists hypervolemic hyponatremia, hypokalemia, hypernatremia.
syndrome of inappropriate EVEREST trial shows small but
antidiuretic hormone. statistically significant increase in risk
of stroke
Abbreviations: SIADH, syndrome of inappropriate antidiuretic hormone secretion; LDL, low-density lipoprotein; CHF, congestive heart failure; ACEIs,
angiotensin-converting enzyme inhibitors; ARBs, Angiotensin II receptor blockers; EVEREST, efficacy of vasopressin antagonism in heart failure outcome study
with tolvaptan.
a
Like thiazides, these agents act on the distal convoluted tubule. However, they lack the benzothiadiazine ring framework of the thiazides and are more potent in
lowering of blood pressure.
b
Familial hyperaldosteronism type 1 (glucocorticoid remedial hyperaldosteronism) and familial hyperaldosteronism type 2 (apparent mineral corticoid excess).
c
Spironolactone in CHF with New York Heart stages 3 or 4. Eplerenone in CHF with New York Heart stage 2 and in those with decreased ejection fraction
following myocardial infarction.

Thus, 0.79 is the best estimate of the RR relating CTDN to
HCTZ in reducing CVEs as derived from observational and net-
work analyses. Recent guidelines have recommended CTDN
over HCTZ for resistant hypertension,18 hypertension manage-
ment in Blacks,19 and in general practice in the United King-
dom.20 The inertia in prescribing patterns is partly due to less
flexibility in pharmaceutical preparations for CTDN, which char-
acteristically comes in just 1 dose of 25 mg versus 12.5 mg, 25 mg,
and 50 mg for HCTZ and in fewer conventional fixed-dose drug
combinations (3 for CTDN versus 21 for HCTZ).
Chlorthalidone Increases Life Expectancy in 22-Year
Follow-up of the Systolic Hypertension in the
Elderly Program
In the systolic hypertension in the elderly program (SHEP)
trial, 4736 patients with a systolic BP of at least 160 mm Hg
and age of 60 or more were randomized to 12.5 to 25 mg of
CTDN versus placebo. After active treatment and mean
follow-up of 4.5 years, the RR (95% CI) in CVEs from the
CTDN arm was 0.68 (0.79, 0.58). All patients were then

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4 Journal of Cardiovascular Pharmacology and Therapeutics 00(0)

Table 2. Half-Life, Duration of Action, and Dosage of Diuretics.

Usual Dosage in Milligram,

Duration of Daily Unless Otherwise noted
Diuretic Half-Life, hours Action, hours (BID, Twice Daily; TID, Thrice Daily)

Loop diuretic
Furosemide 1.5-2 (prolonged in ESRD) 4-6 20-480 (BID or TID)
Torasemide 3-4 (unchanged in ESRD) 12 5-40
Bumetanide 0.3-1.5 (unchanged in ESRD) 4-6 0.5-5 (BID or TID)
Ethacrynic acid 12 25-100
Thiazides
Hydrochlorothiazide 3-10 12-18 12.5-50 (daily or BID)
Chlorothiazide 15-25 6-12 125-500 (daily or BID)
Bendroflumethiazide 2.5-5 18 2.5-5
Trichlormethiazide 1-4 24 1-4
Thiazide like agents
Chlorthalidone 24-55 24-72 12.5-25
Indapamide 6-15 24-36 1.25-2.5
Metolazone 24 0.25-2.5
Quinethazone 10 18-24 25-100
Potassium sparing, pteridine derivatives
Amiloride 17 (prolonged in ESRD) 24 5-10
Triamterene 3 12 50-150
Potassium sparing, aldosterone antagonists
Spironolactone 10-23 48-72 25-100
Eplerenone 3-4 12 25-100
Carbonic anhydrase inhibitor, acetazolamide 13 (prolonged in ESRD) 16 250-1000
Osmotic agent, mannitol 1 (up to 36 in ESRD) 2 50-200 gram (continuous iv
infusion or iv infusion every
3-4 hours of 20% solution
Vasopressin receptor antagonists
Tolvaptan 6-8 15-60
Lixivaptan 7-10 50-100 BID
Conivaptan 14-17 40-80
Satavaptan 14-17 5-25
Mozavaptan 1-8
Abbreviation: ESRD: end-stage renal disease.

advised to undergo active treatment. Recently, Kostis and col-
leagues completed a 22-year follow-up of these patients and
showed that the CTDN arm gave a gain in life expectancy of
105 days (95% CI 39-242), P .07, and a gain in time to car-
diovascular death of 158 days (95% CI 36-287), P .009.21
This is the first trial of any antihypertensive medication with
more than 2 decades of follow-up to demonstrate such a bene-
fit. The results indicate a legacy effect that may stem from
irreversible changes in arterial vasculature in the placebo group
during the first several years of the trial.
Long-Term Follow-up of the ALLHAT Trial
In ALLHAT, patients were randomized to CTDN, lisinopril, or
amlodipine. During the active treatment phase (mean 4.9
years), CTDN was superior to lisinopril in preventing CVEs
and was superior to amlodipine in preventing congestive heart
failure (CHF). Long-term follow-up for a total of 8 to 13 years
revealed the persistent advantage of CTDN over amlodipine in
preventing CHF and an advantage of CTDN over lisinopril in
preventing stroke mortality. The interaction between race and
CTDN versus lisinopril in preventing CVEs was observed in
both the initial 4.9 years and the long-term follow-up.22
Patients Aged 80 Years and Older Benefit From
Treatment for Hypertension With the Step 1 Drug,
Indapamide: The Hypertension in the Very Elderly Trial
Three trials (Systolic Hypertension in the Elderly Program, Sys-
tolic Hypertension in Europe, and Systolic Hypertension in
China) have shown the benefits of treating hypertension in those
aged 60 years and older. The benefit of treating Hypertension in
the Very Elderly has been addressed more recently. The interna-
tional Hypertension in the Very Elderly Trial (HYVET) enrolled
3845 patients without dementia and with age 80 and systolic
BP off treatment of 160 mm Hg. In double-blind fashion,
patients were randomly assigned to indapamide sustained release
at 1.5 mg or placebo at step 1 with perindopril or matching pla-
cebo at step 2 to achieve a target BP of less than 150/80 mm
Hg23. Whether there was allocation concealment was not
reported. Assessment of end points was blinded with respect to
treatment arm, and completeness of follow-up was 100%. At 2

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Roush et al 5

Figure 1. Relative risk estimates of coronary heart disease (CHD) events and stroke in single-drug blood pressure difference trials according to
class of drug excluding CHD events in trials of b-blockers in people with the history of CHD. Totals are less than the sum of the individual
categories, because some trials include more than 1 category.6

Figure 2. Relative risk estimates of coronary heart disease (CHD) events and stroke in single-drug blood pressure difference trials according to
class of drug, excluding CHD events in trials of b-blockers in people with the history of CHD. Totals are less than the sum of the individual
categories because some trials include more than one category. Reprinted with permission from the British Medical Journal.6

years, mean BP was 15/6 mm Hg lower in the treated group. The
RR (95% CI) from the indapamide arm for the primary end point
(fatal or nonfatal stroke) was 0.70 (1.01, 0.49), P .06, for heart
failure was 0.36 (0.58, 0.22), P < .001, for any CVE was 0.67
(0.82, 0.53), P < .001, and for total mortality was 0.79 (0.65,
0.95), P .02. At odds with conventional wisdom, there were
fewer adverse events in the active treatment group.23
Aldosterone Antagonists
Eplerenone Reduces Total Mortality in New York Heart
Failure Class II: The Eplerenone in Mild Patients
Hospitalization and Survival Study in Heart Failure trial
In 1999, Pitt and colleagues reported that spironolactone
decreased total mortality in patients with CHF, New York
Heart Class III and IV.25 Recently, patients with more mild
CHF have also been shown to benefit from the aldosterone
antagonist, eplerenone.24 In this double-blinded trial, patients
(N 2 737 from 29 countries) were those with New York Heart
Class II with ejection fraction <30% or ejection fraction 31% to
35% with a QRS duration of 131 milliseconds. Also, patients
must have been hospitalized for a cardiovascular reason in the
past 6 months or to have had an elevated level of B-type natriure-
tic peptide (BNP) or N-terminal proBNP. Exclusions were those
with acute myocardial infarction (MI) within the past 30 days,
glomerular filtration rate (GFR) <30 mL/min, elevated potas-
sium, or those requiring a potassium sparing diuretic.24
Patients were randomized to placebo or eplerenone with a
starting dose of 25 mg daily advancing to 50 mg daily, or, for
those with compromised renal function, 25 mg every other day
advancing to 25 mg daily. Allocation was concealed, outcomes
were adjudicated by an independent committee using prespeci-
fied criteria, and follow-up was 99% complete.
The trial was terminated prematurely based on prespecified
stopping rules with a median follow-up of 21 months. For the

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6 Journal of Cardiovascular Pharmacology and Therapeutics 00(0)
primary outcome of cardiovascular death or hospitalization
for heart failure, the adjusted hazard ratio (AHR; 95% CI) was
0.63 (0.54-0.74), P < .001, for death from any cause was 0.78
(0.64-0.95), P .01, and for hospitalization for heart failure
was 0.61 (0.50-0.75), P < .001. There was also a trend toward
a reduction in sudden cardiac death with an AHR of 0.77
(0.55-1.08), P .12.
Spironolactone reduced diastolic dysfunction in patients
with preserved ejection fraction in a recent report.26 Further,
spironolactone reduced left ventricular mass in these patients.
Also, spironolactone, but not irbesartan, reduced CTDN-
induced sympathetic activation in a study of 13 patients and
prevented the development of CTDN-induced insulin resis-
tance.3 It is unknown whether these changes translate into a
clinical benefit.
Following an Acute MI, Eplerenone Reduces Total
Mortality only When Treated Within 3 to 6 Days: Further
Analysis of the Eplerenone Post-Acute MI Heart Failure
Efficacy and Survival Trial Longer Acting Loop Diuretics Versus Furosemide in
In patients with systolic dysfunction following a MI, as Reducing CVEs
reported in 2003,28 the RR (95% CI) from eplerenone for total
mortality was 0.85 (0.96, 0.75). In a more recent analysis of the
same data, efficacy was shown to be limited to those given
eplerenone within 3 to 6 days following the MI. For total mor-
tality, the RR for those given eplerenone versus placebo in the
period 3-6 days post-MI was 0.72 (0.81, 0.58), P .002,
whereas for those given treatment or placebo 7 to 14 days
post-MI, the RR was 0.93 (0.79, 1.09), P .37. The interaction
effect was statistically significant, P .003. No important
adverse effects were associated with the earlier administration
of eplerenone. The authors theorized that the beneficial effect
of earlier eplerenone treatment may have been due to preven-
tion of postinfarct remodeling and fibrosis associated with
increased aldosterone levels during the first several days fol-
lowing an MI.27
Aldosterone Antagonists Reduce Sudden
Cardiac Death
Aldosterone antagonists have been shown to reduce ventricular
arrhythmias in animals and clinical trials. Wei and colleagues
conducted a systematic review and meta-analysis of aldoster-
one antagonists in the prevention of sudden cardiac death. In
a pooled analysis of 2 trials with 8295 patients, aldosterone
antagonists (primarily eplerenone) carried a lower risk of sud-
den cardiac death with RR (95% CI) equal to 0.79 (0.93-0.67),
P < .001. In a pooled analysis of 2 trials, patients randomized to
spironolactone had a lower risk of ventricular tachycardia with
RR of 0.28 (0.77-0.10), P < .001.29 It should be emphasized
that the BP-lowering effect from eplerenone is roughly two-
thirds of that from spironolactone, and lumping them together
may be inappropriate.29
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Aldosterone Antagonists Reduce Proteinuria
New data confirm prior work demonstrating the benefits from
aldosterone antagonists added to usual therapy in reducing pro-
teinuria. In a double-blind, crossover randomized trial, patients
with type 2 diabetes receiving either an angiotensin-converting
enzyme inhibitor or an angiotensin receptor blocker were given
either placebo or spironolactone after a 1 month wash out
period.30 The treatment decreased urinary protein by 55%.
Likewise, in type 1 diabetes, spironolactone decreased urinary
albumin by 60%.31 In nondiabetic renal disease, spironolactone
decreased proteinuria by 58% to 72%,32,33 whereas eplerenone
had a significant but more modest decrease in albuminuria by
22%.35
In hyperaldosteronism, spironolactone was markedly more
potent than eplerenone in reducing systolic BP, 27.0 mm
Hg versus 9.9 mm Hg, respectively.36
Loop Diuretics
Azosemide suppresses the sympathetic nervous system rela-
tive to furosemide.36 Masuyama and colleagues randomized
320 patients with New York Heart Class II or III to receive
either azosemide 30 to 120 mg or furosemide 20 to 60 mg
(dosage increased as needed to control symptoms) in an
open-label study with blind determination of the end point.37
Whether there was allocation concealment was not reported.
Excluded were those with uncontrolled diabetes, creatinine
>2.5 mg/dL, acute coronary syndrome or, in the past 3
months, those with acute MI, percutaneous intervention, or
open heart surgery. Follow-up was 98% complete. After a
minimum of 2 years, the RR (95% CI) in the primary end
point (cardiovascular death or unplanned hospitalization) was
0.55 (0.95-0.32), P .03, and for the secondary outcome
(unplanned admission to hospital for CHF or need to modify
treatment of CHF) the RR was 0.60 (1.00-0.36), P .048.
There were no significant differences between the 2 arms in
hypokalemia or hypotension. In a pooled analysis of 2 trials,
relative to furosemide, torsemide reduced heart failure read-
missions, RR 0.41 (0.28-0.61), P < .001.38 These findings
are particularly important in view of the widespread use of
furosemide for heart failure.34-37
Continuous Versus Bolus Dosing of Furosemide
In acute heart failure, 2 recent studies have shown no difference
in changes in serum creatinine between bolus and continuous
dosing of furosemide,39,40 with the latter study also giving no
difference in global symptoms.40 However, in patients with
chronic kidney disease without acute heart failure, continuous
infusion of furosemide was better than bolus administration for
natriuresis and diuresis.42
Roush et al
Relative to Morning Dosing, Evening Dosing of Loop
Diuretics Improves BP Control
Loop diuretics are generally viewed as a third or fourth choice
among diuretics in the treatment of hypertension in patients
with normal renal function because of lower antihypertensive
efficacy and lack of data showing a reduction in CVEs.41 How-
ever, loop diuretics are first among diuretics in treating patients
with hypertension with renal insufficiency (GFR <30 mL/min)
and also figure prominently in treating resistant hypertension
wherein a central component of the resistance is due to excess
salt and water.18 Recently, a low dose (5 mg/d) of the long-
acting agent, torsemide, provided much better BP control
among patients with grades 1 and 2 hypertension when admi-
nistered in the evening when compared to morning: the 24-
hour ambulatory systolic BP reduction was 14.8 versus 6.4
mm Hg, respectively, P < .001.43 The percentage of patients
achieving control was also higher with evening dosing: 64%
versus 23%, respectively, P < .001.43
Evening Dosing of Diuretics
(Not Otherwise Specified)
In a randomized open label trial in a single referral center, eve-
ning dosing of one or more antihypertensive medications low-
ered CVEs relative to dosing all medications in the morning.44
As with other classes of medications, diuretics were associated
with lower risk of CVEs when dosed in the evening versus dos-
ing them in the morning.45 The risk of falls and the occurrence
of nocturia were not discussed.
Long-Acting Diuretics and Reduction of CVEs
As reported above, the long-acting agents, chlorthalidone and
azosemide, are superior to their short-acting counterparts,
hydrochlorothiazide and furosemide, respectively. The long-
acting agents may have better BP control in the nighttime with
reduction in nondipping, a known risk factor for CVEs. The
findings of Hermida et al44 as regards evening dosing of anti-
hypertensives are consistent with this concept.
Arginine Vasopressin Receptor Antagonists
These medications have been shown to promote substantial
diuresis while maintaining electrolyte balance. In the setting
of CHF, both oral tolvaptan and intravenous conivaptan main-
tained serum sodium in the face of a greater diuresis.46-48 Sata-
vaptan minimizes ascites when added to standard therapy with
furosemide and spironolactone.49,50
Conclusion
Diuretics are a diverse class of drugs that remain extremely
important in the management of hypertension and hypervole-
mic states.
Downloaded from cpt.sagepub.com at Bobst Library, New York University on December 1, 2013
7
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, author-
ship, and/or publication of this article
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