Update in Diuretic Therapy: Clinical Pharmacology

D. Craig Brater, MD

Summary: All diuretics except spironolactone exert their effects from the lumen of the nephron. Thus, to exert an
effect, they must reach the urine. Pharmacokinetics (PK) describes this access. Different edematous disorders can
affect access to this site of action and therein affect response to a diuretic. In addition, once a diuretic reaches the
site of action, a response ensues. The characteristics of this response that can be affected by a patients clinical
condition are described by the pharmacodynamics (PD) of a diuretic. To understand the mechanisms of abnormal
response to a diuretic one must dissect its PK and PD in different edematous disorders. For example, in patients
with renal insufficiency, the mechanism of poor diuretic response is PK. In contrast, in patients with cirrhosis or in
those with congestive heart failure, it is PD. In patients with nephrotic syndrome, both PK and PD are operative.
These different mechanisms mandate differences in therapeutic strategy, as explained in this article.
Semin Nephrol 31:483-494 2011 Elsevier Inc. All rights reserved.
Keywords: Diuretic, edema, renal insufficiency, nephrotic syndrome, cirrhosis, congestive heart failure

T his update considers diuretic therapy from the

perspective of pharmacokinetics (PK) and phar-
macodynamics (PD); lest readers panic at the
mathematic implications of those terms, this article will
deal only with PK and PD in general terms. To that end,
strategies, the topic of using combinations of diuretics
arises and also is addressed.

CLINICAL PHARMACOLOGY OF DIURETICS

PK simplistically refers to the fact that for a diuretic or Pharmacology

any drug to exert an effect, it must reach its site of action.
Thus, any condition that affects such access alters di-
uretic response via a PK mechanism and therapeutic
strategies must be designed to account for this. PD de-
scribes how the end-organ responds to the drug; in this
case, how the kidney responds to the amount of diuretic
reaching it. Disease can influence both these determi-
nants of response, singly or concomitantly. The therapeu-
tic strategy to overcome a PK problem differs from a
strategy directed toward a PD problem. Patients with
renal insufficiency have substantial changes in the PK of
loop diuretics with PD little affected, whereas patients
with cirrhosis have virtually normal PK and changes in
PD dominate. These differences extrapolate to different
therapeutic strategies in patients with renal disease com-
pared with what one would use in patients with cirrhosis.
This article first discusses the determinants of normal
response to diuretics, focusing on loop diuretics, for
which data are most robust. This information then serves
as the platform for an examination of disease effects.
When this understanding is translated into therapeutic
Division of Clinical Pharmacology, Department of Medicine, Indiana
University School of Medicine, Indianapolis, IN.
Supported by the General Clinical Research Center (MO1 RR00750)
and R01 DK 37994 and R01 AG 07631.
Address reprint requests to D. Craig Brater, Division of Clinical
Pharmacology, Department of Medicine, Indiana University School
of Medicine Fairbanks Hall, 340 West 10th St, Suite 6200, India-
napolis, IN 46202. E-mail: dbrater@iupui.edu
0270-9295/ - see front matter
2011 Elsevier Inc. All rights reserved.
doi:10.1016/j.semnephrol.2011.09.003
The pharmacology of all loop diuretics is similar, when
administered in comparable doses, they exert comparable
effects. Sometimes the question is raised clinically as to
whether a patient who did not respond to a maximal dose
of one-loop diuretic will have a better response to a
different loop diuretic. There is no pharmacologic ratio-
nale for such to occur and there are no published data to
suggest it does. If this phenomenon is observed, it is the
result of either using doses of diuretics that are not really
equivalent or because of other events occurring in the
patient such as the addition of other drugs or a change in
the patients clinical condition. The clinical importance
of this similar pharmacology is that lack of response to
adequate doses of one-loop diuretic also means lack of
response to others. In this clinical setting administration
of a different loop diuretic is not indicated; rather, com-
binations of diuretics and/or alternative treatments of the
patients primary disease should be used. The same con-
cepts apply to thiazide diuretics.
The solute reabsorptive pumps that are inhibited by all
diuretics except spironolactone and eplerenone are lo-
cated on the luminal as opposed to the peritubular surface
of the nephron. Therein, these diuretics must reach the
urine to cause an effect.1-4 This means the PK in the
plasma is not important except as it might reflect the PK
of diuretic in the urine. It also means that if one asks
whether a certain disease state affects the diuretic reach-
ing the site of action compared with a normal setting, one
must determine what is occurring with the diuretic in the
urine as opposed to plasma. All diuretics that are active
from the luminal surface with the exception of osmotic
agents are secreted actively into the urine at the proximal
tubule. They are so highly bound (95%) to circulating

Seminars in Nephrology, Vol 31, No 6, November 2011, pp 483-494 483

484
Table 1. Pharmacokinetics of Diuretics
Bioavailability, % of Oral Dose Absorbed Healthy
Loop diuretics
Furosemide 50 (high variability) 1.5
Bumetanide 80-10 1 1.6
Torsemide 80-100 3-4
Thiazide diuretics Varies Varies
Distal diuretics
Amiloride Presumably complete 7-26
Triamterene* 80 2-5
Spironolactone Presumably complete 1.5
Active metabolites 15
*Data are for active metabolites.
proteins that only trivial amounts are filtered.1-4 Binding
to serum proteins serves to trap the diuretic in the vas-
cular space, where it then is delivered to the proximal
tubule and secreted. Loop and thiazide diuretics and
acetazolamide are secreted through pathways for organic
acid transport1,2; amiloride3 and triamterene4 are secreted
by pathways for organic bases.
Pharmacokinetics
The organ primarily responsible for metabolism can in-
fluence the selection of a diuretic (Table 1). For example,
furosemide is eliminated primarily by the kidney and if
one desires to avoid accumulation in a patient with renal
insufficiency, one can use a loop diuretic that is metab-
olized by the liver; namely, bumetanide or torsemide.5-10
In a patient with liver disease, because triamterene is
converted to its active metabolite by the liver, one logi-
cally would be concerned whether the patient would be
able to make enough of the active metabolite.11,12 This
concern could be obviated by using amiloride.13 In sum-
mary, knowing what organ primarily eliminates a diuretic
can influence choice among alternatives.
In addition to routes of metabolism, the PK parameters
that are most important are bioavailability and elimina-
tion half-life (Table 1).
Fifty percent of a dose of furosemide is absorbed as
compared with 80% to 100% for bumetanide and
torsemide.5 In general, this means when converting from
intravenous to oral therapy, the dose of furosemide is
doubled, whereas that for bumetanide and torsemide re-
mains the same. Unfortunately, this generalization is too
simplistic because of the high variability in furosemide
absorption; although the average bioavailability is 50%,
the range is from 10% to 100%.5,14 Of course, the indi-
vidual patient is rarely average, therefore there is no way
to know if a patient will absorb 10%, 50%, 100%, or any
other percentage of a furosemide dose. This means the
physician must explore a range of doses in an individual
patient to find the correct oral dose. For example, if a
D.C. Brater
Elimination Half-Life, h
Influence of Disease
Renal Disease Liver Disease CHF
2.6 2.5 2.7
2.3 1.3
4-5 8 6
Prolonged Negligible change Negligible change
100 Negligible change Presumably no change
Prolonged Not formed ?
No change No change Presumably no change
? ? ?
patient requires 80 mg of intravenous furosemide twice a
day to maintain the desired body weight, then a logical
starting oral dose is 160 mg twice a day. However, this
patient may actually need only 80 mg twice a day (if
he/she absorbs 100%); alternatively, the patient may need
800 mg twice a day if only 10% of the dose is absorbed.
The problematic reality is that patients receiving oral
furosemide need close individualized titration to deter-
mine the proper dose.
Bumetanide and torsemide differ considerably from
the pattern of absorption observed with furosemide. Be-
cause they are completely absorbed, the range of absorp-
tion is also narrow.5,10,15,16 There is no need for titration
when switching from an intravenous to an oral dose with
these two diuretics. The variability of loop diuretic ab-
sorption is likely more clinically important than absolute
bioavailability. One small outcomes study suggested that
in high-risk patients with congestive heart failure (CHF),
a completely and predictably absorbed loop diuretic can
decrease hospitalizations for heart failure exacerbation
by about 50%.17,18 Whether these data can be generalized
more broadly to patients with CHF requires further study.
At times, the question is raised as to whether edema-
tous patients who presumably also have edema of the
intestinal wall might malabsorb diuretics, not to mention
other medications. Several studies have addressed this
question with loop diuretics.10,15,16,19-23 The rate of ab-
sorption is slowed to some degree, particularly in patients
with decompensated heart failure,23 but the total amount
of drug absorbed is the same as in healthy individuals.
The clinical implications of slowed absorption are un-
clear. Overall, these data indicate that one does not need
to be concerned about malabsorption per se in patients
with edema.
The elimination half-life of a drug has several impli-
cations, one of the most important of which is how
frequently the drug must be administered (Table 1). The
longer the half-life, the longer the duration of action,
meaning the drug can be administered less frequently
Diuretic therapy update
than a drug with a short half-life. Thiazide and distal-
acting diuretics can be administered once or twice a day
because of the length of their half-lives.5
This is not the case with loop diuretics. The duration
of effect ranges from about 2.5 to 3 hours for bumet-
anide. It is 4 to 6 hours for torsemide, whereas furo-
semide is intermediate.5 Efforts by many companies to
develop a truly long-acting loop diuretic or a sustained-
release form of currently marketed drugs have failed. As
a consequence, if a loop diuretic is administered once or
twice a day, there will be a considerable period of time in
the dosing interval during which there is no diuretic at the
site of action. During this time that follows the diuretic
effect, the nephron is poised to avidly reabsorb sodium so
that the vast majority of sodium taken in during this time
is retained, a phenomenon called rebound sodium re-
tention.24 The sodium retention can nullify the natriuresis
caused by the diuretic so there is no net negative sodium
loss despite the fact that the patient undergoes a diuresis
when he or she takes a dose. This is particularly the case
if the patients diuretic response is low, if the time of
negligible drug effect is long, if the patient ingests so-
dium during the time interval of no diuretic at the site of
action, and/or if the patients dietary sodium intake is
high relative to response. The timing of the dietary intake
is particularly a problem if the sodium load occurs when
the diuretic effect has dissipated. If a patient takes in salt
at the end of a dosing interval of loop diuretic, virtually
all of the sodium is retained. In contrast, if the sodium
load occurs when effective amounts of diuretic are pres-
ent in the nephron, most of the load is excreted.25 The
Figure 1. Pharmacodynamics of a loop diuretic in healthy subjects and in edematous disorders wherein the natriuretic response relative to the
amount of diuretic reaching the urinary site of action defines a sigmoid-shaped curve.
485
implications of short half-lives are that one may need to
dose the diuretic frequently such as three or even four
times a day, fully realizing the challenges of adherence
with such dosing frequencies. In addition, one may wish
to consider having patients take their diuretic shortly
before a meal to make sure the salt ingested has the
greatest likelihood of being eliminated. Dosing needs
will vary among patients so there is not one simple rule
of thumb that can be applied. The need to individualize
therapy is paramount.
Pharmacodynamics
The relationship between the diuretic at the site of action
and response defines its PD. Figure 1 depicts this rela-
tionship for loop diuretics and shows the effect of various
edematous disorders.1 The relationship for all loop di-
uretics is the same except for the position of the curve on
the x-axis. Technically, this means they differ in potency.
But the upper asymptote of the relationship is the same
for all loop diuretics. The technical term for this is
efficacy. If drugs have the same efficacy but different
potencies, different milligram amounts are given but the
same natriuretic effect is attained. This reinforces a point
made earlier that if a patient does not respond to adequate
doses of one loop diuretic, there is no reason to admin-
ister a different one. The same is also true for thiazide
diuretics.5 Choice within these two classes of diuretics
should be governed by factors such as PK and cost.
An important feature of the relationship shown in
Figure 1 is that a maximal response occurs as depicted by
486
the upper plateau. Once this plateau is reached, higher
doses do not cause a greater response, meaning there is
no need to administer higher doses. Doing so only ex-
poses the patient to risk from high doses that will not
increase response. That an upper plateau of response
occurs means one can define the largest dose of a loop
diuretic that needs to be administered. For example, in a
patient with severe renal insufficiency who does not
respond to a loop diuretic dose of X, the question arises
as to whether one should attempt a dose of 2, 3, 4, or
whatever times X. The very nature of the PD relationship
allows one to determine in clinical studies the dose
necessary to attain the upper plateau of response. That in
turn allows derivation of clinical guidelines as to the
largest dose that needs to be administered. Results of
such studies are discussed subsequently.
In healthy individuals the dose of a loop diuretic
required to cause a maximal response is modest; namely,
an intravenous bolus dose of furosemide of 40 mg or the
equivalent of other loop diuretics. The maximal natri-
uretic response in a healthy person is excretion of 200 to
250 mEq of sodium in a urine volume of 3 to 4 L over 3
to 4 hours. This normal frame of reference is helpful to
keep in mind when monitoring response and defining
therapeutic expectations in patients.
The PD of distally acting diuretics are undefined, but
presumably the same principles apply as with loop and
thiazide diuretics.
Diuretic Tolerance
There are two types of diuretic tolerance. Acute toler-
ance, which is also called braking, describes the fact that
within a short period of time hours if not minutes
response to the amount of diuretic at the site of action
diminishes. This occurs within the first dose of a diuretic;
it can be prevented by restoring diuretic-induced volume
losses.26-28 Presumably this phenomenon occurs to pro-
tect the organism from harmful decreases in intravascular
volume. An important clinical ramification of acute tol-
erance is once the loop diuretic at the site of action has
Figure 2. Illustration of the mechanism for the synergistic response to combinations of loop and thiazide diuretics. Chronic therapy with loop
diuretics floods the distal nephron with solute and causes hypertrophy. Blockade of hypertrophied nephrons results in substantial natriuresis
that is greater than that caused by loop and thiazide diuretics separately.
D.C. Brater
dissipated, the nephron is primed to avidly reabsorb
sodium for the rest of the dosing interval until the next
dose is administered. If a patient ingests enough sodium
during this time, the prior natriuresis can be neutralized
completely. This emphasizes the need to restrict dietary
sodium and in some patients to administer multiple doses
of loop diuretics to maintain a net negative sodium bal-
ance.
The mechanism for acute tolerance is unclear, al-
though it must entail short-term physiologic feedback
loops. One would expect mediators such as angiotensin II
and/or norepinephrine, but converting enzyme inhibition,
adrenergic blockade, and both combined do not consis-
tently prevent acute tolerance in experimental set-
tings.29-31 It is clear the trigger for braking is intravascular
volume depletion, but the mediator(s) is unknown.
Another form of diuretic tolerance is chronic toler-
ance. Loop diuretics cause sodium to flood more distal
nephron sites. Over time, increased exposure to sodium
causes hypertrophy of distal nephron segments with con-
comitant increases in the reabsorption of sodium.32-36
Thus, even if substantial amounts of sodium are rejected
from the loop of Henle, much of it can be reclaimed at
distal sites, causing an overall decrease in loop diuretic
response.
Thiazide diuretics block the nephron site at which
hypertrophy occurs, explaining the mechanism for the
additive, often synergistic, and sometimes profound na-
triuresis that occurs when a thiazide and a loop diuretic
are combined.37 In this setting, a thiazide diuretic has
negligible effects because little solute is delivered to
distal sites in sodium-retentive states. But a loop diuretic
similarly has diminished effect because sodium rejected
from the loop of Henle is reclaimed at the hypertrophied
sites that are sensitive to thiazide diuretics. Figure 2
shows how combining the two diuretics can cause a
marked response. The importance of this phenomenon
clinically is the logic of using combinations of loop and
thiazide diuretics when patients do not respond ade-
quately to loop diuretics alone.
Diuretic therapy update
THERAPEUTIC STRATEGIES
Renal Insufciency
Patients with severe renal insufficiency (glomerular fil-
tration rate [GFR] of approximately 15 mL/min) deliver
one fifth to one tenth as much loop diuretic into the urine
as does a healthy volunteer.5 Therefore it is clear that
such patients have a PK problem in not delivering ade-
quate amounts of diuretic to the site of action. Intuitively,
a reasonable therapeutic strategy to overcome this prob-
lem would be to administer a sufficiently large dose to
attain effective amounts in the urine.
Ceiling Doses
Patients with renal insufficiency do not in addition have
a PD problem because the relationship between amounts
of diuretic reaching the site of action and response in
such patients shows the same sigmoid-shaped curve as
occurs in healthy volunteers.38,39 These data mean resid-
ual nephrons in patients with renal insufficiency retain
their responsiveness to amounts of loop diuretic reaching
them (Fig. 1, upper right panel). The challenge in such
patients is administering the right dose that will deliver
enough drug to the active site. Literature reports have
indicated that widely varying amounts of loop diuretics
have been administered in patients with severe renal
insufficiency. More recent studies have specifically ad-
dressed the question of the largest dose that needs to be
administereda so-called ceiling dose. The nature of the
PD relationship and specifically its upper plateau dis-
cussed previously allows one to design such a study. In
essence, to know the ceiling dose one must determine the
dose necessary in a patient with renal insufficiency to
deliver amounts of diuretic in the urine that reach the
upper plateau of response. Such studies have shown this
occurs with intravenous bolus doses of furosemide of 160
to 200 mg or the equivalent of bumetanide and
torsemide.38,40 Importantly, there is nothing to be gained
by administering larger single doses.
The ceiling doses described earlier refer to intravenous
administration of a bolus dose usually given over 20 to
30 minutes to minimize the risk of toxicity. It is impor-
tant to consider comparable oral doses. Because bumet-
anide and torsemide are completely absorbed the intra-
venous and oral doses are the same. It is far more
complicated for furosemide. Its average bioavailability is
50%, therefore on average the oral dose is twice the
intravenous dose; namely, 320 to 400 mg. However,
furosemide absorption has huge variability, ranging from
10% to 100% from patient to patient and also within the
same patient from day to day. In the patient who only
absorbs 10% of a dose the oral dose equivalent to the
intravenous ceiling dose is 2,000 mg. If there is any
suspicion one might be dealing with a patient with low
absorption of furosemide, one could try one of the com-
pletely absorbed diuretics before concluding an inade-
quate response.
487
Although administering such doses causes maximal
response it is important to recall that maximal response is
about 20% of filtered sodium. In a healthy subject caus-
ing this fraction of the filtered load to be excreted is a
substantial natriuresis amounting to 200 to 250 mEq of
sodium. But when the GFR is 15 mL/min, the maximal
amount of sodium that is excreted is small in magnitude:
about 25 mEq (Fig. 1, upper left panel). In such patients
unless severe dietary sodium restriction is possible, there
is no hope of maintaining the desired fluid balance using
a loop diuretic alone. Contrary to what is often believed,
one can attain an additional natriuretic effect even in
patients with severe renal insufficiency by adding a thi-
azide diuretic.41-43
Combination of Loop and Thiazide Diuretics
When a decision has been made to add a thiazide to a
loop diuretic, one must decide which thiazide to add
among the many available and at what dose. Some cli-
nicians seem to believe metolazone has special utility in
this setting.37 This is particularly the case in the United
States, whereas in other parts of the world other thiazides
are used. There is a substantial amount of literature
confirming that all thiazides when used in appropriate
doses are effective as combinations with loop diuretics
including in patients with renal insufficiency.37,41-43 Phar-
macologically, metolazones action is little, if any, dif-
ferent from a thiazide. Many are not aware that metola-
zone also has undesirable PK in that it is poorly and
erratically absorbed.5,37 In addition, its elimination half-
life of about 2 days means it accumulates in patients for
10 days. In an acute setting this makes titration to the
right dose a challenge.5,37 Other thiazides such as hydro-
chlorothiazide are more predictably absorbed and do not
accumulate over long periods of time, making them eas-
ier to use.
Thiazide diuretics also exert their effects from the
luminal side of the nephron. As a result, they also must
be given in large doses to attain effective amounts in the
urine.41-43 For example, patients with mild to moderate
renal insufficiency require doses of hydrochlorothiazide
of 50 to 100 mg/d; those with more severe disease likely
require 100 to 200 mg/d. All thiazides have sufficient
durations of action that they can be given once a day.
Continuous Intravenous Infusion
Another strategy to enhance overall response to a loop
diuretic in a patient with renal insufficiency is to admin-
ister it as a continuous intravenous infusion. Of course,
this means the patient is in the hospital and often in
intensive care. As discussed previously, intermittent dos-
ing of any loop diuretic results in peaks and valleys of
effect because the amount of drug at the active site varies
over time. A continuous intravenous infusion is designed
to maintain effective amounts of the diuretic at the site of
action at all times; so doing results in an increase in the
488
Table 2. Doses for Continuous Intravenous Infusion of Loop Diuretics
Intravenous Loading Dose, mg
Creatinine Clearance (mL/min) All Levels
Furosemide 40
Bumetanide 1 1 then 2
Torsemide 20
NOTE. Before increasing to a higher infusion rate, a repeat loading dose should be administered.
total amount of sodium excreted.44 This is also the case in
other edematous disorders.45-48
What is the right infusion rate if this strategy is to be
used? At the start of therapy a loading dose should be
administered (Table 2). If not, four times the half-life of
the chosen loop diuretic will be required to reach a steady
state; namely, 6 to 20 hours. Presumably, such patients
are sick enough that this delay would not be propitious.
Once a loading dose is given the continuous infusion
should commence at the initial rate indicated in Table 2
according to the patients level of renal function. If the
response is not sufficient after an hour of the infusion, the
infusion rate can be increased (Table 2). Before increas-
ing the infusion rate, another loading dose should be
given.
In summary, in outpatient therapy for a patient with
renal insufficiency one must first find an effective dose of
a loop diuretic. Doing so entails upward titration by serial
doubling of dose until an effective dose is found or the
ceiling dose is reached. One then decides how frequently
to administer this dose, a determination based on the
patients overall response, their sodium intake, and the
diuretics duration of action. For inpatient therapy, if a
continuous intravenous infusion is to be given, a loading
dose is administered followed by the starting infusion
rate. Within an hour one can determine if the response is
adequate; if not, another loading dose is given followed
by increasing the infusion rate as discussed previously. If
response to the loop diuretic alone is inadequate after
reaching the ceiling dose, a thiazide can be added.
Nephrotic Syndrome
Addressing the question of whether the PK of diuretics is
altered in patients with nephrotic syndrome (NS) is more
complicated than in any of the other edematous disorders
because of the unique pathophysiology of hypoalbumin-
emia coupled with proteinuria, each of which could affect
access of the diuretic to the site of action. The high
degree of protein binding of loop diuretics essentially
traps them in the vascular space so they enter the renal
circulation and are delivered to proximal tubular secre-
tory sites and hence to the lumen of the nephron. Theo-
retically, less albumin in the plasma means less bound
and trapped diuretic, causing less to reach the kidney and
urinary sites of action. This hypothesis was tested in
analbuminemic rats; indeed this strain of rats had dimin-
D.C. Brater
Infusion Rate, mg/h
<25 25 to 75 >75
20 then 40 10 then 20 10
0.5 then 1 0.5
10 then 20 5 then 10 5
ished trapping of furosemide in the plasma with less
appearing in the urine and less response compared with
normal animals.49 In this model, administering a mixture
of albumin and furosemide caused more trapping, more
diuretic in the urine, and more natriuresis. In other words,
the hypothesis was confirmed in an animal model. Do the
results extrapolate to human beings? In this same publi-
cation a few patients with NS were administered 30 mg
of furosemide mixed with 25 g of albumin ex vivo and
several patients had enhanced diuresis.49 These results
raise the question as to whether hypoalbuminemic pa-
tients should receive mixtures of loop diuretic and albu-
min to enhance response. It is important to note that this
strategy is aimed at increasing amounts of diuretic in the
urine, therefore it is designed to address a PK component
of diuretic response in patients with NS.
PK studies in hypoalbuminemic patients owing to
either NS or cirrhosis indeed show less trapping of the
diuretic in plasma as reflected by a higher volume of
distribution of furosemide and presumably other loop
diuretics.5 But these data do not necessarily mean that
there is a concomitant decrease in diuretic reaching the
urine because even lower than normal plasma albumin
concentrations may trap sufficient amounts of diuretic in
plasma. In fact, several PK studies in both NS50,51 and
in cirrhosis6,7,52,53 show normal amounts of furosemide in
the urine unless the patient has concomitant renal insuf-
ficiency. If that is the case, there is no need for such an
elaborate and expensive therapeutic strategy of mixing
loop diuretics and albumin to increase amounts of di-
uretic at the site of action. A far easier way to increase the
amount of diuretic reaching the urine is to simply admin-
ister a larger dose. In fact, a study in hypoalbuminemic
patients with cirrhosis showed an albumin and furo-
semide mixture did not increase delivery of diuretic into
the urine and it did not increase the natriuretic effect of
furosemide.54
Should the notion of administering mixtures of loop
diuretic and albumin be rejected categorically? For the
majority of patients the answer to this question is yes. A
caveat, however, is that most of the patients in the studies
cited had serum albumin concentrations of 2 gm% or
higher. Thus, there are no data in patients with very low
serum albumin concentrations and it is still theoretically
possible that such patients might benefit. Thus, in pa-
tients with serum albumin concentrations less than 2
Diuretic therapy update
gm%, using a mixture of a loop diuretic and albumin
could be considered, realizing that such a strategy is
experimental and that repeat administration of these mix-
tures requires objective evidence that the patient has in
fact responded when they have not had adequate re-
sponse to the loop diuretic alone.
The albuminuria that occurs in patients with NS also
could have a PK effect that limits overall diuretic re-
sponse; namely, the urinary albumin could bind diuretic
in the urine, thereby diminishing the amount of unbound,
active drug able to block the Na-K-2Cl pump and de-
creasing response.55,56 To test this hypothesis studies
have been performed in experimental animals using in
vivo nephron microperfusion.57,58 These data show ne-
phrotic range proteinuria binds one half to two thirds of
the diuretic reaching the urine57 and co-administering a
compound that displaces the diuretic from albumin re-
stores response.58 As a consequence, doses two to three
times greater than normal are needed to deliver adequate
amounts of unbound, pharmacologically active drug to
the site of action. But these data also raise the question as
to whether administering a drug to patients with NS that
reaches the urine and is capable of displacing a loop
diuretic from binding might enhance response. This hy-
pothesis has been tested in a small group of patients with
NS using sulfisoxazole.59 There was no enhancement of
response, therefore there is no reason to use this strategy
clinically; the far easier approach is to simply use doses
two to three times higher than normal to make certain
sufficient amounts of unbound, active diuretic are at the
active site. Also note that these dosing suggestions as-
sume a reasonable GFR. If the patient with NS has
concomitant decreases in renal function per se, doses also
need upward adjustment to account for this additional
factor.
After taking into account all the PK factors that influ-
ence diuretic response in patients with NS, such patients
still show diminished response.60,61 In other words, there
is also a PD component of decreased response (Fig. 1).
The mechanism of this effect is unknown. A component
of the altered response occurs within the loop of Henle
itself because microperfusion studies in nephrotic ani-
mals show a diminished effect of furosemide.60 Theoret-
ically, increased proximal and/or distal reabsorption of
sodium also could contribute.5 The mechanism notwith-
standing, the clinical implication is that the upper plateau
of response is diminished in patients with NS (Fig. 1).
This means even the most effective dose will have con-
siderably less effect than in a healthy individual and one
cannot attain a normal response simply by administering
bigger doses. Thus, one must administer doses more
frequently and/or use adjunctive therapies such as con-
comitant use of thiazides.61
In summary, patients with NS have at least two mech-
anisms for decreased diuretic response, one a PK mech-
anism and one a PD mechanism. To account for binding
of diuretic to urinary protein, one administers a dose two
489
to three times higher than normal to attain normal
amounts of unbound diuretic in the urine. This phenom-
enon defines the ceiling dose of 80 to 120 mg of intra-
venous furosemide or the equivalent of other agents. As
noted earlier, concomitant decreases in GFR scale the
ceiling dose upward, being two-fold higher for patients
with moderate renal insufficiency and four-fold higher
for severe declines in renal function. Note that patients
with NS and considerable degrees of renal insufficiency
may require enormous doses of loop diuretics. In addi-
tion, the altered PD mandates frequent dosing and often
the addition of thiazide diuretics, the dose of which also
is governed by the level of renal function. If these strat-
egies are inadequate and a patient has a serum albumin
concentration less than 2 gm%, a therapeutic trial of a
mixture of loop diuretic and albumin can be tried by
mixing a ceiling dose with 25 g of albumin.
Cirrhosis
Patients with cirrhosis and edema are first treated with
spironolactone, to which other diuretics are added if
response is not adequate.62 Because patients with cirrho-
sis are very sensitive to compromises in their intravas-
cular volume,63 an advantage of spironolactone is that it
causes only a modest diuresis, which is typical of distally
acting diuretics.
The usual starting dose of spironolactone is 50 mg/d.
Spironolactone and its several active metabolites have
long elimination half-lives that allow dosing once a
day.62,64 On top of this PK feature, spironolactones bi-
ological half-life is quite long because it interferes with
protein synthesis. Steady state in terms of effects requires
3 to 4 days of dosing. As such, changes in dose should
occur no more frequently than every 3 days. When up-
ward titration occurs, doses as high as 400 mg/d are
sometimes needed. Such doses have substantial fre-
quency of feminizing side effects such as gynecomastia.
If spironolactone at maximal or tolerated doses does
not cause an adequate diuresis, a thiazide can be added at
a dose determined by the patients level of renal function
as discussed previously. If the diuresis is still not suffi-
cient, the thiazide should be stopped for 3 to 4 days to
allow its elimination, after which a loop diuretic can be
started; spironolactone should be continued as back-
ground therapy.
The PK and PD of loop diuretics have been well
studied in patients with cirrhosis, revealing PK (Table 1)
to be essentially normal but with changes in PD (Fig. 1)
that diminish diuretic responsiveness. If renal function is
preserved, such patients deliver normal amounts of di-
uretic into the urine.6,7,52,53 Thus, PK is normal and there
is no need to administer larger than normal doses of loop
diuretics unless renal insufficiency is present.
Abnormal responses to loop diuretics in patients with
cirrhosis occur via a change in PD,7,52,53 the mechanism
of which is unknown (Fig. 1), but could be owing to
increased proximal and/or distal tubular reabsorption of
490
sodium.5 In addition, theoretically there could be a
change in the dynamics of the interaction between the
diuretic and the Na-K-2Cl pump at the molecular level.
No matter the mechanism, the clinical relevance to a PD
mechanism is that the upper plateau of response is less
than occurs normally and administering large doses of
diuretic will not attain normal responses. For example,
and as noted previously, a maximally effective dose of a
loop diuretic in a healthy subject would cause excretion
of 200 to 250 mEq of sodium; in contrast, in a patient
with cirrhosis a maximally effective dose might cause
excretion of only 25 to 30 mEq of sodium (Fig. 1, lower
left panel). Rather than administering larger and larger
doses of diuretic to such a patient, the modest, effective
doses need to be given more frequently. If diuresis is still
inadequate with spironolactone and a loop diuretic, a
thiazide can be cautiously added to the regimen. One
should start with low doses of a thiazide and increase if
necessary every few days. Caution is warranted to make
certain the patient does not have an overly vigorous
diuresis and suffer harmful intravascular volume deple-
tion.
In summary, spironolactone is the mainstay of diuretic
therapy in patients with cirrhosis, on top of which some
patients need thiazides, or loop diuretics, and sometimes
a combination of both. Because PK of diuretics is essen-
tially normal if renal function is preserved, large single
doses of thiazides or of loop diuretics are not needed.
Instead, loop diuretics should be given on multiple oc-
casions; thiazides such as spironolactone can be given
once a day. As in all the edematous disorders, patients
and their families must be counseled in dietary sodium
restriction.
CHF
Although some patients with mild CHF and good renal
function can maintain fluid homeostasis with a thiazide
diuretic, most will need a loop diuretic.
Patients with CHF and reasonable renal function are
similar to those with liver disease in that there is no
change in PK compared with healthy subjects; thus,
access of loop diuretics to their urinary site of action is
normal (Table 1).65,66 As discussed previously, despite
considerable peripheral and presumably gut wall edema,
patients with CHF do not malabsorb diuretics.20-23 Al-
though total amounts of diuretic are absorbed normally,
there are delays in absorption. Interestingly, in one study
the delay was greatest when the patients CHF was
decompensated and returned toward, but not to, normal
when each patient attained dry weight.23 This delay
means that the peak diuretic level at the site of action
occurs latersometimes up to 4 hours instead of 1 hour
laterin patients with CHF. The clinical extrapolation of
these data is that if an immediate response is desired,
intravenous dosing may be necessary.
Because patients with CHF have no PK problem with
loop diuretics (Table 1), they do not need large doses of
D.C. Brater
these diuretics unless they have concomitant renal insuf-
ficiency. This means a diminished response in patients
with CHF occurs through a PD mechanism (Fig. 1).16,67
Quantitatively, patients with New York Heart Associa-
tion classes II to III have one quarter to one third the
natriuretic response to maximally effective doses of loop
diuretics as occurs normally. Thus, if the normal re-
sponse is 200 to 250 mEq of sodium, patients with CHF
are likely to excrete 50 to 75 mEq (Fig. 1, lower left
panel). Of course, some patients with severe disease may
have an even more compromised response to loop diuret-
ics alone. As emphasized previously, when the mecha-
nism of diminished response to a loop diuretic is PD,
response cannot be normalized by giving larger and
larger doses. Rather, one must administer effective doses
more frequently.
Because of the diminished response to loop diuretics
and the challenge of decreasing dietary sodium suffi-
ciently to control volume status, adding a thiazide is a
frequently used strategy. The logic for doing so and
dosing suggestions have been discussed previously in
this article.
In some patients, loop combined with thiazide diuret-
ics is not sufficient and the question arises as to whether
to add more distally acting agents. A number of patients
may benefit from distal agents simply as a measure to
maintain potassium homeostasis. The sequential nephron
blockade of loop plus thiazide diuretics causes substan-
tial kaliuresis that can be mitigated with distal agents.
One can predict which patients also will have enhanced
natriuresis with the addition of a distal diuretic. If mean-
ingful amounts of sodium are being reclaimed distally,
urinary electrolyte measurements will show low sodium
and high potassium concentrations. In contrast, if little
sodium is reaching distal sites, both sodium and potas-
sium in the urine will be low. In the former case, addition
of a distal diuretic will result in enhanced natriuresis
whereas in the latter, increased sodium excretion does not
occur.68,69
Among the distally acting diuretics, amiloride is likely
the preferred choice. Most patients with CHF already will
be taking eplerenone owing to the data showing its ben-
eficial effect on outcomes.70 This fact coupled with the
challenges of titration to find an effective dose make
spironolactone a poor choice. Triamterene is converted
by the liver to an active metabolite; this metabolic acti-
vation step is impaired in liver disease including conges-
tive hepatopathy12 (Table 1). Because it is impossible to
predict in an individual patient the potential degree of
metabolic compromise much less how it might change
with different degrees of congestive hepatopathy, the
correct dose of triamterene is unknown in patients with
CHF. Amiloride is active as the parent compound and
thus avoids all the complications of spironolactone and
triamterene.
In summary, patients with CHF have normal loop
diuretic PK (Table 1) unless they have concomitant
Diuretic therapy update
renal insufficiency. Diminished response is through a
PD mechanism (Fig. 1), meaning large doses are not an
appropriate therapeutic strategy. Instead, smaller doses
must be given more frequently. It is important to
emphasize that any improvement in cardiac function
likely lessens the PD effect. Although indirect, one of
the most important elements of diuretic therapy in
patients with CHF is making certain they are receiving
optimal therapy in the broadest sense. Many patients
also will require combinations of loop and thiazide
diuretics and some will benefit from superimposed
distal agents.
OTHER DIURETIC STRATEGIES
Acetazolamide Plus Loop Diuretics
Acetazolamide is a carbonic anhydrase inhibitor. It
is used in patients with metabolic alkalosis severe
enough to suppress respiratory drive to the point where
one needs an alkaline diuresis to reverse the alkalemia.
Acetazolamides effects are dominantly at the proxi-
mal nephron. Used by itself, it is a weak diuretic
because most solute rejected by the proximal tubule is
absorbed more distally. Although data are scant at
best, clinicians have used acetazolamide in patients
refractory to large doses of loop diuretics. The logic
for this use is the physiology that when the loop of
Henle is blocked, solute rejected proximally will be
excreted. In addition, because the bulk of solute is
absorbed proximally, sequential blockade of the prox-
imal nephron and the loop of Henle theoretically can
cause a substantial diuresis.71-74
Despite the logic for using acetazolamide when pa-
tients are refractory to loop diuretics, no studies have
examined the benefits of this strategy in patients with
CHF. One report studied healthy volunteers on a severely
restricted sodium diet to create a model of enhanced
proximal sodium reabsorption; in this study, acetazol-
amide had a synergistic effect on response to furo-
semide.75 These results support the logic of using acet-
azolamide for refractory patients but doing so still
represents a hypothesis remaining to be proved. If one
intends to use acetazolamide with a loop diuretic, a
reasonable approach to test for benefit is to administer a
single 500-mg intravenous bolus dose superimposed on
a continuous intravenous infusion of a loop diuretic. In
such a highly controlled setting, one can determine
whether an effect occurs that is of sufficient magnitude to
be beneficial and whether to continue with this combi-
nation.
Increasing Renal Blood Flow
In prior years aminophylline enjoyed some use as an
adjunct in patients refractory to loop diuretics. It was
presumed it increased renal perfusion and GFR and in
doing so would enhance response. Interestingly, its ef-
fects do not occur via a hemodynamic mechanism but
491
instead are owing to a pharmacologic effect akin to
thiazide diuretics.75-77 Because aminophylline has such a
narrow therapeutic margin, it should be relegated to
historical interest.
Renal-dose dopamine also has enjoyed a flurry of
interest both as a renoprotective agent and also to en-
hance diuresis. Unfortunately, it has failed to live up to
expectations for either use. In particular, relative to the
topic of this article, a study has shown renal-dose dopa-
mine does not enhance response to adequate doses of
furosemide.78 Because even low doses have considerable
potential for adverse effects, this drug should not be used
to enhance diuretic response.79,80
Adenosine Antagonists
The kidney has adenosine A1 receptors in the vasculature
and various tubular cells.81 When adenosine activates
these receptors in the vasculature, renal blood flow and
GFR decrease and proximal tubular sodium reabsorption
increases; inhibition of these receptors with adenosine
A1-receptor antagonists increases renal perfusion and
GFR and increases sodium excretion.81 This effect is
particularly interesting in patients with CHF who com-
monly have decreased GFR as a function of the sever-
ity of their disease; moreover, one of the most vexing
aspects of diuretic therapy in such patients is that
furosemide and presumably other loop diureticsthe
mainstays of diuretic therapy in CHF cause de-
creases in GFR concomitant with the diuresis they
induce. This decline in renal function can be a limiting
factor in the use of these drugs, for which one has to
weigh the potential gain of further diuresis versus the
cost of decreased GFR. The pharmacology of adeno-
sine A1 antagonists predicts they not only would in-
crease GFR and cause diuresis as single agents when
given to patients with CHF but they also would ame-
liorate the decrease in GFR caused by loop diuretics
while at the same time increasing the natriuretic re-
sponse to them; indeed, this has proven to be the case
with early clinical testing of three different such com-
pounds.81-87 A recent study of efficacy was disappoint-
ingly negative when assessing an outcome of improve-
ment in CHF symptoms and signs as opposed to
focusing on the diuretic effect.88 In fact, in this study
patients receiving the adenosine A1 antagonist lost
more weight despite receiving smaller doses of loop
diuretics. These drugs are still in development. To
date, most do not have oral formulations and there is a
risk of seizures so it is not clear whether they will
survive formal efficacy studies. If they do, they may be
a welcome addition to our diuretic armamentarium.
SUMMARY
An effective diuresis can be attained in the vast ma-
jority of patients by using a systematic approach to
diuretic therapy that takes into account whether
blunted response is from a PK mechanism, a PD, or
492 D.C. Brater

Table 3. Therapeutic Strategies for Use of Loop Diuretics

Renal Insufficiency

Moderate Severe NS* Cirrhosis* Heart Failure*

Mechanism of diminished Impaired delivery to Diminished nephron response Diminished nephron Diminished nephron
response to diuretic site of action response response
Binding of diuretic to urinary
protein
Therapeutic strategy Sufficient dose to Increased frequency of Increased frequency Increased frequency
attain effective effective dose of effective dose of effective dose
amounts of
diuretic at site of
action
Sufficient dose to attain
effective amounts of
unbound drug in urine
Ceiling dose, intravenous (mg)
Furosemide 80-160 160-200 80-120 40 40-80
Bumetanide 4-8 8-10 2-3 1 1-2
Torsemide 20-50 50-100 20-50 10 10-20
Adjunctive strategies After reaching the ceiling dose for a given clinical condition, add thiazide diuretics (dose
determined by level of renal function)
*Preserved renal function (eg, creatinine clearance 75 mL/min).

both (Table 3). Because the pathogenesis of dimin-
ished response to diuretics differs across the edema-
tous disorders, the therapeutic strategy that should be
used also must differ. In other words, one shoe indeed
does not fit all (Table 3). Diuretic strategy should be
directed first to the primary disease process and then to
the individual patient. Doing so will result in success-
ful therapy in the majority of patients and diuretic
failure will occur very infrequently.
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