Pharmacology of Diuretics
D. CRAIG BRATER, MD
ABSTRACT: The diuretics in our therapeutic armamen-
tarium have predictable effects based on their nephron
sites of action. All but spironolactone must reach the
lumen or urinary side of the nephron to exert their
effects. Thus, in settings of decreased renal function,
doses must be increased to deliver more diuretic into the
urine. In other edematous disorders, such as congestive
heart failure (CHF) and cirrhosis, adequate amounts of
diuretic reach the site of action if renal function is
satisfactory. Diminished response in these conditions is
caused by a decrease in the sensitivity of the nephron to
the diuretic, the mechanism of which is unknown.
Rather than using large single doses of diuretic in CHF
D iuretics differ considerably in chemical deriva-
tion, efficacy, sites of action, and mechanism of
action; namely, their pharmacology and pharmaco-
dynamics. (Table 1). Effective use of diuretics re-
quires knowledge of the pharmacology of each di-
uretic agent coupled with an understanding of the
pathophysiology of the patient's disease. Diuretics
have uses in clinical conditions other than edema-
tous disorders and hypertension, including treat-
ment of hypercalcemia with loop diuretics, treat-
ment of diabetes insipidus or hypercalciuria with
thiazide diuretics, treatment of glaucoma with car-
bonic anhydrase inhibitors, and treatment of cere-
bral edema with osmotic agents (Table 2).1 The ob-
jective of this article is to review and summarize the
pharmacology and pharmacokinetics of commonly
used diuretics to facilitate their clinical use.
HISTORY OF DIURETIC DISCOVERY
Carbonic Anhydrase Inhibitors
The carbonic anhydrase inhibitor acetazolamide
is a derivative of the sulfonamide antibiotic sulfanil-
amide, which was noted to cause a diuresis with
metabolic acidosis as a side effect. 2 This effect was
subsequently found to be caused by inhibition of
From the Department of Medicine, Division of Clinical Phar-
macology, Indiana University School of Medicine, Indianapolis,
Indiana.
Correspondence: D. Craig Brater, M.D., Indiana University
School of Medicine, Department of Medicine, 545 Barnhill Drive,
Emerson Hall 317, Indianapolis, IN 46202-5124 (E-mail:
dbrater@iupui.edu).
38
and cirrhosis, multiple doses and/or combinations of
diuretics should be used. Therefore, thiazide diuretics
coupled with loop diuretics are most logical because
they affect different nephron sites and the thiazide coun-
teracts distal nephron hypertrophy that may occur with
loop diuretics alone. Ample studies have shown that
such combinations can result in a truly synergistic re-
sponse. Using pharmacokinetics and pharmacodynam-
ics of diuretics, we can design therapeutic regimens in
which satisfactory control of fluid and electrolyte ho-
meostasis can be achieved in the vast majority of pa-
tients. [Am J Med Sci 2000;319(1):38-50.]
carbonic anhydrase. Various chemical modifications
of the structure of the antibiotic were studied and
acetazolamide was the drug with the most desirable
diuretic features. Parenthetically, in addition to
clinical use, acetazolamide has been used in physi-
ologic studies to define the role of carbonic anhy-
drase in the kidney.s
Osmotic Diuretics
Mannitol is a sugar that remains within the vas-
cular space, and is freely filtered at the glomerulus.
After being filtered, mannitol creates an osmotic
force throughout the length of the renal tubule that
blunts reabsorption of sodium and water. This same
effect occurs with other sugars and causes the vol-
ume depletion in patients with uncontrolled diabe-
tes mellitus in whom renal excretion of glucose re-
sults in osmotic diuresis.
Loop Diuretics
The site of effect of the first consistently effective
diuretics was the thick ascending limb of the loop of
Henle. These organic mercurials are no longer pro-
duced because better agents have been developed
that are less toxic.
Ethacrynic acid and furosemide were developed
independently and virtually simultaneously. Devel-
opment of ethacrynic acid followed a strategy based
on mercurial diuretics wherein it was assumed that
inhibition of sulfhydryl groups in the kidney would
cause a diuresis. Screening for such compounds led
to the discovery of this agent. At the same time,
screening of compounds for diuretic activity resulted
in a group of active sulfamoylanthranilic acids that
January 2000 Volume 319 Number 1
 Brater

Table 1. Characteristics of Diuretics

Maximum
Effect(% of
Filtered Load of
Type Chemical Class Sodium) Site and Mechanism of Action

Carbonic Anhydrase (CA) Inhibitors Sulfonamide derivative 3-5 Proximal tubule; inhibit CA
Acetazolamide
Osmotic Agents Sugar 20-25 Proximal tubule and thick
ascending limb of the loop of
Henle; osmotic effect
Mannitol
Loop Diuretics Carboxylic acid 20-25 Thick ascending limb of the loop
of Henle; N a+ -K+ -2Cl-
cotransporter
Bumetanide, furosemide, ethacrynic acid, torsemide sulfonamide derivatives
Thiazide Diuretics Sulfonamide derivatives 5-8 Distal tubule; electroneutral
N aCl reabsorption
Bendroflumethiazide, benzthiazide, chlorothiazide,
chlorthalidone, cyclothiazide, hydrochlorothiazide,
hydroflumethiazide, indapamide, methyclothiazide,
metolazone, polythiazide, quinethazone,
trichlormethiazide
Potassium-Retaining Diuretics Pyrazinoyl-guanidine, 17- 2-3 Distal tubule and collecting
spirolactone, and duct; Na+, K+ exchange by
Pteridine, respectively inhibiting aldosterone or
blocking luminal sodium entry
Amiloride, spironolactone, triamterene

Modified from Brater DC. Diuretics. In: Munson PL, Mueller RA, Breese GR, editors. Principles of pharmacology. Basic concepts and
clinical application. New York: Chapman and Hall; 1995. p. 657-72. Copyright 1995 Chapman and Hall. Used with permission.

were substituted on the amine group of the aromatic that would result in a N aCl diuresis as opposed to a
ring. 4 5 Of this group, furosemide was developed; in NaHC0 3 diuresis. Additional chemical modifica-
later years, bumetanide, azosemide, piretanide, and tions of the sulfa nucleus were studied until chloro-
torsemide followed. These loop diuretics represented thiazide was discovered. 6 7 Additional thiazides
a major breakthrough. Their large magnitude of were then developed that have different pharmaco-
effect made them useful in patients who did not kinetic features but the same pharmacology.
respond adequately to other drugs, including those Other modifications of the sulfa nucleus resulted
with severe renal insufficiency, severe heart failure, in quinethazone, metolazone, and chlorthalidone;
etc. these drugs have pharmacological effects similar to
Thiazide Diuretics those of the classical thiazides but represent a dif-
ferent chemical category.
The discovery of acetazolamide led to the realiza-
tion that it would be preferable to have a diuretic Potassium-Retaining Diuretics
Physiologic studies had identified the pivotal role
Table 2. Other Uses of Diuretic Agents of aldosterone in stimulating reabsorption of N a+ in
the distal tubule and collecting duct in exchange for
Type of Diuretic Uses K+ and H+. Derivatives of the steroid nucleus of
spirolactone were found to be active in animals with
Carbonic anhydrase inhibitors Glaucoma, metabolic intact adrenals and inactive in those with adrenal-
alkalosis, altitude sickness
Osmotic agents Cerebral edema ectomy. Thus, it was presumed that the activity of
Loop diuretics Hypercalcemia, hyponatremia, these agents occurred by blocking aldosterone. As
renal tubular acidosis methods for studying steroid receptors and effects
Thiazide diuretics Hypertension, hypercalciuria, became available, these compounds were shown to
diabetes insipidus
Potassium-retaining diuretics Potassium and/or magnesium block the receptor for aldosterone competitively.
loss From this series of compounds, spironolactone was
developed clinically. 8
Modified from Brater DC. Diuretics. In: Munson PL, Mueller RA, Triamterene was discovered from studies of the
Breese GR, editors. Principles of pharmacology. Basic concepts
and clinical application. New York: Chapman and Hall; 1995. p. biological activity of pteridines. Chemical modifica-
657-72. Copyright 1995 Chapman and Hall. Used with permis- tion of xanthopterin, a pigment in butterfly wings,
sion. resulted in the discovery oftriamterene. 9 Amiloride

THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES 39

Pharmacology of Diuretics
20 Loop Diuretics
FENa (%)
10
5 Thiazide Diuretics
LOG URINARY DIURETIC AMOUNT
or
LOG URINARY DIURETIC EXCRETION RATE
Figure 1. Schematized pharmacodynamics of loop and thiazide
diuretics; namely, the relationship between diuretic at the in-
traluminal site of action and response expressed as fractional
excretion of sodium (FENa). (Reprinted from Brater DC. Diuret-
ics. In: Munson PL, Mueller RA, Breese GR, editors. Principles of
pharmacology. Basic concepts and clinical application. New York:
Chapman and Hall; 1995. p. 657-72. Copyright 2111995 Chap-
man and Hall. Used with permission.)
is essentially an open ring version of the pteridines. 9
Like many of the other diuretics, it has been an
extremely useful physiologic probe because it specif-
ically blocks the luminal N a+ channel of the distal
tubule.
DIURETIC PHARMACOLOGY
General
All diuretics except spironolactone must reach the
lumen of the renal tubule to cause an effect. Osmotic
diuretics are filtered at the glomerulus, whereas
other diuretics are actively secreted into the lumen
at the proximal tubule. Acetazolamide, loop diuret-
ics, and thiazide diuretics are transported via the
organic acid secretory pathway; amiloride and tri-
amterene are transported via the pathway for or-
ganic bases. 9 - 11 Different classes of diuretics affect
different nephron segments (Table 1). These discrete
sites of action along the nephron account for the
additive effects that occur with combinations of di-
uretics, the so-called sequential nephron blockade.
In addition, these sites of effect, coupled with the
physiology of nephron function at these sites, allow
prediction of the various responses to different types
of diuretics.
In assessing the pharmacodynamics of diuretics,
studies have shown that the best index of drug at
the intraluminal site of action is its excretion rate in
the voided urine. 12,13 This parameter can be related
to the amount of sodium excretion as illustrated
schematically for loop and thiazide diuretics in Fig-
ure 1. This relationship is a typical sigmoid Emax
model, in which the critical parameters are the basal
40
response, the "dose" causing 50% response, an upper
asymptote (or maximal response), and a slope factor
that defines the steepness of the relationship.
Carbonic Anhydrase Inhibitors
By catalyzing the hydration of bicarbonate at the
proximal tubule, carbonic anhydrase facilitates the
reabsorption of virtually all the bicarbonate filtered
at the glomerulus. Sodium reabsorption accompa-
nies bicarbonate. Carbonic anhydrase inhibition
predictably causes a NaHC0 3 diuresis This loss of
base leads to a metabolic acidosis.
Because the proximal tubule absorbs the majority
of filtered sodium (60-70%), one might expect a
proximally acting diuretic to have a large effect.
This is not the case, however, because most but not
all of the sodium rejected from the proximal tubule
is reabsorbed at the thick ascending limb of the loop
of Henle, thereby diminishing the overall efficacy of
proximally acting diuretics. Increased delivery of
sodium to the distal nephron and collecting duct
results in increased exchange for potassium. Addi-
tionally, the luminal bicarbonate creates a negative
charge that facilitates potassium secretion. The net
result is that bicarbonate is excreted with both Na+
and K+; thus, carbonic anhydrase inhibitors can
cause potassium depletion.
The pharmacokinetics of acetazolamide are pre-
sented in Table 3.1 4 - 16 Acetazolamide seems to be
completely absorbed after oral dosing. Its half-life of
about 13 hours means twice-a-day dosing is suffi-
cient and that steady-state concentrations are at-
tained after 2 days of therapy (4 times the half-life).
Because virtually all acetazolamide is excreted in
the urine, its renal elimination is compromised in
patients with renal insufficiency.15
Acetazolamide is now used infrequently as a di-
uretic. In patients refractory to loop diuretics, par-
ticularly those with heart failure, proximal tubular
reabsorption of sodium seems increased.l 7 Thus,
loop diuretics alone have limited efficacy, because
less sodium is delivered to their site of action. Occa-
sionally, coadministration of acetazolamide in this
setting can cause a clinically important diuresis
when such was unobtainable before.l8 - 20 In this
setting, the theory of combining a proximally acting
and a loop diuretic is sound. The inevitable meta-
bolic acidosis that occurs with chronic use of acet-
azolamide limits its utility. Blocking adenosine re-
ceptors at the proximal tubule also inhibits sodium
reabsorption at this site. 21 Recent data with specific
adenosine antagonists confirm their diuretic ef-
fects.21-23 As such, they may prove to be useful
agents for future use.
Because carbonic anhydrase is also important for
intraocular fluid formation, inhibitors of this en-
zyme are effective in decreasing intraocular pres-
sure and are therefore used to treat glaucoma. Ac-
etazolamide and its derivatives, such as
January 2000 Volume 319 Number I
 Brater

Table 3. Diuretic Pharmacokinetics

Bioavailability Clearance Vd Half-life

(%) (mUminlkg) (Ukg) (h) Comments

Carbonic Anhydrase Inhibitor

Acetazolamide 100 13
Osmotic Agent 7 0.5 1
Mannitol Tv, in ESRD = 36 h
Loop Diuretics
Bumetanide 80-90 2-3.5 0.15 0.3-1.5 Tv, unchanged in ESRD
Ethacrynic Acid Kinetics presumed similar to furosemide
Furosemide 10-100 1.5-3 0.15 0.3-3.4 Tv, prolonged in ESRD
Torsemide 80-100 3-4 Tv, unchanged in ESRD
Thiazide Diuretics
Bendroflumethiazide 90 4.3 1-1.5 2.5-5 Duration of action: 18-24 h
Benzthiazide 100 10 Duration of action: 12-18 h
Chlorthalidone 65 24-55 Duration of action: 24-72 h
Chlorothiazide 30-50 4.3 1 15-25 Duration of action: 6-12 h
Clopamide 8-12 Duration of action: 18-24 h
Cyclothiazide Duration of action: 18-24 h
Hydrochlorothiazide 65-75 4.6 2.5 3-10 Duration of action: 6-12 h
Hydroflumethiazide 75 6.4 5 6-10 Duration of action: 18-24 h
lndapamide 90 1.6 6-15 Duration of action: 24-36 h
Methyclothiazide Duration of action: 24-48 h
Metolazone Duration of action: 12-24 h
Polythiazide 25 Duration of action: 24-48 h
Quinethazone Duration of action: 12-24 h
Trichlormethiazide 3.4 1-4 Duration of action: 24 h
Potassium-Retaining Diuretics
Amiloride 17-26 Tv, in ESRD = 100 h
Spironolactone 1.5 Tv, of active metabolites = 15 h
Triamterene 83 (55) 14 (0.7) 3.0 (0.14) 3 (3) Parentheses denote active metabolite;
Tv, in ESRD = 10 h

Vd, volume of distribution; T'~> half-life; ESRD, end-stage renal disease.

Modified from Brater DC. Diuretics. In: Munson PL, Mueller RA, Breese GR, editors. Principles of pharmacology. Basic concepts and
clinical application. New York: Chapman and Hall; 1995. p. 657-72. Copyright 1995 Chapman and Hall. Used with permission.

methazolamide, are used in glaucoma. The latter
was developed to have comparable effects on ocular
carbonic anhydrase but little systemic effect. As
such, benefit is retained but the diuresis and meta-
bolic acidosis that occur with acetazolamide are less.
The systemic metabolic acidosis caused by acet-
azolamide can be used to correct metabolic alkalosis.
If sufficiently severe, metabolic alkalosis per se re-
sults in hypoventilation, which is a normal reflex
aimed at raising blood C0 2 concentrations to correct
systemic pH. In some patients, such as those with
chronic obstructive pulmonary disease, this hy-
poventilation can cause further hypoxemia. Correct-
ing the alkalosis with short-term use of acetazol-
amide can reverse this scenario and improve
oxygenation.
Acetazolamide has also proven to be an effective
treatment of and prophylaxis against altitude sick-
ness. Several days before ascending and while at
elevation, patients can take twice-daily doses as low
as 125 mg and ameliorate the effects of altitude. The
mechanism of this effect is not known.
As noted above, metabolic acidosis and potassium
depletion are the primary adverse effects of carbonic
anhydrase inhibitors; these effects are extensions of
the pharmacologic activity of the diuretic. In addi-
tion, acetazolamide, particularly in large doses, can
cause central nervous system side effects, including
light-headedness, paresthesias (particularly circu-
moral), weakness, and confusion. The mechanism(s)
of these effects are unknown.
Osmotic Diuretics
Mannitol is freely filtered at the glomerulus. 2 4-26
Because it is not reabsorbed in the nephron, it re-
mains in the tubule lumen, where it exerts an os-
motic effect, thereby impairing the ability of the
proximal tubule and thick ascending limb to reab-
sorb sodium. Although the proximal effect of man-
nitol causes some excretion ofbicarbonate, the effect
at the loop of Henle predominates, so that sodium is
mainly excreted along with chloride. In addition, the
increased delivery of Na+ to distal tubular sites
allows increased exchange forK+ so that potassium
is also lost. This effect accounts for the potassium
deficits encountered in most patients with uncon-
trolled diabetes mellitus and a glucose-mediated os-
motic diuresis.
Mannitol is eliminated quickly, with a half-life of
about 1 hour in patients with normal renal function

THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES 41

Pharmacology of Diuretics
(Table 3),27 Thus, its onset of effect is rapid, but it
dissipates quickly. For this reason, it is often admin-
istered as a continuous intravenous infusion. Man-
nitol elimination is markedly impaired in patients
with renal insufficiency (half-life of 36 hrs). 28 As
noted below, retention of this agent in such patients
can be dangerous.
For the most part, loop diuretics have relegated
osmotic diuretics to nondiuretic uses (Table 2). Man-
nitol is a highly effective treatment of cerebral
edema and is used frequently in neurosurgical pro-
cedures, in head trauma, and in patients with ful-
minant hepatic failure awaiting transplant who de-
velop increased intracranial pressure. This use is
inevitably associated with a pronounced osmotic di-
uresis that, in this setting, is an unwanted effect.
Scrupulous attention must be paid to sufficient vol-
ume repletion in such patients.
In animal models, generation of a diuresis before
virtually any renal insult (eg, hypotension, nephro-
toxic drugs, contrast agents) has been shown to
protect renal function. Mannitol has therefore been
explored as prophylaxis in patients likely to suffer
ischemic insults to the kidney (as in some types of
surgery) and at one time it enjoyed widespread use
before dosing with cisplatin. 26 There is little if any
evidence to demonstrate that mannitol is better
than simply administering sufficient parenteral sa-
line to cause a brisk diuresis. Rather than using
osmotic agents for prophylaxis against renal injury,
a better alternative is assuring adequate volume
status in the patient.29,3o
Mannitol has also been used in patients with
acute renal failure in attempts to "open up" the
kidney. There is no good evidence that this strategy
is effective; assuring adequate volume status in the
patient is probably the best treatment. 2629,3o If man-
nitol is administered to a patient with acute renal
failure, and the patient's renal function remains
suppressed, the mannitol remains in the vascular
space, where its osmotic effect expands blood volume
with risks of precipitating heart failure. Today,
mannitol should be used as a diuretic agent only
rarely.
Loop Diuretics
Loop diuretics inhibit the N a+-K+ -2Cl- reabsorp-
tive pump at the thick ascending limb of the loop of
Henle, causing a diuresis ofNaCl and KC1. 9- 11 They
bind with this transporter at the chloride binding
site. At the thick ascending limb, 20 to 30% of
filtered sodium is reabsorbed. Because a maximally
effective dose of a loop diuretic can cause excretion of
20 to 25% of filtered sodium, these agents can block
virtually all reabsorption by this segment of the
nephron. 12
Calcium is reabsorbed in parallel to sodium at the
thick ascending limb. As such, use of loop diuretics
also cause a calciuresis and can thereby be used to
42
treat hypercalcemia. 31 However, their use should be
withheld until the volume depletion associated with
hypercalcemia is corrected. Volume repletion itself
may suffice; if not, loop diuretics can be used, but
scrupulous attention must be paid to maintaining
intravascular volume in the face of the vigorous
diuresis caused by these agents.
The thick ascending limb is also important for
urinary concentrating ability. Formation of concen-
trated urine requires not only antidiuretic hormone,
which permits reabsorption of water across the col-
lecting duct, but also a hypertonic medullary inter-
stitium that serves as the osmotic driving force for
water absorption. This hypertonic medullary inter-
stitium is generated and maintained by solute reab-
sorption at the thick ascending limb. Thus, loop
diuretics decrease this driving force and thereby
prevent generation of concentrated urine.
Intravenous loop diuretics have a short-lasting
vasodilating effect that seems to derive from renal
release of such vasodilating prostaglandins as pros-
tacyclin.3233 This effect explains the immediate im-
provement that often occurs in patients with acute
pulmonary edema before any diuresis has occurred.
The venodilation results in decreased cardiac pre-
load, a fall in pulmonary artery wedge pressure, and
symptomatic relief. This effect, however, can also
trigger activation of the sympathetic nervous sys-
tem, causing increased afterload and diminished
cardiac function. 34 One must balance the potential
benefits and risks of these 2 effects in individual
patients. Usually the need to quickly induce a sub-
stantial diuresis prevails.
All loop diuretics are highly bound to serum albu-
min (>95%) and enter the urine by being actively
secreted at the proximal tubule (Table 1).9-11,35,36
The high protein binding restricts these drugs to the
vascular space, resulting in a small volume of dis-
tribution (Table 3). The short half-lives of these
agents mean that their duration of action is brief,
although intense. After intravenous administration,
response begins within minutes and continues for 2
to 3 hours. Mter oral dosing, peak response occurs
within 30 to 90 minutes and lasts another 2 to 3
hours. Because of this short duration of action, in
many patients, these drugs must be administered
multiple times a day. Torsemide, the newest loop
diuretic, has a somewhat longer half-life and dura-
tion of action and can therefore be administered less
frequently. 37
Bumetanide and torsemide are completely ab-
sorbed (:::::80%), whereas, on average, 50% of a dose
of furosemide is absorbed. 9- 11 3536 Therefore, when a
patient is changed from intravenous to oral dosing of
bumetanide or torsemide, the dose is the same; in
contrast, the oral dose of furosemide needs to be
about twice the intravenous dose. Unfortunately,
absorption of these drugs is more complicated. In
particular, the variability of absorption of furo-
January 2000 Volume 319 Number 1

semide is enormous both among patients and within
an individual patient from day to day, 38 with a range
of absorption of 10 to 100%38- 40 In addition, concom-
itant ingestion of furosemide and bumetanide with
food dramatically decreases bioavailability41,42 This
does not occur with torsemide. 43 Compared with
furosemide, variability of absorption of bumetanide
and torsemide is modest. 44 Highly variable absorp-
tion of furosemide might translate to unpredictabil-
ity of diuresis and the potential for a poor long-term
outcome. An interim analysis of a recent study sup-
ports this hypothesis. Hospitalized patients with
CHF were randomized to either furosemide (vari-
able absorption) or torsemide (predictable absorp-
tion) and observed for a year after discharge. Those
on torsemide had statistically fewer hospitalizations
for CHF, hospitalizations for any cardiac cause, and
better measures of quality of life. 4546 Thus, a pre-
dictably absorbed diuretic seems advantageous.
.AI3 one would predict, in patients with renal dis-
ease, less total drug reaches the urine. 35,36,39,40 This
accounts for the need to administer larger doses of
all of these drugs to attain effective amounts of the
diuretic at the site of action. In addition, entry into
the urine of furosemide, but not bumetanide and
torsemide, is prolonged, so that the duration of re-
sponse is longer than in patients with normal renal
function (Table 3). The explanation for this differ-
ence is preservation of nonrenal (hepatic) pathways
of bumetanide and torsemide elimination so that
overall clearance and half-life are not affected ap-
preciably in patients with decreased renal func-
tion.39,40 In contrast, in patients with hepatic dys-
function, including congestive hepatopathy,
elimination of bumetanide and torsemide, but not
furosemide, is slowed, resulting in a longer half-life
and duration of action (Table 3).39,40
Loop diuretics are the most effective diuretics
currently available. Many patients, particularly
those with severe heart failure, severe cirrhosis,
nephrotic syndrome, and renal insufficiency, require
loop diuretics rather than less efficacious diuretics.
If creatinine clearance is less than about 40 mUmin,
other diuretics as single agents are unlikely to be
clinically effective and loop diuretics will usually be
required. Although patients may require large doses
of these drugs, small doses should be tried first,
followed by upward titration according to clinical
response. Thus, 40 mg of furosemide or the equiva-
lent dose of another agent is administered first. If
inadequate, the dose can be doubled sequentially
until a response ensues or until a maximum dose is
reached. The maximum single dose that should be
tried differs for different clinical conditions and is a
function of the pharmacodynamics of loop diuretics
in different edematous disorders.
AI!, noted above, the pharmacodynamics of a di-
uretic are quantified by relating the amount of di-
uretic at the active site (urinary excretion rate of the
THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
Brater
SEVERE RENAL INSUFFICIENCY
SODIUM
3.0 20
EX'i.'l~ON 2 _0 FENa(%)
(mEq/min) 10
1.0
-HEALTHY
----- EDEMATOUS DISORDER
CHF, CIRRHOSIS, AND NEPHROTIC SYNDROME
3.0 20
SODIUM
EX~'lWN 2.0
(mEq/min)
FENa(%)
10
LOOP DIURETIC EXCRETION RATE
Figure 2. Schematized pharmacodynamics of loop diuretics in
patients with renal insufficiency (top) and with CHF, cirrhosis, or
nephrotic syndrome (bottom). FENa fractional excretion of so-
dium.
diuretic) to response as either sodium excretion rate
or fractional excretion of sodium. When this analysis
is performed in patients with renal insufficiency
(Figure 2), residual nephrons seem to respond "nor-
mally," because response expressed as fractional ex-
cretion of sodium is similar to that occurring in
healthy subjects (Figure 2, top right). 4748 Because of
impaired delivery of diuretic into the urine, attain-
ing maximal response requires a higher dose. Doses
that reach this upper plateau have been determined
in clinical studies and are presented in Table 4. This
dose represents a ceiling dose, because larger doses
will not result in an increase in response. It is
important to emphasize, however, that in patients
with renal insufficiency, although remammg
nephrons respond adequately, response measured
as overall sodium excretion is limited because of the
constraints imposed by the diminished filtered load
of sodium (Figure 2, top left). Importantly, response
is not increased by doses higher than the ceiling
dose. Only administering effective doses on multiple
occasions per day increases cumulative response.
In patients with CHF, cirrhosis, or nephrotic syn-
drome, the pharmacodynamics ofloop diuretics (and
probably others) are altered so that maximal re-
sponse is lower (Figure 2, bottom).39,4o The mecha-
nism of this change is unknown. It could be caused
by increased proximal and/or distal reabsorption of
sodium and/or a change in the dynamics of the
interaction with the Na+-K+-2cl- transporter. Re-
cent data in animals suggest up-regulation of this
transporter in CHF. 49 The clinical ramification of
this change is that the diminished response to a loop
diuretic is not improved by administering large
doses. Consequently, ceiling doses of loop diuretics
in CHF and cirrhosis are modest (Table 3). If such
43
Pharmacology of Diuretics
Table 4. Maximum Doses of Loop Diuretics
Furosemide
Clinical Condition IV
Renal Insufficiency
0 < ClcR <50 80
ClcR < 20 200
Nephrotic syndrome with preserved 120
renal function
Cirrhosis with preserved renal function 40
CHF with preserved renal function 40-80
ClcR, creatinine clearance; IV, intravenous; PO, by mouth.
Modified from Brater DC. Diuretics. In: Munson PL, Mueller RA, Breese GR, editors. Principles of pharmacology. Basic concepts and
clinical application. New York: Chapman and Hall; 1995. p. 657-72. Copyright 1995 Chapman and Hall. Used with permission.
doses do not cause a sufficient overall response, then
multiple doses should be given rather than larger
individual doses.
Nephrotic syndrome is a complex process in terms
of the pharmacokinetics and pharmacodynamics of
loop diuretics. One half to two thirds of all the loop
diuretic that reaches the urine in patients with
nephrotic syndrome is bound to urinary albu-
min.50-53 Thus, higher doses are used to attain "nor-
mal" amounts of unbound, active drug in the urine.
In addition to this effect of binding, pharmacody-
namics are also changed in nephrotic syndrome as
shown in Figure 2. 54 The net result is a need to
administer higher doses, but these doses will not
cause the same diuresis as in healthy subjects, and
frequent dosing is usually needed.
A recent study in analbuminemic rats has raised
the question of the potential utility of using ex vivo
mixtures of albumin and loop diuretic in patients
with nephrotic syndrome. 55 The rationale for this
strategy is that normally the avid binding of loop
diuretics to serum albumin "traps" the diuretic in
the plasma and carries it to the kidney where it can
be secreted into the urine and exert its effect. In
hypoalbuminemic patients a hypothesis has been
formulated wherein diminished albumin binding re-
stricts a smaller amount of diuretic to the plasma
and, therefore, less reaches the urine, accounting for
decreased diuretic response. Indeed, in analbumin-
emic rats this scenario prevails and administering
mixtures of albumin and loop diuretic restores re-
sponse.55 These findings, however, do not seem to
extrapolate to most patients with nephrotic syn-
drome. Several studies have shown that patients
with serum albumin concentrations as low as 2
g/100 mL deliver adequate amounts of diuretic into
the urine, 56 -57 and preliminary studies suggest no
benefit of administering albumin.58,59 As such, using
mixtures of albumin and loop diuretic in such pa-
tients would be trying to fix something that is not
broken. This strategy should be reserved for the
44
Dose (mg)
Furosemide Bumetanide Ethacrynic Acid Torsemide
PO IV&PO IV&PO IV&PO
160 2 100 40
400 8-10 250 100
240 4 150 40-60
80 1 50 20
80-160 1-2 50-100 20-40
occasional patient who is severely hypoalbumin-
emic. Even then, such therapy is experimental. It is
important to emphasize that patients with CHF,
cirrhosis, and nephrotic syndrome who have con-
comitant decreases in renal function need higher
doses than those listed in Table 3 to attain effective
amounts of diuretic at the site of action.
Once an effective dose is determined, the fre-
quency of its administration must be determined.
Dosing frequency differs among individual patients
and depends on the sodium excretion needed rela-
tive to the effectiveness of the drug in the individual
patient coupled with the amount of sodium restric-
tion with which the patient will comply. The impor-
tance of the utility of sodium restriction cannot be
overemphasized. The more sodium the patient in-
gests, the more frequent is the need for the diuretic.
Loop diuretics also are used to treat hypertension.
Several studies demonstrate greater efficacy ofthia-
zides than furosemide in mild hypertension because
of the ability of thiazides to decrease peripheral
vascular resistance as well as produce diuresis.so,s1
On the other hand, low doses of torsemide (2.5 to 5
mg) are effective as an antihypertensive agent with
minimal or no diuretic effect. 62
Loop diuretics can be helpful in treating hypercal-
cemia, hyponatremia, and occasionally renal tubu-
lar acidosis.l As noted above, the major site of cal-
cium reabsorption is the thick ascending limb of the
loop of Henle. Thus, by inhibiting solute reabsorp-
tion at this segment of the nephron, loop diuretics
cause a calciureisis. 31 Loop diuretics cause excretion
of water in excess of sodium. As such, replacement of
loop diuretic-induced volume losses with iso- or hy-
pertonic saline results in a net gain of sodium rela-
tive to water, causing the serum sodium concentra-
tion to increase. 63 Whether to use this strategy
depends on the desired speed of correcting the hy-
ponatremia. In some patients with distal renal tu-
bular acidosis who are unable to maintain an ade-
quate systemic pH with conventional therapy, loop
January 2000 Volume 319 Number 1

diuretics will allow excretion of an acid urine and
facilitate correction of the metabolic acidosis.
The majority of toxicity from loop diuretics is
attributable to their effectiveness; the vigorous di-
uresis may result in volume depletion and/or potas-
sium deficits. Loop diuretics can cause both auditory
and vestibular toxicity. 64 65 This is usually associ-
ated with administration of high doses, particularly
in patients with renal insufficiency and in those
receiving other ototoxins such as aminoglycoside
antibiotics. Its mechanism is not well understood
but is associated with loss of cochlear hair cells.
Most clinicians feel that the risk of ototoxicity is
greatest with ethacrynic acid, which accounts for its
low use compared with other loop diuretics. With the
other loop diuretics, it seems that ototoxicity from
them per se is rare. Truly massive doses (4 to 5 g/day
of furosemide, for example) have been administered
without ototoxic effects.66,67
Allergic interstitial nephritis can also occur with
chronic use of loop diuretics. This diagnosis should
be entertained in historically stable patients taking
loop diuretics whose renal function clinically begins
to deteriorate. If the diagnosis is made and the
patient still needs a loop diuretic, ethacrynic acid is
the best alternative, because it differs structurally,
whereas the chemical structures of other loop di-
uretics are similar.
Thiazide Diuretics
Thiazide diuretics block electroneutral NaCl reab-
sorption at the distal convoluted tubule, connecting
tubule, and early collecting duct. 68 Interestingly,
there is a genetic syndrome (Gitelman syndrome)
caused by a variety of mutations that render this
transporter inactive. The phenotype of this syn-
drome mimics the pharmacology of thiazide diuret-
ics.6970 In sufficient concentrations, all thiazides
have inhibitory activity toward carbonic anhydrase,
but in doses used clinically, any effect at the proxi-
mal tubule is negligible because it is obviated by
reabsorption of solute rejected from the proximal
tubule by the loop of Henle. The diuresis that is
manifest in the final urine occurs from distal tubu-
lar effects. 71 Thiazides cause a NaCl diuresis and
the enhanced distal delivery of Na+ facilitates po-
tassium secretion, so these drugs can also cause
potassium depletion. The distal tubule reabsorbs
only about 5% of filtered sodium. Thus, the efficacy
ofthiazides is limited. However, these drugs are still
sufficient in most patients with mild edematous
disorders unless they have concomitant renal dys-
function.
The thiazide diuretics have a very shallow dose-
response curve, as shown in Figure 1. This means
that there is little difference between the lowest
effective dose and the maximally effective dose.
Thus, the starting dose of a thiazide is 12.5 mg of
hydrochlorothiazide, or the equivalent of another
THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
Brater
agent, and the maximal dose is 50 mg. Higher doses
result in no greater benefit but increase risks, par-
ticularly of potassium depletion and altered glucose
and lipoprotein homeostasis.
The disposition of some of the thiazide diuretics
has been defined in detail, whereas the disposition
for most of them has been little studied (Table 3). 72
Extensive clinical experience has demonstrated
pharmacological equivalence among them. Thus, the
maximal response (efficacy) to all is the same. Be-
cause their potencies differ, different amounts are
needed to achieve the same effect.
The major distinguishing features among thia-
zides are cost and duration of action. The former
varies among pharmacies and in large health sys-
tems is determined by contractual discounts. In ad-
dition to cost, the duration of effect is occasionally a
factor in deciding which of these drugs to use. Thia-
zides are usually grouped according to short (6-12
hour), medium (12-24 hour), and long (>24 hour)
durations of effect. It is best to use those with short
and medium durations of action, because those with
longer duration of effect usually cause more potas-
sium loss.
The greatest use of thiazide diuretics has been as
antihypertensive agents. Initial doses of a thiazide
are associated with diuresis-induced decreases in
blood volume and a consequent lowering of blood
pressure. This decrease in blood volume, however,
activates homeostatic reflexes such as the plasma
renin-angiotensin-aldosterone and sympathetic ner-
vous systems, which cause increased proximal tu-
bule sodium reabsorption and restoration of blood
volume. The antihypertensive effect, however, is
maintained, presumably because chronic use of
these agents results in diminished peripheral vas-
cular resistance. 73 This lowering of vascular resis-
tance, the mechanism of which is unknown, has
made thiazide diuretics a mainstay of antihyperten-
sive therapy. They are effective not only as single
agents in patients with mild hypertension but also
in multiple drug therapy of patients with more se-
vere disease. They are particularly useful for blunt-
ing the sodium retention that occurs with vasodila-
tors.
The homeostatic reflexes described above can be
helpful in treating hypercalciuria and diabetes in-
sipidus (Table 2). Some patients with nephrolithia-
sis have idiopathically increased urinary calcium
excretion. Increased proximal reabsorption of cal-
cium plus increased distal reabsorption result in
diminished calcium excretion and amelioration of
renal stone formation. 74 This effect also causes
slight increases in serum calcium concentration. 75
Thus, although loop diuretics can be used to lower
serum calcium concentration, thiazide diuretics can
increase it. These effects are predictable based on
the pharmacology of the drugs and the known phys-
iology of calcium homeostasis.
45
Pharmacology of Diuretics
The increased proximal tubular solute reabsorp-
tion associated with chronic thiazide use is also
accompanied by increased water reabsorption. In
addition, the distal site at which thiazides act is also
responsible for generating a dilute urine. Conse-
quently, thiazide diuretics impair the ability to di-
lute the urine maximally. Patients with central di-
abetes insipidus can have urine volumes of up to 20
Uday. Thiazide diuretics in such patients can often
diminish urinary output to half its pretreatment
value, an effect sufficient to improve the quality of
these patients' lives. Thus, a diuretic agent in this
setting is actually used to diminish urinary volume,
a seemingly paradoxical effect that makes sense
once the site of action and pharmacology of the drug
is coupled with the pathophysiology of diabetes in-
sipidus.
As with other diuretics, much of the toxicity from
thiazides is predictable based on their pharmacol-
ogy. Increased serum calcium concentrations can be
mistaken for hyperparathyroidism. Impairment in
urinary dilution prevents patients who drink large
volumes of hypotonic fluids from excreting them.
Thus, free water is retained and hyponatremia can
occur. 76 In fact, thiazide diuretics are the most com-
mon drug-induced cause of hyponatremia, which can
be a particular problem in elderly patients or in
patients with psychogenic water drinking.
The increased proximal tubular solute reabsorp-
tion with thiazide administration can affect other
cations that are transported in the proximal
nephron, such as lithium. Chronic treatment with
thiazides increases lithium reabsorption, decreasing
its renal excretion and causing accumulation to po-
tentially toxic concentrations. 77 As a consequence,
patients concomitantly treated with thiazides
should receive lower doses of lithium and dosing
should be guided by measured serum concentra-
tions.
Thiazide diuretics also cause other adverse ef-
fects, the mechanisms of which are poorly under-
stood. They disrupt glucose homeostasis. Some have
argued that this adverse effect is linked to potas-
sium depletion and can thereby be prevented by
maintaining potassium homeostasis. There seems to
be little current support for this hypothesis. Thia-
zides have also been implicated in increasing serum
concentrations of low-density lipoprotein choles-
terol. This effect is dose-related and currently rec-
ommended antihypertensive doses of thiazides have
negligible effects on it. Low doses also have negligi-
ble effects on glucose, potassium, and magnesium
homeostasis. 78 79
Potassium-Retaining Diuretics
In the distal nephron and collecting duct, sodium
exchanges with K+ and H+. This process depends on
luminal entry into the cell of N a+, a pathway
blocked by amiloride and triamterene. Exchange of
46
sodium forK+ and H+ is also stimulated by aldoste-
rone. Mineralocorticoid receptors in the cytoplasm of
principle cells bind aldosterone; this hormone-recep-
tor complex translocates to the nucleus of the cell,
where protein synthesis, presumably ofNa+ pumps,
is stimulated. 80 81 Spironolactone blocks the receptor
for aldosterone.
Thus, this class of drugs blocks N a+ reabsorption
by mechanisms both dependent upon and indepen-
dent from aldosterone. Amiloride and triamterene
reabsorption is independent of aldosterone, whereas
that for spironolactone requires the presence of min-
eralocorticoid. This latter mechanism of action is the
rationale for specifically using spironolactone in pa-
tients with primary or secondary hyperaldosteron-
ism. Such patients include those with mineralocor-
ticoid-producing tumors, adrenal hyperplasia, renal
artery stenosis, and cirrhosis. The most common
clinical setting is the patient with cirrhosis and
ascites. In such conditions, the dose of spironolac-
tone needed will depend on the endogenous level of
mineralocorticoid in each individual patient. Thus,
each patient must undergo titration until an effec-
tive dose is reached. The duration of effect of spi-
ronolactone is 1 or more days and plateau effects are
not reached until3 or 4 days oftherapy. 8 Therefore,
in titrating patients, doses should not be increased
more frequently than every 3 or 4 days.
The actions of amiloride and triamterene contrast
with spironolactone. They are effective in the ab-
sence of mineralocorticoid and additionally are
shorter acting, making dosage adjustments possible
on a daily basis. These agents are preferable to
spironolactone when a potassium-retaining diuretic
is needed in a patient without mineralocorticoid
excess.
Because only a small amount of sodium is reab-
sorbed at the site of action of these agents, they are
not sufficiently effective to be of benefit in most
patients (excluding mineralocorticoid excess). Their
main use, then, is to correct potassium and/or mag-
nesium deficiency. The mechanism by which these
drugs diminish magnesium excretion has not been
fully elucidated.
Triamterene has a short half-life and duration of
effect (Table 3). Thus, it needs to be administered
multiple times per day. Triamterene must be con-
verted to an active metabolite, which is a sulfate
ester, by the liver. This process can be impaired in
patients with liver disease, which can make this
drug ineffective in such patients. 82
Amiloride has a moderately long half-life (Table
3).83 ,84 In patients with liver disease in whom an
alternative to spironolactone is sought, amiloride is
preferred over triamterene because it does not re-
quire metabolic activation. Amiloride can be admin-
istered twice a day and steady state is reached
within 2 days.
Though spironolactone has a short half-life, it
January 2000 Volume 319 Number 1

seems that activity resides, for the most part, in
several metabolites with half-lives of about 15 hours
(Table 3). 85 In addition, the duration of effect is even
longer (several days), as discussed above.
Potassium-retaining diuretics are most frequently
used in combination preparations with thiazide di-
uretics. The rationale for these preparations is that
the thiazide component causes renal potassium and
magnesium losses, whereas the potassium-retaining
agents have the opposite effect. Hence, the combina-
tion is presumed to have a neutral effect on potas-
sium and magnesium excretion and to maintain the
efficacious effects to lower blood pressure. This ra-
tionale is flawed. 86,87 Firstly, only about 5% of pa-
tients receiving thiazide diuretics become potassi-
um-depleted. Thus, the remaining 95% of patients
do not need therapy with potassium-retaining di-
uretics. Secondly, potassium-retaining diuretics en-
tail a risk ofhyperkalemia, which is more life threat-
ening than potassium depletion. This fact argues
against prophylactic use.
A number of common clinical settings increase the
risk of hyperkalemia with these agents. Coadminis-
tration of potassium supplements is obvious. Angio-
tensin-converting enzyme inhibitors and nonsteroi-
dal anti-inflammatory drugs can also cause
hyperkalemia; combined with potassium-retaining
diuretics, these effects are likely to be additive.
Lastly, patients with renal insufficiency have dimin-
ished ability to eliminate potassium; these diuretics
are particularly risky in such patients and should be
avoided.
Blockade of H+ exchange for N a+ by these drugs
can cause Type IV renal tubular acidosis. 88 Patients
may have an acid urine, but they are unable to
acidify maximally. They characteristically demon-
strate a hyperchloremic metabolic acidosis with hy-
perkalemia. Patients with mild renal insufficiency or
with diabetes mellitus may be particularly susceptible.
Other adverse effects of these diuretics include
nephrolithiasis from triamterene, in which its me-
tabolite precipitates in concentrated urine and
serves as a nidus for stone formation. 89 High doses of
spironolactone have antiandrogenic effects and can
thereby cause gynecomastia. 90 This occurs only
rarely at conventional doses.
DIURETIC COMBINATIONS
The use of potassium-retaining diuretics com-
bined with other diuretics that cause potassium and
magnesium losses was discussed above.
Other diuretic combinations are used to obtain
additive or even synergistic effects in patients who
respond poorly to single agents. The strategy em-
ployed is to block different nephron segments so that
each diuretic enhances response of the other. Most
commonly, patients have had an inadequate re-
sponse to maximal doses of loop diuretics. By block-
THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
Brater
ing additional sites in the nephron, a greater re-
sponse can often be achieved.
Th~ most useful combination of agents for this
purpose is that of a loop diuretic plus a thiazide
diuretic. 91 Response to a loop diuretic alone can be
blunted considerably by increased reabsorption of
sodium at sites distal to the thick ascending limb.
Chronic dosing of loop diuretics causes hypertrophy
of distal tubule cells with an enhanced capacity to
reabsorb sodium.9 2 ,93 Blocking sodium reabsorption
at these sites with thiazide diuretics usually in-
creases response to a clinically important degree and
can occasionally result in a pronounced diuresis. 94
Patients should be monitored carefully for volume
and potassium status when such combinations are
used. lfthiazides are combined with loop diuretics in
patients with renal insufficiency, they must be given
in sufficient doses to attain effective amounts of the
thiazide in the lumen of the nephron. Doses as high
as 200 mg/day of hydrochlorothiazide or the equiv-
alent of other thiazides may be needed. 95 96 If a
thiazide is to be used with a loop diuretic, any
thiazide can be selected, because their pharmacolo-
gies are similar and clinical trials have shown that a
variety of them work similarly in this setting.94-99
Some patients, particularly those with severe
heart failure, have increased proximal tubular reab-
sorption of sodium, which blunts response agents
that act more distally. Addition of an agent with
proximal effects, such as acetazolamide, can be help-
ful in some patients. It is best to try combinations of
thiazides and loop diuretics first and reserve addi-
tion of acetazolamide for patients who are still un-
responsive.
Distally acting, postassium-retaining diuretics
can also be used to enhance natriuretic effects. The
effects are not as great as adding thiazides, and this
strategy should be additive to loop and thiazide
diuretics. Two studies have shown that measuring
urinary electrolytes allows prediction of patients
who will respond to addition of a distal agent.wo,1o 1
Low N a+ and K+ predicts negligible response and
low Na+ and high K+ predicts response.
Development and use of diuretics has been inex-
tricably linked to understanding renal physiology.
On the one hand, patterns of effect of a diuretic have
allowed prediction of its tubular site of action. On
the other hand, knowing a diuretic's site of action
allows accurate prediction of its effects (eg, hypona-
tremia as a side effect of thiazide diuretics, calciure-
sis from loop diuretics). The net result is that under-
standing diuretic pharmacology allows their rational
use in a diverse set of clinical conditions.
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January 2000 Volume 319 Number 1