RATIONAL USE OF DIURETICS AND

PATHOPHYSIOLOGY OF EDEMA

12 : 1 OP Kalra, Amitesh Aggarwal, Delhi

Introduction
The use of diuretics for therapeutic purposes is not new. They were used for the treatment of dropsy as
early as 16th century. Diuretic drugs increase urine output by the kidney by altering sodium handling.
Increased sodium excretion by kidneys leads to increase in water excretion. Most diuretics produce
diuresis by inhibiting the reabsorption of sodium at different segments of the renal tubular system.
Diuretic use in clinical practice spans conditions like edema, hypertension, metabolic acidosis and
hyperkalemia. Patients with nephropathy or heart failure may have a 10 to 30% increase in extracellular
and blood volume, even in the absence of overt edema1.
Classification
Multiple classes of diuretics are available for use including loop diuretics, thiazides and potassium-
sparing diuretics. The level of GFR and need and urgency for reduction in ECF volume dictates the
choice of diuretic agent.
Thiazide diuretics
Thiazide diuretics inhibit the apical Na+-Cl- cotransport system in the distal tubule. Metabolism of
thiazide diuretics is variable. Bendroflumethiazide and indapamide are primarily metabolized by the
liver; while hydrochlorothiazide and metolazone are metabolized by the kidney. They are delivered
to their luminal site of action by organic anion transporters in the straight segment of the proximal
tubule, consequent of their extensive protein binding. Considerable protein binding makes role of
glomerular filtration inconsequential in entry of thiazide diuretic into the urinary space.
Loop diuretics
Loop diuretics act by inhibiting the Na+-K+-2Cl- cotransporter in the thick ascending limb of the
loop of Henle delivered to their luminal site of action by organic anion transporters. By blocking the
transporter in the cortical segments, the loop diuretics enhance free water clearance. The bioavailability
of loop diuretics is not affected by renal insufficiency. On an average, 50% (range 10-100%) of
an orally administered dose of furosemide is absorbed2. In contrast, absorption of bumetanide and
torsemide, is nearly complete (80- 100%). Loop diuretics are primarily bound to albumin. Torsemide
is approximately 80% cleared by the liver. Bumetanide is approximately 50% metabolized by the
liver and its half-life does not appreciably change in kidney failure. Approximately 50% of the dose
of furosemide is excreted unchanged; the remainder is conjugated to glucuronic acid in the kidney.
Therefore, in patients with kidney failure, the plasma half-life of furosemide is prolonged.
Potassium sparing diuretics
There are two principal types of potassium-sparing diuretics, those that inhibit epithelial sodium
channels (triamterene and amiloride) and those that inhibit mineralocorticoid receptors (aldosterone
antagonists). For both types, the site of action is in the collecting tubule. The absorption of potassium-
sparing diuretics is quite variable. The total protein binding is low for amiloride and high for
spironolactone. Amiloride and triamterene undergo significant excretion by the kidney, both by
glomerular filtration and tubular secretion by the organic cation secretory pathway. Spironolactone

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 Medicine Update 2012  Vol. 22

is metabolized by the liver; its pharmacokinetic property is free water excretion leads to extracellular volume expansion
not significantly affected by chronic kidney disease (CKD). and total body volume overload manifesting clinically when
the GFR falls to less than 10-15 mL/min. As kidney function
Loop Thiazide Potassium
declines further, peripheral edema and pulmonary edema
sparing
appears. At a higher GFR, excess sodium and water intake
Pharmacody- Increases Increases Increases
could result in a similar picture if the ingested amounts
namic effects excretion of Na, excretion of Na, excretion of
K, Ca, Mg K, Mg, decrease Na, decrease of sodium and water exceed the available potential for
excretion of Ca excretion of Ca, compensatory excretion.
K, Mg
The interstitial inflammation of the kidney has a key role
Site of action Thick ascending Distal tubule Collecting tubule
limb
in the pathogenesis of nephrotic edema by inducing primary
sodium retention. Both decrease in sodium filtration and
Transporters Na+ K+ 2Cl- co Apical Na+ Cl- co Epithelial Na+
increase in net sodium reabsorption occur due to generation
affected transporter transporter channels or min-
eralocorticoids of vasoconstrictive substances in the interstitium, driven by
receptors the inflammatory cell infiltrate. Reduction in plasma oncotic
% of filtrate 20-30% 6-11% < 5% pressure also plays a key role in the pathogenesis of edema.
reabsorbed at site Thus, hypoalbuminemia effectively buffers the hemodynamic
of action effects of acute increments in blood volume as the fluid
Bioavailability 50-100% 40-90% 30-90% overload is sequestered into the tissues5 and is responsible
(Adapted from K/DOQI clinical practice guidelines on hypertension and for the fact that while patients with acute glomerulonephritis
antihypertensive agents in chronic kidney disease) Am J Kidney Dis. 2004 show a steep relationship between weight gain and the
May; 43(5 Suppl 1):S1-290) humoral response, indicating plasma expansion, the patients
Pathophysiology of edema with nephrotic syndrome do not6. Low plasma colloid oncotic
pressure and primary sodium retention combine to overwhelm
Cardiac: Fluid retention is a consistent finding in almost all the mechanisms protecting from changes in interstitial
acute and most chronic heart failure patients. It manifests as volume7-10 and drive the development of edema (Fig. 1).
pulmonary and peripheral edema. The pathophysiology of
edema in heart failure involves the activation and interplay of Hepatic: Patients with cirrhosis of liver share a common
multiple neurohumoral and cellular systems. Pathobiologically pathophysiology of arterial underfilling secondary to decreased
important alterations occur in the sympathetic nervous cardiac output and decreased systemic vascular resistance,
system, the renin-angiotensin-aldosterone system (RAAS), respectively, with eventual stimulation of neurohumoral
the vasopressin axis, and vasodilatory/ natriuretic pathways. axis and sodium and water retention. The resultant renal
These disturbances are translated at the renal circulatory and vasoconstriction and sodium and water retention lead to ascites
tubular level in such a way that avid retention of sodium and and hepatorenal syndrome in advanced cirrhosis. Two key
water occurs3. The state of the arterial circulation, as governed
PROTEINURIA
by cardiac output and peripheral vascular resistance, is the chief
determinant of sodium and water retention in heart failure4. Tubulointerstitium Glomeruli HYPOALBUMINEMIA
In particular, either a primary decrease in cardiac output or Infiltration T cells, MФ ↓ Kf
arterial vasodilatation brings about arterial underfilling, which ↑ All, ↓ NO ↓ SNGFR
activates neurohumoral reflexes that in turn incite sodium
and water retention. Sympathetic nervous system activity ↑ Na reabsorption ↓ Filtered Na

contributes to peripheral and renal vasoconstriction and to Secondary

Primary ↓ UNa V
sodium and water retention. Activation of renal sympathetic Na retention Na retention
nerves leads to angiotensin II release, stimulating the renin-
Intravascular
angiotensin-aldosterone system. Sympathetic stimulation volume
also prompts release of arginine vasopressin, excess levels of ↑PC ↓ PCOP
Overwhelmed mechanisms
which lead to water retention and hyponatremia. Angiotensin of edema removal
II acts as a potent vasoconstrictor, stimulates aldosterone
release from the adrenal gland, and promotes renal tubule EDEMA
sodium reabsorption. Aldosterone increases reabsorption of
sodium in the collecting duct. Fig. 1: Overview of pathophysiology of edema formation in
nephrotic syndrome. (Adapted from Rodríguez-Iturbe B, Herrera-
Renal: Chronic renal insufficiency (CRI) leads to alteration in Acosta J, Johnson RJ. Interstitial inflammation, sodium retention,
salt and water handling by the kidney. Failure of sodium and and the pathogenesis of nephrotic edema: A unifying hypothesis.
Kidney Int 2002; 62: 1379–1384.)

602
 Rational Use of Diuretics and Pathophysiology of Edema
factors are involved in the pathogenesis of ascites formation—
sodium and water retention, and portal hypertension.
There is an overlap between CKD and heart failure11,
having a complex bidirectional pathophysiologic state12 that
worsens the function of both organs known as cardio renal
syndrome (CRS). In Chronic CRS (Type 2), longstanding
heart failure leads to progressive CKD, possibly via episodes
of acute kidney injury (AKI). Optimal management of
sodium and extracellular fluid volume through low-sodium
diet and diuretics is important in prevention of chronic
CRS. Many studies indicate that the lowest doses of loop
diuretics necessary to maintain hemodynamics are optimal13.
Conversely, those patients requiring the highest doses of
loop diuretics have the highest rates of CRS and mortality
probably by further activation of neurohumoral pathways14.
Another form of chronic CRS (Type 4) may be recognized who
have repetitive bouts of cardiac ischemia and injury reflected
by chest pain, electrocardiogram changes and elevations in
cardiac biomarkers. In this form of CRS, worsening kidney
function reduces the effectiveness of diuretics.
Rationale for use
Cardiac disease: In heart failure, loop diuretics may improve
cardiac function by decreasing cardiac filling pressure,
functional mitral insufficiency, ventricular wall stress, and
endomyocardial ischemia. In some patients, this may also
lead to improved renal function. In patients with acute left
heart failure, pulmonary edema is the main abnormality
and is usually treated with intravenous loop diuretics. The
improvement in symptoms and the accompanying reduction
in filling pressures occur even before diuresis is initiated and
have been attributed to vasodilatation15.
Renal diseases: In CKD, they reduce ECF volume, lower
blood pressure, potentiate the effects of ACE inhibitors,
ARBs, and other antihypertensive agents; and reduce the risk
of cardiovascular disease in CKD. The addition of diuretics
and calcium channel antagonists to RAS inhibitor therapy
is also considered to be a rational strategy to reduce blood
pressure and preserve renal function. Extracellular fluid
volume overload as a result of sodium retention is one of
the major causes of hypertension in renal disease16,17. In
principle, the mechanism of decreased sodium excretion in
CKD is reduced glomerular filtration of sodium, increased
tubular reabsorption of sodium, or both. Diuretics act
primarily by decreasing tubular sodium reabsorption, thereby
increasing sodium excretion, reversing extracellular fluid
volume expansion, and lowering blood pressure. Diuretics
potentiate the antihypertensive effects of ACE inhibitors
and ARBs by stimulating renin and reducing fluid volume,
thus making blood pressure more sensitive to the action of
these agents16-19. A randomized study designed specifically
to test the effectiveness of a diuretic-based treatment on
603
microalbuminuria in diabetic patients with hypertension
found that diuretic-based therapy was equivalent to an ACE
inhibitor-based therapy20. It is generally recommended that
patients with chronic renal disease receive a diuretic along
with an ACE inhibitor or ARB as part of the strategy to reach
target blood pressure16,21,22.
Increased rate of fluid delivery and reabsorption per nephron
in the loop segment and relative preservation of the target
transporters is a critical factor in the retained efficacy of loop
diuretics even in advanced renal insufficiency. On the other
hand, thiazide diuretics when used alone become relatively
ineffective in patients with a moderate to severe degree of CRI
(creatinine clearance < 35 ml / min), although high doses of
thiazide diuretics, such as metolazone, do retain some efficacy
in even advanced CRI23.
Loop diuretics have been prescribed to patients with end-
stage renal disease (ESRD) in an attempt to slow the rate
of loss of GFR. An observational study of 125 patients with
ESRD treated by peritoneal dialysis (PD) showed that total
sodium and fluid removal by PD were powerful predictors
of longer survival24. In contrast, a controlled clinical trial of
the effects of furosemide in patients treated with continuous
ambulatory peritoneal dialysis (CAPD) showed no benefit of
regular diuretic therapy in delaying the loss of residual renal
function25. Thus, optimal dialysis, rather than loop diuretic
therapy is the best treatment for these patients.
Relevant clinical issues
Maximum dose of diuretics
Diuretic action relies on an adequate amount of the drug
reaching its site of action at the renal tubule. Once present
in the circulation, a diuretic must gain entry into the renal
tubule in a sufficient concentration to exceed the threshold
for response; thereafter, there exists an optimal rate of drug
delivery leading to a rate of a maximal response. Additional
diuretic delivery does not produce a greater response26,27. High
doses of furosemide can increase urine production in patients
with chronic renal failure28. The effects in hemodialysis
patients are equivocal. Chronic administration of the drug
in doses ranging from 250 to 500 mg orally in these patients
has been associated with a remarkably long duration of
residual urine production. High dose furosemide increases
the urinary excretion of sodium, chloride, and water in CAPD
patients without affecting GFR, urea clearance, and creatinine
clearance29.
Combination therapy
In patients with nephrotic syndrome, addition of thiazides
to furosemide markedly increases natriuresis30,31. But
this finding contrasts with repeated recommendations to
withhold thiazides in such patients because of their assumed
inefficacy32,33. On pharmacokinetic principles, it is usually not
 Medicine Update 2012  Vol. 22
advisable to combine substances with different half-lives of
action. In the particular case of loop diuretics (short half-life)
and thiazides (long half-life) this approach may, however,
have distinct advantages. First, co-administration of thiazide
and loop diuretics may help to overcome “resistance” to the
action of conventional therapeutic doses of loop diuretics
which is frequently observed in patients with advanced renal
failure34,35. Administration of high doses of loop diuretics
may cause more frequent and severe side effects36. Co-
administration of thiazide diuretics may therefore permit use
of smaller doses of loop diuretics and this may reduce the
frequency of side effects. Second, because of the long half-
lives, the duration of action of thiazides outlasts that of loop
diuretics and thus prolongs the overall duration of natriuresis.
Third, administration of a thiazide may interfere with the so-
called “rebound effect” following loop diuretic treatment, that
is, with antinatriuresis after the short acting natriuretic effect
of the loop diuretic has waned37,38.
Continuous vs bolus administration
There are potential benefits of continuous infusion when
compared with intermittent bolus dosing. Bolus diuretic dosing
may be associated with a higher rate of diuretic resistance
due to prolonged periods of subtherapeutic drug levels in
the kidney. Continuous infusion results in a more constant
delivery of diuretic to the tubule, potentially reducing this
phenomenon. Additionally, continuous infusion is associated
with lower peak plasma concentrations, which may be
associated with a lower incidence of other side effects such as
ototoxicity, especially at higher doses. A recent meta-analysis
from the Cochrane Collaboration comprehensively addresses
this question and reviewed studies including a total of 254
patients39-42. Continuous infusion was associated with greater
urine output, shorter length of hospital stay, less impairment
of renal function, and lower mortality when compared with
intermittent bolus dosing. In the Diuretic Optimization
Strategies Evaluation (DOSE) study, among patients with
acute decompensated heart failure, there were no significant
differences in patients’ global assessment of symptoms or
in the change in renal function when diuretic therapy was
administered by bolus as compared with continuous infusion
or at a high dose as compared with a low dose43.
In patients who have poor response to intermittent doses of a
loop diuretic, a continuous intravenous infusion can be tried.
If an effective amount of the diuretic is maintained at the
site of action at all times, a small but clinically important
increase in the response may occur36. Before administering a
continuous infusion of a loop diuretic, the physician should
give a loading dose in order to decrease the time needed to
achieve therapeutic drug concentrations; otherwise, 6 to 20
hours is required to achieve a steady state, depending on the
diuretic used.
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The frequency of administration of diuretic is determined
by its plasma half life. In case of administration of short-
acting loop diuretic, sodium reabsorption is increased shortly
after the diuretic effect has waned, which may be sufficient
to completely nullify the gain from the prior natriuresis.
This rebound antinatriuretic effect (braking phenomenon)
attenuates the normal dose-response relationship and can
last several hours, thus limiting the efficacy of therapy. It
can be overcome by administering multiple daily doses of
the diuretic44.
Predosing for metolazone
The recommendation for pre-dosing metolazone is based
solely on the pharmacodynamic rationale of delayed onset
of action observed following a single orally administered
metolazone dose45. Given the lengthy half-life of metolazone,
this delayed onset is unlikely to be a concern during ongoing
chronic treatment, particularly once steady-state is achieved.
However, no published clinical studies have compared pre-
dosing to simultaneous dosing. At present, the practice of pre-
dosing metolazone prior to a loop diuretic is not supported
by the literature.
Diuretic resistance
Refractoriness to diuretics in heart failure is due to blunting
of relationship between urinary sodium excretion and the
urinary diuretic excretion rate compared with normal subjects.
Typically, heart failure patients with mild to moderate disease
have a response that is one fourth to one third of that normally
observed with maximally effective doses of loop diuretics.
The threshold for effect is noticeably increased.
Multiple factors lead to diuretic resistance in CKD. The
factors may be increased tubular reabsorption of sodium, use
of non-steroidal anti-inflammatory agents, increased plasma
levels of organic anions and urate, and metabolic acidosis
impairing proximal tubule secretion of diuretics. High dietary
intake of sodium may lead to apparent diuretic resistance.
The “braking phenomenon” (post diuretic sodium retention)
describes avid sodium retention that can develop in response
to a rapid diuresis due to hemodynamic and neurohumoral
changes produced, thereby limiting response to further doses
of diuretics. The braking phenomenon may occur during either
short-term or long-term therapy. In CKD, the tubular secretory
capacity for a diuretic is lowered in parallel with the reduction
in GFR warranting requirement of higher blood levels to affect
tubular delivery sufficient to prompt a diuresis.
Several mechanisms may contribute to diuretic resistance
in nephrotic syndrome, including intratubular binding of
loop diuretic by filtered albumin, decreased GFR, excessive
tubular reabsorption of sodium at site proximal to the loop of
Henle, or a disease state-related resistance to diuretic action
at the cellular level. These patients have an impaired response
 Rational Use of Diuretics and Pathophysiology of Edema
to loop diuretics and there is reduced tubular sensitivity and
responsiveness to diuretics. Many patients with advanced
nephrotic syndrome have a marked stimulation of plasma
renin activity, especially during diuretic therapy. The ensuing
hyperaldosteronism further reinforces NaCl reabsorption in
the distal nephron and collecting ducts. Four pharmacokinetic
mechanisms that could impair the responsiveness to loop
diuretics in patients with the nephrotic syndrome are decreased
renal diuretic delivery, decreased peritubular diuretic uptake,
enhanced renal metabolism of furosemide to the inactive
glucuronide and decreased free diuretic levels in tubular fluid.
Treatment of nephrotic syndrome may require high doses of
loop diuretics, a combination of loop and thiazide diuretics,
or loop diuretics with albumin infusions. With long-term
administration of a loop diuretic, the solute that escapes from
the loop of Henle floods more distal regions of the nephron.
By unknown mechanisms, increased exposure to solute causes
hypertrophy of distal nephron segments, with concomitant
increases in the reabsorption of sodium38,46,47. Sodium that
escapes from the loop of Henle is therefore reabsorbed at
more distal sites, decreasing overall diuresis resulting in long-
term tolerance to loop diuretics. Thiazide diuretics block the
nephron sites at which hypertrophy occurs, accounting for
the synergistic response to the combination of a thiazide and
a loop diuretic44,48.
Newer methods of delivery
In nephrotic syndrome, the efficacy of diuretic therapy may be
increased by administering a mixture of albumin and a loop
diuretic; in several patients with severe hypoalbuminemia, an
infusion of 30 mg of furosemide mixed with 25 g of albumin
enhanced diuresis49. However, in most patients with the
nephrotic syndrome50,51, renal tubular secretion of furosemide
is normal (unless the patient also has renal insufficiency),
and combined infusions are therefore unnecessary. This
conclusion may not be applicable to patients with serum
albumin concentrations of less than 2 g per deciliter. In such
patients, it may be reasonable to try combined infusions.
Diuretic therapy in diverse clinical set-
tings
Acute kidney injury
In the acute care setting, loop diuretics are often prescribed
to maintain or increase urine output. Furosemide and other
loop diuretics reduce oxygen demand in the medullary thick
ascending limb and attenuate the severity of acute kidney
injury in animal models52. They may protect the human
kidney from ischemic injury. There have been several small,
randomized, controlled trials of diuretics for the treatment or
prevention of AKI in various clinical settings. Some studies
showed a reduction in dialysis requirement53, reduced urinary
albumin and N-acetyl glucosaminidase concentration54, or
605
improved dialysis free survival in oliguric patients56. Others,
however, showed either worsened renal function56-58 or no
difference in various measured outcomes59-62.
Mehta et al.63 published an observational study of diuretic use
in patients with AKI in the setting of critical illness and showed
that, using multivariate analysis and propensity scores, the use
of diuretics was associated with an increased risk of death.
However, another analysis by Uchino et al refuted this claim
and found that diuretic use in critically ill patients with acute
kidney injury is not associated with higher mortality64.
Hypertension
Many physicians consider thiazides the diuretics of choice
for long-term therapy. On average, after adjustment for
reductions seen with the use of placebo, thiazides induce a
reduction in the systolic and diastolic blood pressures of 10
to 15 mm Hg and 5 to 10 mm Hg, respectively. Hypertension
responding preferentially to thiazides is considered to be
low-renin or salt-sensitive hypertension. The elderly, blacks,
and patients with characteristics associated with high cardiac
output (e.g., obesity) tend to have this type of hypertension.
Thiazides potentiate the action of other antihypertensive
agents when they are used in combination, often producing
an additive decrease in blood pressure. For many hypertensive
patients, several agents will be needed to achieve desired
blood-pressure targets. Combination regimens that include
a thiazide can achieve therapeutic synergy while minimizing
adverse effects65.
Combined meta-analyses and systematic reviews report that,
as compared with placebo, thiazide-based therapy reduces
relative rates of heart failure (by 41 to 49%), stroke (by 29 to
38%), coronary heart disease (by 14 to 21%), and death from
any cause (by 10 to 11%)66-68. Despite a long, well-established
record of efficacy, the role of thiazides in hypertension therapy
continues to provoke debate69. Based on the benefits observed
in studies in which thiazides were used as initial therapy in
a stepped-care approach, with agents added sequentially,
guidelines for hypertension therapy in the United States have
advocated thiazides as initial treatment65. In contrast, British
guidelines recommend diuretics more selectively, such as for
use in the elderly and blacks70. European guidelines endorse
several antihypertensive agents, including diuretics, as initial
therapy71. An update from the Joint National Committee is
anticipated in the near future.
Heart failure
Loop diuretics are recommended as the first line of therapy
as per the updated guidelines by Heart Failure Society of
America72. The use of loop diuretics in heart failure may be a
double-edged sword. There is, however, a meta-analysis of 3
small randomized trials that concludes a benefit of diuretics on
mortality73. The use of diuretics in some cardiac failure patients
 Medicine Update 2012  Vol. 22
occasionally may lead to deterioration of renal function. In
general, compared with normal individuals, patients with
heart failure need higher doses of loop diuretics to achieve a
similar sodium excretion, and the magnitude of the “maximal”
response is attenuated74.
A low sodium diet (less than 2.4 g sodium) and fluid restriction
(less than 1.5 l fluid) can reduce the need to use higher doses
in advanced heart failure. Non-steroidal anti-inflammatory
drugs blunt the effects of diuretics and should be avoided.
Diuretics are the mainstay of therapy for symptomatic chronic
heart failure but are now rarely used as monotherapy. Together
with angiotensin converting enzyme inhibitors they improve
patients’ symptoms and in most cases also improve their effort
tolerance75. Thiazide diuretics can be used in milder cases,
particularly if there is no renal impairment. However, in more
symptomatic patients (NYHA III–IV) and in patients with
renal impairment, loop diuretics are more useful owing to
their relatively strong diuretic action and fewer side effects76.
Consistent with pathophysiological process, evidence for
pleiotropic benefits of mineralocorticoid blockade is rapidly
emerging. The analysis of SOLVD revealed a significantly
lower risk for hospitalization and/or death from heart failure,
cardiovascular mortality, and all-cause mortality when a
potassium-sparing diuretic was used alone or in combination
with a non–potassium-sparing diuretic77. Eplerenone is a
novel agent that selectively blocks the mineralocorticoid
receptor and not those for glucocorticoids, progesterone,
or androgens78. It has also been shown to reduce morbidity
and mortality in patients with acute myocardial infarction
complicated by left ventricular dysfunction and heart failure79.
Ascites
Loop and distal diuretics are the basic drugs for the treatment of
ascites. Management of ascites is based on improving the renal
sodium excretion with diuretics and dietary sodium restriction.
Despite the natriuretic potency of loop diuretics being greater
than other diuretics, only half of the nonazotemic cirrhotic
patients have satisfactory natriuresis76,80. Reasons for this poor
diuretic effect include reduced tubular secretion of furosemide
into the lumen, decreased delivery of fluid to the loop of Henle
secondary to enhanced proximal sodium reabsorption, and
hyperaldosteronism. In a comparative trial in patients with
cirrhosis, spironolactone was found to be more effective than
furosemide. Thus, patients with marked hyperaldosteronism
did not respond to furosemide and required high doses of
spironolactone (400 to 600 mg/day)76. Generally, a ‘‘stepped
care’’ approach is used in the management of ascites starting
with modest dietary salt restriction, together with an increasing
dose of spironolactone. Frusemide is only added when 400 mg
of spironolactone alone has proved ineffective81-83.
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Chronic kidney disease
The choice of diuretics is guided by both the status of ECF
volume in the patient and the stage of CKD.
Thiazide diuretics can be used in CKD Stages 1-3. In the
recommended doses, thiazides are effective in generating
diuresis in patients with GFR > 30 mL/min/1.73 m2 84. They
may lower blood pressure and reduce cardiovascular risk
by mechanisms in addition to reduction in ECF volume.
Chlorthalidone is longer-acting than hydrochlorthiazide,
resulting in better blood pressure control, but causing higher
incidence of hypokalemia. Chlorthalidone may be effective
at a lower GFR than hydrochlorthiazide. If blood pressure
control worsens or if volume expansion occurs as CKD
progresses from Stages 1-3 to Stages 4-5 during treatment with
a thiazide diuretic, a loop diuretic should be substituted for the
thiazide diuretic. Unlike other thiazide diuretics, metolazone
retains effectiveness at GFR below 30 mL/min/1.73 m2. Once
metolazone has effected a diuresis, it can typically be dosed
as infrequently as two to three times a week because of its
very long half-life44.
Loop diuretics can be used in all stages of CKD and hence are
the most commonly used diuretics. The maximal natriuretic
response occurs with intravenous bolus doses of 160 to 200
mg of furosemide, or the equivalent doses of bumetanide and
torsemide. Larger doses have little incremental value85. Loop
diuretics are not as effective as thiazide diuretics in lowering
blood pressure in CKD Stages 1-3. In CKD Stages 4-5, loop
diuretic therapy is a useful adjunct therapy in the treatment
of hypertension. One may use the most bioavailable drug,
torsemide, when using the oral route and the drug with the least
hepatic elimination, furosemide, when using the intravenous
route.
Potassium-sparing diuretics must be used with caution
in CKD consequent to risk of hyperkalemia. The risk is
especially high in patients with GFR < 30 mL/min/1.73 m2
receiving concomitant therapy with ACE inhibitors or ARBs
or other conditions that raise serum potassium. Indications
for potassium-sparing diuretics in CKD are persistent
hypokalemia or resistant hypertension86. The presence of
hyporeninemic hypoaldosteronism is a contraindication to
their use.
Adverse effects
Loop diuretics may have detrimental effects in patients with
heart failure. Administration of loop diuretics may result
in a significant decrease in glomerular filtration rate in
some patients with heart failure, presumably due to renin-
angiotensin-aldosterone system and sympathetic nervous
system activation with related changes in renal blood flow
and glomerular filtration pressure11,87,88.
New-onset diabetes has been reported in patients receiving
 Rational Use of Diuretics and Pathophysiology of Edema
thiazides; however, newly diagnosed diabetes occurs over
time in many hypertensive patients, regardless of which
class of antihypertensive agent is used. Use of thiazides over
several years may lead to an excess of 3 - 4% of new cases
of diabetes as compared with other antihypertensive agents
82
. But no analyses of ALLHAT data have indicated that the
development of diabetes obviates the benefit of the thiazide89.
Depending upon the site and mode of action, some diuretics
increase excretion of potassium, chloride, calcium,
bicarbonate, or magnesium. Some can reduce renal
excretion of electrolyte-free water, calcium, potassium, or
protons. Consequently, electrolyte and acid-base disorders
commonly accompany diuretic use. Except for the mildly
natriuretic collecting duct agents, which are used mainly to
limit potassium excretion, all diuretics can cause volume
depletion with prerenal azotemia. Loop agents and thiazides,
produce hypokalemic and hypochloremic metabolic alkalosis.
Carbonic anhydrase inhibitors produce less hypokalemia
and volume depletion but at the cost of inducing metabolic
acidosis that is often symptomatic. The potassium-sparing
agents like spironolactone may also produce metabolic
acidosis. Hyperkalemia is a leading complication of the
potassium-sparing agents, especially in patients with an
underlying tendency. Whether diuretic-induced hypokalemia
increases cardiovascular risk is controversial. All diuretics
promote excretion of sodium. Hyponatremia, a frequent
accompaniment of use of loop agents and thiazides may cause
permanent neurologic damage, especially with thiazides use.
Loop agents may cause dose-related reversible or irreversible
ototoxicity. Some diuretic agents have the potential to cause
nephrocalcinosis, nephrolithiasis, hypomagnesemia, and
hyperuricemia. Reported idiosyncratic reactions to diuretics
include interstitial nephritis, noncardiogenic pulmonary
edema, pancreatitis, and myalgias90.
Conclusion
Multiple classes of diuretics are available for use including
loop diuretics, thiazides and potassium-sparing diuretics
with use primarily focused in edema of various causes.
The pathophysiology of edema involves the activation and
interplay of multiple neurohumoral and cellular systems with
alterations in the sympathetic nervous system, the renin-
angiotensin-aldosterone system, the vasopressin axis, and
vasodilatory/ natriuretic pathways. These disturbances are
translated at the renal circulatory and tubular level in such a
way that avid retention of sodium and water occurs resulting
in edema.
High doses of loop diuretics can increase urine production in
patients with chronic renal failure. Loop diuretics combined
with thiazides have distinct advantages especially in resistant
cases. Continuous infusion of loop diuretics offer potential
benefits compared with intermittent bolus dosing. Treatment
607
of diuretic resistance may require high doses of loop diuretics,
a combination of loop and thiazide diuretics, or loop diuretics
with albumin infusions. The level of GFR and need for
reduction in ECF volume dictates the choice of diuretic agent.
Electrolyte and acid-base disorders commonly accompany
diuretic use and thus their use should be prudent and in tune
with the clinical profile of the patient.
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