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StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-.

Therapeutic Uses of Diuretic Agents

Vijay B. Arumugham; Mohamed H. Shahin.

Author Information and Affiliations

Last Update: May 29, 2023.

Continuing Education Activity

Diuretics are a medication used in the management and treatment of edematous and other non-
edematous disease conditions. Diuretics are a class of drugs. This activity reviews the
indications, action, and contraindications for diuretics as a valuable agent in treating heart
failure, hypertension, ascites, etc., (and other disorders when applicable). This activity will
highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label
uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent
for members of the interprofessional team in the treatment of patients with heart failure and
related conditions.

Objectives:

Identify the mechanism of action of diuretics.

Describe the most common adverse effects associated with diuretics.

Review appropriate monitoring needed for patients on diuretic therapy.

Summarize interprofessional team strategies for improving care coordination and

communication to advance diuretics and improve outcomes.

Access free multiple choice questions on this topic.

Indications
Water constitutes about 60% of the average adult body weight and is responsible for many
physiological processes in the human body. Thus, fluid and electrolyte homeostasis is critical for
human survival, as exemplified by the potentially devastating consequences of fluid imbalance.
The balance of total body fluid is an extremely well-regulated process that ensures the
maintenance of a balance between fluid gain and loss through different physiological
mechanisms such as neural regulation of thirst, hormonal regulation (vasopressin and natriuretic
peptides), management through the skin, hemodynamic changes, and renal control of salt and
water excretion. In particular, renal excretion of urine also ensures the elimination of products of
metabolic activity and excess electrolytes in addition to water, thus maintaining fluid
homeostasis. Fluid balance so inextricably links with electrolyte balance both in the intracellular
(rich in K+ ions) and extracellular (rich in Na+ & Cl- ions) compartments, that unsurprisingly,
trading of electrolytes is the core strategy of renal fluid regulation. Drugs that affect renal
regulation of electrolyte excretion have the greatest effect in terms of the quantity of fluid control
and thus water homeostasis.[1][2][3]

Diuretics are drugs that pharmacologically tilt the renal fluid regulation in favor of the excretion
of water and electrolytes. Thus, diuretics are substances that increase the production and volume
of urine. This class of drugs achieves this objective primarily by suppressing receptors that aid in
the reabsorption of Na+, the most abundant extracellular cation, from the renal tubules, thereby
:
 increasing the osmolality of the renal tubules and consequently suppressing water reabsorption.
Osmotic diuretics cause a direct increase in luminal hyperosmolarity in the renal tubules without
affecting electrolyte balance, whereas aquaretics are substances that act directly by only affecting
the excretion of water.[4][5]

This comprehensive review addresses all the relevant aspects of diuretic therapy, emphasizing
the understanding of the basic pharmacophysiological mechanisms of drug action and that of
adverse effects but also to more pragmatic aspects of dosing. Diuretics fall into several classes
and subcategories depending on their mechanism and site of their action along the nephron. The
classification is presented in Table 1, which lists all the available individual drugs in all the
different classes, their peculiarities, chemical nature, their major site of action along the nephron,
diuretic target molecule, and the percentage of Na+ reabsorption blocked.[6][7][8] Additionally,
Table 1 also gives information (to put things in a broader perspective) about miscellaneous
agents that do not have a conspicuous diuretic action and are not used for diuresis, but they do
have some diuretic effect which is noticeable which must be taken into account during therapy
with these agents.

Indications

Diuresis is necessary for a variety of non-edematous and edematous conditions, which require
clearing out excess water when the body abnormally sequesters fluid in the third space in the
form of edema. Indications for each individual drug are given below in tables 2 through 5. The
quintessential of edematous conditions is heart failure (HF), where the inefficiency of the heart’s
pumping ability results in:

1. Decreased renal perfusion leading to activation of the renin-angiotensin-aldosterone-system

(RAAS) and

2. Long-standing venous stasis leading to extravasation of fluid into the interstitial space, both of
which lead to intravascular volume expansion and result in signs of congestion such as weight
gain, dyspnea, and generalized edema.[9]

Pulmonary edema, most commonly resulting from HF, is also an indication for diuretic use. Loop
diuretics (due to their greater effectiveness) are the cornerstone of diuretic therapy in
symptomatic HF, with furosemide being the most widely used loop diuretic (albeit Torsemide
with better pharmacological properties remains underexploited and a comparison trial,
TRANSFORM-HF, is currently underway) according to both New York Heart Association
(NYHA) and European Society of Cardiology (ESC). These agents are started at lower doses,
titrated upwards, and monitored through urine output and body weight measurements. The
addition of thiazide diuretics (metolazone, hydrochlorothiazide) to loop diuretics can help relieve
symptoms when loop diuretics are not sufficient in HF, as detailed below in the administration
section. Aldosterone receptor antagonists (ARA) reduce the mortality and morbidity of advanced
systolic HF and patients with ejection fraction less than 35% falling into NYHA-HF
classification categories II-IV. This effect is because aldosterone escapes suppression on chronic
use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers
(ARBs), whereas the addition of ARAs can protect from the effects of aldosterone in such
patients.[10][11][12]

Diuretics, along with salt restriction, are also recommended as the first-line therapy in ascites due
to liver cirrhosis.[13] In cirrhotic ascites, spironolactone is the drug of choice for initial therapy
(due to its antiandrogenic effect), although a loop diuretic may be added as an adjunct if the
treatment fails or can be added at the outset in synergistic combination therapy.[14][15] In both
HF and cirrhosis, renal dysfunction contributes to the pathophysiology through further activation
:
 of RAAS to increase fluid retention.[16][17] Fluid overload that develops in renal insufficiency
or acute kidney injury patients increases mortality, and loop diuretics are the favored initial
therapy in these patients though renal replacement therapy is the long-term solution.[18]
[19] Nephrotic syndrome (NS), characterized by hypoalbuminemia, proteinuria, and
hyperlipidemia, is an edematous condition that requires diuretic therapy.[18] Activation of
epithelial Na+ channels (ENaCs) in the collecting ducts is the mechanism of edema formation in
NS, while RAAS activation could also play a minor role. All the diuretics are serum albumin-
bound, and hence hypoalbuminemia in NS decreases the load of diuretic delivered to the renal
tubules. Co-administration of albumin with furosemide or a combination of furosemide and
ENaC inhibitor such as triamterene has shown some success in kidney disease patients with
hypoalbuminemia.[20][21] A gain-of-function mutation in ENaC receptors clinically causes
Liddle syndrome, for which ENaC inhibitor amiloride is the treatment of choice.[22]

Thiazides are the best first choice for hypertension, as concluded in a recent Cochrane review,
and chlorthalidone is the best first-line agent among all the anti-hypertensive compared
according to the 2017 American college of cardiology (ACC) hypertension guidelines.[23]
[24] Chlorthalidone, with its longer duration of action and longer half-life at lower doses, was
found to significantly reduce the risk of cardiovascular (CV) events when compared to other
anti-hypertensive medications. Indapamide has lower metabolic adverse effects when compared
to chlorthalidone due to its non-interference in lipid or glucose metabolism and much safer for
use in hypertension, making it suitable for patients with diabetes. Direct vasodilatory effects of
thiazide-like diuretics also contribute to lowering blood pressure (BP) on long-term therapy. On
the other hand, loop diuretics may be the preferred agent when hypertension is associated with
chronic kidney disease (CKD) or glomerular filtration rate (GFR) less than or equal to 30
mL/min (though some recent reports still favor thiazides in this setting) and potassium-sparing
diuretics (PSD) are used in hypertensive patients with K+ or Mg2+ loss.[25][26][27][28][29]

Thiazide-related reabsorption of calcium might be advantageous in nephrolithiasis and

hypercalciuria, whereas loop diuretics cause calciuresis and therefore are suitable for use in
symptomatic hypercalcemia patients.[30][31] Diabetes insipidus, a polyuric disease, results in a
loss of dilute urine with low sodium levels, and paradoxically thiazide diuretics can help by
increasing distal tubule Na+ excretion, which compensatively increases water and Na+
reabsorption in the proximal tubule (PT); thus impairing the maximum diluting capacity of
kidneys.[32][33] Acetazolamide, the only carbonic anhydrase inhibitor available, induces
metabolic acidosis by increased bicarbonate excretion and is used as a prophylaxis in high
altitude sickness where it counteracts the hypoxia-induced respiratory alkalosis raising the PaO2.
With similar logic, its use is warranted in reversing metabolic alkalosis.[34] Acetazolamide
effectively reduces the intraocular pressure and is used for short-term therapy for open-angle
glaucoma when topical therapy is not feasible.[35] There is inconclusive evidence “for” or
“against” the use of diuretics in Ménière disease.[36]

Osmotherapy is the mainstay of medical therapy for raised intracranial pressure (ICP) after
traumatic brain injury and cerebral edema. Hyperosmolar therapy with mannitol reduces elevated
ICP rapidly in less than an hour though a rebound (an initial increase of ICP) is possible.
Mannitol also promotes diuresis in acute renal failure and excretion of toxic metabolites and
substances. Though hypertonic saline similarly is used to treat high ICP and sometimes has
demonstrated greater efficiency than mannitol is not considered a diuretic.[37][38]

Diuretics can also be employed less commonly in the active elimination of toxic substances by
forced diuresis, which increases urine volume per unit time. Clinicians employ loop diuretics
along with alkalinization of the urine in forced alkaline diuresis in the treatment of salicylate,
phenobarbital, and lithium poisoning.[39][40] Loop diuretics (along with salt tablets) are also
:
 used as a second-line therapy to decrease urine concentration in the syndrome of inappropriate
antidiuretic hormone secretion (SIADH), where the mainstay of therapy is the restriction of
water intake.[41] The loop diuretic bumetanide has shown effectiveness as an anti-seizure drug.
It is used in temporal lobe epilepsy in addition to other central nervous system pathologies such
as autism and schizophrenia.[6]

Mechanism of Action
Almost all diuretics act by targeting ion transport receptors present on the luminal surface in the
renal tubules, except for ARAs, which act on cytosolic steroid receptors. All the diuretics are
bound to albumin, and as glomerular filtration excludes macromolecules such as albumin, active
secretion of diuretic agents into the lumen is a prerequisite for their action. ARAs reach the distal
tubule via the blood and act on the mineralocorticoid receptor (MR) in the cytoplasm of the
principal cells.[42] Diuretics, which are acidic (loop, thiazides, and acetazolamide) or basic
(ENaC inhibitors), are secreted respectively via the organic anion or organic cation transporters
(OATs, OCTs), located on the basolateral surface of cells in the straight segment of PT.[43]

Certain general principles regarding renal physiology are critical for a thorough understanding of
diuretic action and its adverse effects. The following section will explain the mechanisms of
action of different diuretics, starting with a brief physiological introduction of the concerned
portion of the renal tubule followed by the mechanism of action of the particular diuretic.

Carbonic Anhydrase Inhibitors

In the Bowman’s capsule, plasma from the renal artery passes through the three-layered
glomerular ultrafiltration system and delivers an ultrafiltrate that is isotonic to that of plasma.
The contiguous PT reabsorbs about 60 to 70% of the filtered load, including Na+, water along
with bicarbonates (HCO3+), organic solutes (glucose and amino acids), electrolytes, and other
substances. Such massive reabsorptive capacity occurs with the help of the specific transport
receptors in the brush border cells, which increases the surface area of the PTs yielding a fluid, in
the end, that is isotonic (300 mOsm/kg) with the plasma.[44] Na+ in the filtrate gets reabsorbed
and enters the cell in exchange for H+ (present inside the cells) through Na+-H+ exchanger
(NHE3) present in the luminal membrane and maintains electrical neutrality across the
membrane. The H+ ions that reached the lumen combine with the filtered HCO3+ ions to form
carbonic acid (H2CO3) in the lumen, and this breaks down into H2O and CO2 with the help of
the enzyme carbonic anhydrase present on the luminal side of the brush border cell. CO2 diffuses
back into the cell, and H2O is reabsorbed via aquaporin-1 channels into the cell, both of which
combine to form H2CO3 with the help of cellular carbonic anhydrase, which further catalyzes
them to form HCO3+ and H+ ions inside the cells. Almost 80% of filtered HCO3+ is reabsorbed
in the PT cells in this way and exits the basolateral membrane along with Na+ (that entered via
NHE3 channels) through the Na+/HCO3+ co-transporter (NBCe1). Na+-K+-ATPase pump
avidly depletes the excess cellular Na+ ions along the basolateral membrane while also providing
the energy for NHE3 channels by creating low Na+ levels inside the cell.[45][46][47][48] The
renal reabsorption of HCO3+ and secretion of H+ ions play an important role in acid-base
homeostasis and the steady maintenance of pH in the body.

Acetazolamide, the only CAI, acts on this segment. Acetazolamide interferes non-competitively
with both the luminal and cellular carbonic anhydrase enzymes resulting in impairment of Na+,
HCO3+, and water reabsorption. Though acetazolamide targets the proximal portion of the renal
tubule, where the majority of the Na+ ions undergo reabsorption, compensatory processes
develop in the distal portions to reabsorb the increased distally delivered Na+ ions. These
processes include the Na+ reabsorption mechanisms in the loop of Henle, the distal convoluted
:
 tubule (DCT), the activation of tubuloglomerular feedback (TGF), and in amiloride-sensitive
distal nephron (ASDN) through ENaCs. Increased HCO3+ leads to alkaline diuresis, causing
decreased serum HCO3+ levels which further undermines the substrate availability for carbonic
anhydrase mediated Na+ reabsorption in the PTs resulting in decreased efficiency of
acetazolamide.[49][50]

Acetazolamide acts on carbonic anhydrase, causing loss of HCO3+ ions in the urine leading to
metabolic acidosis. The physiological response of the body to compensate for this loss of
HCO3+ ions is by decreasing the levels of CO2, in other words, by causing respiratory alkalosis;
this takes place by hyperventilation, which leads to increased expiration of CO2, leading to
higher partial pressures of O2 in the arterial blood. As high altitude is a low O2 environment, the
action of acetazolamide decreases the incidence of tissue hypoxia in high altitudes. Thus it is the
drug of choice in altitude sickness.

Loop Diuretics

The cortical proximal convoluted tubule descends into the outer medulla to continue as the thin
descending limb of the loop of Henle, forms a hairpin loop in the inner medulla, and ascends
back as thin and thick portions of the ascending limb of the loop and reaches back to the cortex.
This structural arrangement is critical for the urinary concentrating ability of the kidney achieved
by the countercurrent multiplier system of the loop of Henle. Electroneutral Na+-K+-2Cl- co-
transporter 2 (NKCC2) present in the apical surface of thick ascending limb (TAL) reabsorbs 25
- 30% of the filtered Na+ into the cells. The driving force for this action is the favorable low Na+
concentration in the tubular cells achieved by the Na+-K+-ATPase antiporter pump present in the
basolateral membrane. This channel pumps 3 Na+ out of the cell (into the interstitium) for every
2 K+ that comes into the cell. Excess chloride from the cells is transported via the chloride-
specific channels (ClC-Ka and ClC-Kb) and the basolateral side, which requires Barttin beta-
subunits for their action. Renal outer medullary K+ (ROMK) channel present in the luminal
membrane, in turn, secretes and recycles back the K+ from the cell into the lumen with the help
of ATP. Collectively, this not only results in creating a hyperosmolar medullary interstitial
environment but also a luminal positive charge that repels luminal cations Na+, Ca2+, and Mg2+
via the paracellular pathway into the interstitium. Of note, TAL, devoid of aquaporins, is
impermeable to water, and reabsorption of only the tubular solutes leads to dilution resulting in a
hypotonic fluid inside the lumen (thus aka diluting segment). The thin descending segment of the
loop is permeable to water, and the hyperosmolarity in the medulla draws the water out of this
segment through the aquaporin-1 channels resulting in a hypertonic tubular fluid. As this tubular
fluid flows continuously in the loop, repeated actions in thick and thin limbs create an osmolar
gradient in the length of the medulla with concentrations in the inner medulla that can reach up to
1200 mOsm/kg of H2O.[51][52][53][54] Loop diuretics act on this segment.

Loop diuretics act principally by blocking the electroneutral NKCC2 (isoform in the kidneys)
channels located on the luminal (apical) membrane of the TAL. Every loop diuretic has a distinct
chemical structure, but all are anions that assist in blocking the chloride-binding site of the
translocation pocket of the NKCC2 transmembrane receptor.[55] Blockage of NKCC2 action in
the TAL results in inhibition of Na+, K+, and 2Cl- reabsorption and reduced interstitial tonicity,
thereby thwarting the countercurrent mechanism of urinary concentration. Within the lumen,
however, the dilution function of the TAL is compromised and results in excess Na+ delivery to
the distal tubules by which one would expect would lead to an activation of the tubuloglomerular
feedback (TGF) mechanism. TGF is a mechanism that is activated when macula densa,
specialized epithelial cells in the distal tubule, senses increased NaCl levels in the lumen and
causes constriction of afferent glomerular arterioles, thereby reducing the GFR. It turns out
macula densa cells also contain the NKCC2 symporters, and their antagonism by loop diuretics
:
 causes decreased salt sensing ability in these cells, which results in inhibition of the TGF
mechanism. Low-salt or diuretic volume depletion also induces the release of renin, activating
the RAAS pathway, which helps maintain GFR by increasing BP.[56] Loop diuretics are the
most potent among all the diuretics as they inhibit the largest amount of Na+ reabsorption (25%
of filtered Na+). The high efficiency of loop diuretics results from profound diuretic action and
therefore has acquired the tag of “high-ceiling” and “high-efficiency” diuretics.[54][57]

Acute tolerance to loop diuretics occurs within sometime after dosing and can cause a ‘braking
phenomenon,’ which is rebound retention of Na+ due to increased reabsorption from the distal
tubules, while chronic tolerance can occur due to distal tubular structural adaptation by the
kidneys to increase Na+ retention. Acute tolerance can be overcome by choosing the correct
dosage, dosing frequency, the timing of diet, and dietary salt restriction. Chronic tolerance in HF
may cause diuretic resistance leading to refractory HF, and this can sometimes be overcome by
increasing the dose of loop diuretics, co-administering thiazide-like diuretics along with loop
diuretics to perform a sequential nephron blockade and/or dopamine can be administered to
improve renal perfusion. Also, the combination of acetazolamide and loop diuretics has
demonstrated effectiveness in diuretic resistance as acetazolamide can overcome the proximal
tubular Na+ reabsorption.[58][59][60][61]

Mutation of NKCC2 channels causes Type I Bartter’s syndrome, which is usually present at birth
and characterized by hypokalemic metabolic alkalosis, hypomagnesemia, and nephrocalcinosis.
[62]

Thiazide Diuretics

The distal convoluted tubule (DCT) starts at the macula densa and ends at the collecting duct,
and 5 to 10% of the filtered Na+ load is reabsorbed here via the NaCl co-transporter (NCC).
NCC channels can be activated by aldosterone, insulin, vasopressin, and angiotensin II, leading
to increased NaCl reabsorption. NCC is an electroneutral Na+ and Cl- symporter, expressed
throughout the DCT, and like NKCC2, derives its energy from low cellular Na+ achieved by
basolateral Na+-K+-ATPase pump. As NCC channels are the predominant mechanism for Na+
reabsorption in DCT, this segment is endowed with abundant mitochondria to supply ATP for the
pump. Reabsorbed Na+ exits the cell via the basolateral Na+-K+ pump into the interstitium,
while Cl- is transported to the interstitium via the basolateral ClC-Kb and K+-Cl- co-transporter4
(KCC4). Tubular K+ secretion occurs through both ROMK and “maxi”-K+ channels in high-
flow conditions and only through ROMK in low-flow conditions. In contrast to TAL, 10% of
both Ca2+ and Mg2+ reabsorption occurs only via active transport via transient receptor
potential (TRP) channel subfamilies. The early portion of DCT (with only NCC channels) has a
zero potential, while the late DCT has a luminal negative voltage due to the presence of
electrogenic ENaC channels here. Due to the absence of aquaporins, it is considered the terminal
diluting segment of the nephron and dilutes the urine further before it reaches the next segment.
Thiazide diuretics and ENaC inhibitors act on this segment.[63][64]

Thiazide diuretics are superior to any other diuretic agent for hypertension treatment and
subdivide into two subcategories, i.e., thiazide-type and thiazide-like diuretics. Thiazide-like
diuretics are so-called because they lack the benzothiadiazine backbone (thus the chemical
properties associated with it), which is characteristic of Thiazide-type agents. Among the
thiazides, thiazide-like drugs are exceptional and better than thiazide-type diuretics in handling
high BP with the least adverse effects such as metabolic or electrolyte disturbances.[65]

In the DCTs, the most abundant Na+ reabsorption occurs through the NCC channels, which are
the lone targets of thiazide diuretics. Thiazides exert their action by competitively binding to the
chloride binding site of the NCC’s transmembrane domain and inhibiting the Na+ reabsorption.
:
 The important role of NCC channels is well-established as in patients with loss-of-mutation of
this channel causes Gitelman syndrome manifesting with hypokalemic metabolic alkalosis,
hypomagnesemia, hypocalciuria, and lower systemic BP. Gordon’s syndrome is the inverse of
Gitelman’s phenotype in that they cause gain-of-function mutation of NCC leading to salt
retention and is treatable with thiazides.[66]

TGF mechanism is not inhibited by thiazides (in contrast with loop agents) as the anatomical
positioning of DCTs is after the macula densa. Increased renin secretion by thiazides is mediated
only through volume depletion rather than low-salt delivery to the macula densa, as in loop
diuretics.[67]

Low-dose thiazide-like agents are considered the best antihypertensive agent as it lowers BP on
chronic use irrespective of volume depletion.[68] Though the exact mechanism is still unclear, it
is theorized to occur through direct endothelial or vascular smooth muscle-mediated vasodilation
(probably by altering Ca2+ regulation), reverse whole body regulation, and/or renal
autoregulation.[69][23]

Potassium-sparing Diuretics

Connecting tubules are short segments of renal tubules connecting the DCT with the collecting
duct. Collecting duct forms the concluding segment of the nephron and receives only about 10%
of the glomerular filtrate, and the Na+ reabsorptive capacity of this segment varies significantly
from 1 to 5%.[70] Aquaporin-2 is the subtype of aquaporins expressed in both connecting
tubules and collecting ducts, and their density is the highest in the medullary collecting duct. The
antidiuretic hormone vasopressin acts only on the aquaporin-2 subtype of aquaporin channels
located in the distal nephron and does not bind to the aquaporin-1 channels located in the
proximal nephron.[71]

Apart from these structural segments, there is a functional segment of the distal nephron
comprised of late DCT, connecting tubules, and collecting ducts (both cortical and medullary)
are referred to as the aldosterone-sensitive distal nephron (ASDN). The principal cells are one of
the major epithelial cell types located in ASDN and identify with the cytoplasmic MR for
aldosterone and luminal membrane ENaC receptors. ENaC receptors expressed in ASDN are
responsible for the final fine-tuning of the tubular fluid and accounts for the reabsorption of
about 3% of the filtered Na+ load. The energy required for the function of ENaC derives from
the electrochemical gradient created by the basolateral Na+-K+-ATPase pump. Increased
reabsorption of Na+ through electrogenic ENaC creates a more negative luminal potential,
paving the way for the cells to secrete K+ through the luminal ROMK channels, which express
specifically in ENaC positive cells.[72][73] Alpha-intercalated cells, however, are responsible
for H+ secretion in response to luminal negative charge causing tubular acidification via the
proton pump H+-ATPase.[74] Both types of PSDs act on the ASDN segment.

As the name suggests, PSD overcomes the increased loss of K+ ions in the urine, thereby
preventing hypokalemia, a predominant side effect of other diuretics. ENaC inhibitors and
ARAs, two subcategories belonging to this class, are structurally different, and they target
different types of receptors. ENaC inhibitors are pteridine analogs and are secreted in the PTs to
reach the tubular lumen to bind to ENaC receptors located in the principal cells of ASDN, while
ARAs are synthetic steroid analogs and bind to the cytoplasmic MR. Notwithstanding these
differences, K+ retaining ability of both the subtypes of this class at the end is by their action on
ENaC receptors, while the ENaC inhibitors achieve this by acting directly to suppress these
receptors, ARAs act indirectly by suppressing the aldosterone-induced proteins, which increase
production, redistribution (from the cytosol to membrane) and activation of ENaC receptors.[75]
[49]
:
 These drugs account for the inhibition of only 3% of the filtered Na+ load and are thus not very
potent diuretics. ENaC inhibitors, amiloride, and triamterene are primarily used in situations to
correct hypokalemia induced by other diuretics without mineralocorticoid excess. They are also
used to treat hypomagnesemia that can occur with diuretics, antibiotics, chemotherapeutic drugs,
and immunosuppressants.[76][49] ENaC inhibitors are, therefore, both K+-sparing and Mg2+-
sparing agents. Spironolactone being non-selective also mediates its effect through its anti-
androgenic activity and can be used in the treatment of androgen-excess syndromes such as
hirsutism.[77] Eplerenone is favored for the pharmacological treatment of primary aldosteronism
due to its selective mineralocorticoid antagonism.[78].

Osmotic Diuretics

As opposed to other agents, osmotic diuretics do not interfere with electrolyte reabsorptive
mechanisms, and their main diuretic action is mediated through increasing osmolarity of the
tubular fluid in PT and TAL of the loop of Henle. Mannitol is freely filtered nonmetabolized
sugar, which increases the osmolality of both plasma and renal tubular fluid, causing osmotic
diuresis. Mannitol raises the serum osmolality and since it does not cross the blood-brain barrier
causes a positive blood-cerebrospinal fluid osmotic-gradient resulting in brain dehydration
(without affecting the brain blood flow), the effect required for reducing the intracranial pressure.
Mannitol is poorly reabsorbed and causes a wash-out of medullary solute gradient inhibiting the
countercurrent urinary concentration function, thus drawing water along with it to the collecting
ducts. This osmotic effect is similar to that of excess tubular glucose due to diabetes mellitus
leading to polyuria.[37][38][79]

Miscellaneous Diuretics

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are novel oral anti-diabetic medications that
inhibit the low affinity, high capacity SGLT2 receptors in the PT. SGLT2 receptors are involved
in the reabsorption of 90% of filtered glucose along with Na+ ions from the renal tubules and
become overexpressed in Type-2 diabetes mellitus. By blocking these receptors, SGLT2
inhibitors increase glucose excretion in the urine, thereby increasing the tubular osmolarity,
which in turn causes osmotic diuresis. These agents ending with the suffix –gliflozins can thus
cause diuresis, natriuresis (due to associated Na+ loss) and reduce extracellular fluid volume.
The diuretic action of these agents is only transient due to the development of compensatory
adaptive mechanisms to maintain fluid volume by the kidneys.[80][81][82]

ACEIs and ARBs can cause natriuresis and diuresis primarily by blocking the production of the
downstream molecules of the RAAS pathway, angiotensin II and aldosterone, which are involved
in renal conservation of water and salt.[83] Though the antihypertensive action of these drugs is
primarily due to the systemic effects of BP reduction, diuretic actions also play a minimal role.
They are sometimes combined with other diuretics to enhance the effect.[84][85][86] Stronger
alcoholic beverages (more than 13.5% alcohol), when consumed in moderation, can cause a
transient diuretic effect without any electrolyte disturbances. Under conditions of hypohydration,
alcohol does not induce any diuretic effect to restore fluid balance.[87][88]

Conivaptan and tolvaptan are not classified under diuretics but are called aquaretics due to their
effects in increasing only the water excretion without any saluretic action of a diuretic.
Conivaptan (IV route only) acts nonselectively on both V1A & V2 vasopressin receptors,
whereas tolvaptan (oral agent) is a selective antagonist of V2 vasopressin receptors. Arginine
vasopressin agonist action on its receptor leads to increased expression of luminal aquaporin-2
channels (thus promoting water reabsorption), whereas its antagonism by aquaretics leads to
enhanced aquaresis. Aquaretics, with their electrolyte-sparing effect, are currently indicated for
:
 use only in hyponatremia.[89][90]

Administration
Diuretic administration is usually via the oral route, but when maximum potency is required,
such as in cases of advanced HF, it can be given intravenously in a hospital setting. In such
situations, continuous infusion over a specified period is preferable to bolus injections. Adverse
effects (or complications) in a particular patient should be well-anticipated, and the choice of
diuretic, the dose required, route of administration, and needed clinical improvement, should all
merit consideration before administering any diuretic agent.

Loop Diuretics

Loop diuretics are more than 95% albumin-bound and reach peak concentrations in 30 min to 2
hours as they are absorbed swiftly with an oral bioavailability that exceeds 80% for bumetanide
and torsemide, while that of furosemide is the lowest at 50% on average. Loop diuretics are
available in both oral and intravenous (IV) forms, and IV infusions can be for immediate effect.
Furosemide is excreted unchanged in urine or through a renal metabolism, while bumetanide and
torsemide undergo hepatic metabolism (hence respective organ damage will prolong their half-
life). Torsemide has the longest half-life (3 to 4 hours) and the longest duration of action (12
hours) compared to both furosemide and bumetanide, with the practicability of once-daily
dosing. Torsemide absorption is not affected by food intake, while that of furosemide and
bumetanide decreases dramatically and essential to be taken on an empty stomach. Since
furosemide is the most commonly used agent, dose conversion between different loop
diuretics must be cautiously applied. In general, for oral diuresis 80 mg furosemide = 20 mg
torsemide = 1 mg bumetanide are the conversion equivalents. While that for intravenous agents,
40 mg furosemide = 20 mg torsemide = 1 mg bumetanide are to be employed.[49][57][91] Loop
diuretics are threshold drugs meaning that no diuretic effect will occur below the threshold drug
concentration. The threshold level also depends on different clinical conditions and could be
different for different patients. Hence to achieve effective diuresis, different doses might be
required to achieve the threshold level. The lowest dose that is clinically effective should be
chosen for HF treatment.[92] The frequency of dosing is also very important as loop diuretics
with a shorter duration of action can cause post-diuretic Na+ retention (anti-natriuresis) as the
diuretic effect wears off. Thus they are usually given on a twice-daily schedule.

CKD causes a diuretic resistant state both by reducing maximal natriuresis induces a shift in the
diuretic dose-response curve rightward and downward. Loop diuretics are the primary agents
used in CKD, and higher starting doses are the recommendation. For furosemide, this is in the
range of 40 to 80 mg is recommended for stages 4 and 5 of CKD, whereas the usual 20 to 40 mg
is recommended in stages 1 through 3 of CKD. Also, continuous infusion of loop agents is
recommended in hospitalized patients (to overcome anti-natriuresis), which is particularly
important in CKD patients.[57][93]

Dosage for the most common indications of the individual loop diuretics appear in Table 2.[94]
[95][96][11][14][92]

Thiazide Diuretics

All thiazides are sulfonamide derivatives that are readily absorbed from the gastrointestinal (GI)
tract after oral administration. The oral bioavailability of thiazides ranges from 50 to 95%, and
for the two most frequently used agents, hydrochlorothiazide and chlorthalidone, it is 70% and
65%, respectively. Once in the plasma, thiazides are plasma albumin-bound and do not undergo
any metabolism prior to excretion, and are secreted unchanged via urine and feces.[97] The only
:
 exception is indapamide, a thiazide-like diuretic, which undergoes extensive hepatic metabolism,
and less than 7% is excreted in the urine.[98]

With a half-life of approximately 42 hours, chlorthalidone has a larger volume of distribution

than its thiazide-type counterpart hydrochlorothiazide because they bind to red blood cell (RBC)
carbonic anhydrase and are sequestered in these cells, reaching a concentration 7 to 10 times
more than that of plasma. Thus RBCs act as a reservoir, and the drug is released into the plasma
gradually, which can be utilized clinically by a once-daily dosing regimen.
[99] Hydrochlorothiazide, in contrast, has a shorter half-life of about 6 to 9 hours, but this
increases with long-term dosing, and some studies thus recommend once-daily dosing for this
drug as well. Hydrochlorothiazide is a pregnancy category B medication.[100] While loop
diuretics are recommended in all stages of CKD, Thiazides are advised only in stages 1 to 3. The
risk of metabolic side effects increases at higher doses of thiazides and is usually not preferred
near the maximum dose range. Dosage for the most common indications of the individual
thiazide diuretics appear in Table 3.[94][95][99][23][101][96][11]

Potassium-sparing Diuretics

ENaC inhibitor amiloride does not undergo any metabolic transformation in the body, while
triamterene is metabolized into a sulfate ester by extensive hepatic metabolism. Thus in patients
with liver pathology, amiloride is preferred, half of which is excreted in the urine unmetabolized
while the other half passes through the feces. However, amiloride must be avoided in patients
with renal dysfunction as it is excreted through tubular secretion, and due to its longer half-life,
the drug can accumulate in the body in such patients and predispose to life-threatening
hyperkalemia. Though comfortable once-daily dosing is possible with amiloride, its peer
triamterene needs twice-daily dosing, and both these drugs have an oral bioavailability of
approximately 50%.[102][103] Amiloride being a pregnancy category B medication, is safer to
use for the treatment of Liddle syndrome in pregnant patients.[104]

ARA spironolactone largely undergoes metabolism in the liver into its active form canrenone,
which is more than 90% bound to plasma proteins. The oral bioavailability of spironolactone
varies from 60 to 90%, while that of eplerenone is about 69%. Eplerenone undergoes a hepatic
metabolism as well, but there are no active metabolites and is 50% bound to albumin in the
serum, and about 67% is excreted in the urine while 32% passes through the feces. Food intake
does not interfere with the absorption of these drugs, and taking it with food can, in effect,
reduce gastric irritation and adverse symptoms associated with it.[105][106] Dosage for the most
common indications of the individual PSDs appear in Table 4.[94][95][11][107][14]

Carbonic-anhydrase Inhibitors and Osmotic Diuretics

Acetazolamide, the only diuretic CAI, is well absorbed from the GI tract, not metabolized, and is
93% protein-bound in the plasma. The onset of action of the oral form is 1 to 1.5 h with an oral
bioavailability of almost 100%. It has a plasma half-life of 13 hours, and twice-daily dosing is
recommended. Almost 90% of the drug is excreted in the urine by tubular secretion and is
ineffective in renal insufficiency.[108][109]

Mannitol is poorly absorbed when given orally, and hence it is administered only via intravenous
route as a bolus and hence has a bioavailability of 100%. Once in the plasma, mannitol, being an
osmotic substance, draws fluid into the plasma, decreasing the blood viscosity and thereby the
hematocrit. Mannitol is freely filtered with limited reabsorption, and it undergoes only slight
metabolism in the liver to glycogen. The majority of the rest (more than 90%) is excreted
unchanged in the urine, with an elimination half-life reported from 70 to 150 minutes.[79][110]
[111] Dosage for the most common indications of the individual CAIs and osmotic diuretics
:
 appear in Table 5.[50][11][112][113][37][114]

Adverse Effects
General Adverse Effects

The most common adverse effect for any diuretic is mild hypovolemia, which can lead to
transient dehydration and increased thirst. When there is an over-treatment with a diuretic, this
could lead to severe hypovolemia, causing hypotension, dizziness, and syncope. More
generalized side-effects of diuretic agents include headache, urinary frequency, restlessness,
weakness, fatigue, and lethargy. GI disturbances like nausea, vomiting, constipation, diarrhea,
anorexia and abdominal pain can occur with loop diuretics and PSDs than any other diuretic
group.

Electrolyte abnormalities are commonly associated with all the diuretic agents, and their
mechanisms of such effect are well-established, and these mechanisms are explained under the
respective class of diuretics below. To give a broader picture, hypokalemia, for example, is
caused by all the diuretics except PSDs, which causes hyperkalemia. Acid-base disorders usually
accompany the electrolyte derangement due to their close association with their reabsorption in
the renal tubules. Metabolic disturbances can lead to derangement of glucose, uric acid, or lipid
levels with certain diuretics and are individually discussed. Other rare adverse effects include
impotence, hyperglycemic hyperosmolar non-ketotic syndrome, skin reactions, aplastic anemia,
thrombocytopenia, agranulocytosis, hemolytic anemia, muscle cramps, and myalgia. In general,
adverse effects are dose-dependent and are higher with loop diuretics as they have the most
significant diuretic effect. With controlled low-dose formulations, adverse effects have reduced
substantially, especially with thiazide diuretics.[115][116][117][118]

Loop Diuretic-specific Effects

Hypokalemia and metabolic alkalosis can occur with both loop and thiazide diuretics but
more common with loop diuretics. Loop agents increase distal Na+ delivery at macula
densa and cause volume depletion, both of which indirectly activate the RAAS pathway.
Aldosterone thus produced, which causes aggressive Na+ reabsorption leading to a
negatively charged lumen and causing trapping of K+ and H+ ions in the lumen and
eventually causing hypokalemia and metabolic alkalosis, similar to Conn syndrome.
Increased distal Ca2+ delivered by loop agents may decrease the severity of hypokalemia
but inhibiting K+ secretion indirectly by blocking ENaCs.[119] Contraction alkalosis can
result from the rapid loss of large volumes of sodium-rich, bicarbonate-low extracellular
fluid from the body; high-ceiling loop diuretics most commonly cause this.[120]

Hypocalcemia and hypomagnesemia: Blocking NKCC2 function leads to suppression of

ROMK-mediated K+ recycling into the lumen, which leaves a decreased transepithelial
voltage (with a less positive luminal charge). This reduced luminal positivity reduces the
driving force required for Ca2+ and Mg2+ reabsorption via the paracellular pathway,
causing (see above) hypocalcemia and hypomagnesemia.[121] Despite the popular belief
about hypomagnesemia caused by loop agents, a recent cohort study has concluded that
thiazides but not loop diuretics are associated with the risk of hypomagnesemia.[122]

Hyperuricemia: Both loop and thiazide diuretics are anions that are secreted in exchange
for urate molecules via the OATs leading to urate reabsorption and hence hyperuricemia.
Thus these diuretics are associated with an increased risk of gouty attacks.[123] Of note,
probenecid, a uricosuric agent used in gout, competes with urate to bind OATs leading to
urate excretion.
:
 Hypertriglyceridemia and Hypercholesterolemia: Loop diuretics can increase the levels
of low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) levels, but the
mechanism for this remains unclear.[124]

Hypochloremia is associated with increased fractional excretion of Cl- relative to that of

Na+.[125]

Ototoxicity is a specific adverse effect of loop agents not shared by any other diuretic, and
it manifests as sensory neural hearing loss, tinnitus, vertigo, or dizziness.[126] Mechanism
discussed further under toxicity.

Hypersensitivity reactions: Furosemide can cause hypersensitivity reactions such as skin

rashes or acute interstitial nephritis. Reports also exist of more severe anaphylactic
reactions.[127][54]

Stevens-Johnson syndrome: Loop diuretics have implications as a rare cause of Stevens-

Johnson syndrome.[128][129]

Other less common adverse effects of loop diuretics include photosensitivity, nausea, and
allergic interstitial nephritis.[130] Loop diuretics, especially furosemide and bumetanide,
can displace bilirubin from albumin and cause hyperbilirubinemia leading to an increased
risk of kernicterus in jaundiced neonates.[131] Furosemide, rarely, can cause aplastic
anemia and agranulocytosis.[132]

Thiazide-specific Effects

Electrolyte abnormalities are the most common adverse effects associated with chronic thiazide
therapy in hypertension. They occur most commonly with longer-acting agents such as
chlorthalidone and metolazone, but this is mitigated to an extent with a low-dose strategy.

Hypokalemia and metabolic alkalosis: Thiazides can cause RAAS activation only via
volume depletion (see above) as they act on NCC channels located distal to the macula
densa and do not influence salt-sensors located there. Aldosterone from the RAAS
pathway enhances the excretion of K+ and H+ in the tubules, as explained above. Also,
thiazides cause decreased distal Ca2+ delivery, which stimulates ENaCs leading to
increased K+ secretion, thereby contributing to hypokalemia.[69][119] They usually
respond to K+ replacement therapy very well.

Hyponatremia: Even though loop diuretics suppresses a greater load of Na+ reabsorption
than other agents, hyponatremia most often results from thiazides because thiazides lead to
reduced free-water clearance and they do not interfere with urine concentrating ability
(countercurrent pathway) when compared to loop agents. Furthermore, increased water
intake and increased vasopressin secretion contribute to dilutional hyponatremia.[133]

Hypercalcemia/hypocalciuria Volume depletion by thiazides causes enhanced Na+

reabsorption in the PTs, which in turn stimulates increased passive Ca2+ reabsorption via
paracellular pathway there, a proximal response. As a distal response, inhibition of NCC
channels by thiazides could play a role in enhancing Ca2+ reabsorption by modulating the
activity of TRP vanilloid-5 channels.[134][135]

Hypomagnesemia also correlates with the chronic use of thiazides and is mediated
through thiazide-mediated inhibition of NCC channels, which indirectly inhibits Mg2+
reabsorption via downregulating TRP melastatin-6 channels.[122] Of note, a proton pump
inhibitor also mediates hypomagnesemia via the same channels in both gastrointestinal
(GI) and renal tubules.[136]
:
 Glucose intolerance: Thiazide-induced hypokalemia in pancreatic interstitium
hyperpolarizes the islet cells, thereby inhibiting calcium influx and thus decreasing the
calcium-dependent release of insulin resulting in hyperglycemia. Thiazides also cause an
increase in the inflammatory response, abnormal lipid metabolism, RAAS activation, and
oxidative stress, thus decreased insulin sensitivity that arises as a consequence is
multifactorial. New-onset diabetes due to thiazides is also of concern in obese and
hypertensive individuals.[137][69][138]

Hyperuricemia: The incidence of this adverse effect increases with the number of years
using thiazides for hypertensive therapy.[139]

Hypertriglyceridemia and Hypercholesterolemia: Thiazides, while not affecting high-

density lipoproteins, have been shown to increase LDL-C levels by 10%, total cholesterol
by 4%, and TG levels by almost 15%. There is evidence on the dose-dependency of this
side-effect and reduced occurrence with low-dose therapy.[124].

Stevens-Johnson syndrome: Thiazides, like loop diuretics, are also implicated as a rare
cause of Stevens-Johnson syndrome [128][129]

Rarely Thiazides can increase the risk of developing acute pancreatitis owing to increased
serum calcium levels.[140] Thiazides, rarely, have also been implicated in drug-induced
hematological abnormalities, including thrombocytopenia and agranulocytosis.
[141] Orthostatic hypotension and impotence are other side-effects of thiazide use.

Potassium-sparing Diuretic Specific Effects

More generalized and less common side-effects of K+-sparing agents include headache, fatigue,
and GI disturbances like nausea, vomiting, constipation, diarrhea, anorexia, and abdominal pain.

ENaC Inhibitor Specific Effects

Hyperkalemia and hyperchloremic metabolic acidosis are the most common side-effect
of this class of diuretics due to their inhibition of ENaCs and, consequently, suppressed
secretion of K+ ions and H+ ions from the ASDN.[142] This action results in
hyperkalemia, and as with CAIs, the metabolic acidosis thus produced is hyperchloremic
but via a different initial mechanism. Hyperkalemia produced by these K+-sparing
diuretics can lead to impaired PT ammonia generation and reduced collecting duct
ammonia transport resulting in impaired ammonia excretion. The HCO3+ in the blood
reacts with excess ammonia to buffer the pH while getting used up in the process leading
to reduced HCO3+ levels. The reduced serum HCO3+ causes lead to shifting of Cl- ions to
the plasma from the cells leading to hyperchloremic metabolic acidosis.[143][144][145]

Amiloride carries a black-box warning for hyperkalemia. Nausea, flatulence, and skin
rashes can occur with amiloride or triamterene. Rarely, nephrolithiasis can result from
triamterene use.[146]

Aldosterone Receptor Antagonist Specific Effects

Side-effects of this category are attributed to spironolactone and are dose-dependent in

most situations and can include menstrual irregularities, breast tenderness, and orthostatic
hypotension.[147]

Gynecomastia: Spironolactone is a non-selective ARA and is structurally similar to

progesterone and results in progestogenic and anti-androgenic effects, which block both
the production of androgens such as testosterone and their binding to their androgenic
:
 receptors. Such a decrease in androgens decreases the androgen to estrogen ratio, opening
the way for estrogens to exert their unrestrained action causing gynecomastia.[148] Thus
drugs affecting this ratio, such as tamoxifen, danazol, and letrozole, are the mainstay of
medical therapy of this condition.[149] Eplerenone is more selective for MR and does not
cause gynecomastia. Decreased libido and galactorrhoea are other anti-androgenic side-
effects associated with spironolactone.

Carbonic Anhydrase Inhibitor Specific Effects

Hyperchloremic metabolic acidosis: Acetazolamide most commonly cause symptomatic

metabolic acidosis. The majority of HCO3+ ions are reabsorbed in the PT with the help of
carbonic anhydrase enzyme, and inhibition of this enzyme by acetazolamide causes
wastage of HCO3+ ions in the urine (bicarbonaturia). This activity leads to reduced serum
HCO3+ levels, and intracellular Cl- ions are then released into the plasma to compensate
for the loss of negative charge causing normal anion gap metabolic acidosis, aka
hyperchloremic metabolic acidosis. Chronic use of acetazolamide is not warranted due to
this side-effect.[150][151]

Hypokalemia: is due to increased distal delivery of Na+ ions and their reabsorption in
exchange for K+ ions.

Fanconi syndrome: Inhibition of HCO3+ ions also cause type-2 proximal renal tubular
acidosis, which can cause PT dysfunction leading to drug-induced Fanconi syndrome.
[150]

Other less common side effects include Light-headedness, circumoral paresthesias,

weakness, and confusion.

Osmotic Diuretic Specific Effects

Electrolyte abnormalities: Though mannitol does not interfere with electrolyte

reabsorptive mechanisms, it can cause inhibition of water transport, and this diminishes the
ability of renal tubules to reabsorb Na+ ions, which can cause hyponatremia. Increased
distal delivery of Na+ ions can lead to K+ loss as described above and thus hypokalemia.
As it causes increased serum osmolality, mannitol causes a shift of water from the
intracellular compartment to the plasma, leading to an increase in blood volume, which can
further result in dilutional hyponatremia and hypokalemia.[79]

Mannitol-induced overt expansion of extracellular fluid volume can precipitate pulmonary

edema in HF patients due to hypervolemia.[152] With frequent use, mannitol sometimes
can worsen cerebral edema as it can cross the already damaged blood-brain barrier (as in
intracranial hemorrhage) and draws water into the brain. Mannitol less commonly can
form precipitates at low temperatures, which can cause vascular and end-organ damage.
Other adverse effects include nausea, vomiting, fever, confusion, and a lethargic state.[37]

Contraindications
Severe dehydration or established anuria is a contraindication for any type of diuretic. Patients
with known hypersensitivity to any of the diuretic agents are contraindicated to receive the same
drug. Diuretics are contraindicated in severe electrolyte derangement and should not be
administered until a detected electrolyte abnormality is corrected.

Loop and thiazide diuretics are contraindicated in patients already diagnosed with gout.[153]

Loop diuretics (except ethacrynic acid), thiazide diuretics, and CAIs are all sulfonamide
:
 derivatives and were generally regarded as contraindicated in sulfa-allergy patients. Recent
evidence suggests otherwise, and several reports of instances of uneventful use of sulfa-diuretic
use in documented sulfa-allergy patients exist. In conclusion, only a low risk of cross-
allergenicity between sulfonamide antibiotics and sulfonamide non-antibiotics and diuretics can
be prescribed with caution in sulfa-allergic patients. Notwithstanding, documented allergy to any
of the sulfonamide diuretic agents themselves should be considered an absolute contraindication,
and for sulfonamide non-antibiotics, it is a relative contraindication.[154][155][156][157]

Loop diuretics are contraindicated in patients with hypokalemia (only to be administered after
correction), severe hyponatremia, hypotension, azotemia, oliguria/anuria, and hepatic coma. It is
also contraindicated in any situation where fluid depletion is foreseen, such as surgery.
Furosemide and bumetanide are pregnancy category C, while torsemide is category B and
relatively safe in pregnancy.

Thiazide diuretics induce hyperglycemia, but are these agents contraindicated in hypertensive
patients for the risk of new-onset diabetes or worsening of preexisting diabetes? Thiazides are of
crucial importance as first-line therapy in patients with hypertension, a condition treated
primarily to reduce the high risk of CV mortality. To compare the two important drugs in this
class, chlorthalidone (thiazide-like diuretic) has demonstrated superiority to hydrochlorothiazide
(thiazide-type diuretic) in reducing systolic BP levels and in achieving target BP values. Also, in
comparison to other anti-hypertensives, chlorthalidone has been repeatedly shown in various
clinical trials to greatly reduce the risk of adverse CV events. Also, chlorthalidone has been
shown to cause the fewest clinical events of diabetes in contrast to any other anti-hypertensive.
In a hypertensive population with preexisting diabetes, the salutary anti-hypertensive effects of
low-dose (12.5 mg) chlorthalidone outweigh the risk of glucose intolerance and will particularly
benefit young non-obese patients. The 2018 ESC guidelines on hypertension give the highest
class I recommendation for the use of thiazide/thiazide-like diuretics along with a RAS blocker
in the treatment of diabetics with hypertension.[25][23][158][159][160]

Guidelines advised against the use of thiazides in patients with severe stage 4 or stage 5 CKD
(see Table 2), though recent reports are in favor of its use as anti-hypertensive (even if GFR less
than 30 mL/min) as the BP-lowering mechanism of thiazides are not related to their diuretic
function in the kidney. Nevertheless, thiazides are contraindicated when the diuresis is the
predominant action required in patients with CKD, where loop diuretics are preferred. The only
exception is metolazone, a thiazide diuretic that can be used for diuresis in CKD.[100][161]

K+-sparing diuretics are contraindicated in hyperkalemia (K+ levels more than 5 mEq/L) until
the underlying pathology is corrected. PSDs are contraindicated in advanced renal failure or
CKD as these patients are at risk of hyperkalemia; this is particularly true when GFR <30
mL/min/1.73 m^2 corresponding to CKD stages 4 and 5.[162][93] Spironolactone is pregnancy
category C, and along with triamterene, should be avoided in pregnancy, while eplerenone is a
category B medication.[163]

In hyperchloremic metabolic acidosis (see adverse effects), acetazolamide is contraindicated, and

extreme caution should be exercised in severe chronic obstructive pulmonary disease when
considering acetazolamide for treatment.[164]

The kidneys primarily excrete mannitol, and in patients with renal impairment, it should be used
with caution as it can cause osmotic nephropathy.[111] Intravascular volume overload due to
mannitol may be of concern in cardiac and renal failure patients and are hence contraindicated in
such patients. Mannitol should not be used in patients with active cranial bleeding, severe
dehydration, and in patients with hypersensitivity history to its use. When using mannitol in
treating patients with anuria, it requires an initial test dose to verify the diuretic response.[165]
:
 Drug-interactions

Salicylates can displace acetazolamide from plasma protein, thereby causing an increase in free
acetazolamide in the plasma leading to toxicity secondary to RBC carbonic anhydrase inhibition.
Acetazolamide should not be used to alkalinize urine following salicylate overdose since it may
worsen metabolic acidosis.[166][167][168]

Prostaglandins are involved in the modulation of systemic and renal vasodilation, GFR, RAAS,
water, and salt secretion. Their blockade by nonsteroidal anti-inflammatory drugs (NSAIDs) in a
patient with hypertension could suppress the effects of antihypertensive medications, including
diuretics. NSAIDs are not very influential in regulating renal functions under normal
circumstances, but they can blunt the natriuretic response, reduce GFR and suppress renin
production when used along with loop or thiazide diuretics and can cause acute renal failure.
[169][170]

The ototoxic ability of loop diuretics can become potentiated with other ototoxic drugs such as
aminoglycosides or platinum-containing chemotherapeutic compounds.[126]

Diuretic-induced hypokalemia can increase the risk of digitalis-induced arrhythmia.

[163] Digoxin competes with K+ ions for its binding site on the Na+-K+-ATPase pump in the
heart, and thus in diuretic-induced hypokalemia, the action of digoxin is unopposed, leading to
fatal arrhythmias.[171] Although any diuretic causing hypokalemia can lead to this effect, loop
diuretics carry the greatest risk when compared to other classes of diuretics, but as an individual
agent, hydrochlorothiazide had the greatest risk.[172] Hence the combination of hypokalemia-
inducible diuretics and digoxin can be dangerous and must be avoided. Similarly, clinicians must
avoid using quinidine because thiazide-induced hypokalemia can potentiate its cardiovascular
effects.[173]

Bendroflumethiazide can cause calcium retention, and care is necessary when administered along
with calcium supplements or vitamin D.[174] Thiazides can cause lithium accumulation when
the drugs are co-administered as they can increase lithium reabsorption in the PT.[175]

RAAS inhibiting agents like ACEIs, ARBs, beta-blockers, NSAIDs, or aliskiren can result in a
small amount of potassium retention, and their concomitant use with PSDs may cause
hyperkalemia and hence a relative contraindication.[115] PSDs apparently must not be
administered along with another PSD to avoid the risk of dangerous hyperkalemia.

Monitoring
Diuretic treatment calls for careful assessment of extracellular fluid volume, urine output,
electrolyte levels in plasma and urine, body weight, acid-base status, serum glucose, and BP
regularly with particular emphasis on patients with cardiovascular, hepatic, renal, or metabolic
disorders and in elderly individuals. Prerenal azotemia is of concern due to diuretic-induced
hypovolemia, and blood urea nitrogen and creatinine levels require monitoring.

Ototoxicity is a risk with the use of loop diuretics, and special precautions are necessary.
Baseline auditory tests are necessary (especially when planning large bolus doses at high
infusion rates), which will help evaluate on a case-by-case basis the effect of loop diuretics on
auditory functions after a certain length of treatment. Periodic sequential monitoring of auditory
functions is also advisable, and the possibility of switching to a different diuretic therapy should
be contemplated in case of any adverse outcomes.[126]

Clinical cardiac status should be assessed in patients on diuretics (especially MI, HF, or other
cardiac conditions), as they are prone to develop HF due to the abrupt increase in the fluid shift
between the compartments.
:
 Failure of a diuretic agent to increase urine output should prompt cessation of the diuretic agent
as it could be evidence of undiagnosed underlying renal pathology.

Frequent administration of mannitol can worsen cerebral edema and hence should be
administered every 6 to 8 hours, as suggested in Table 4.

Diuretic Abuse

Diuretics are not highly controlled drugs and hence have a high probability for misuse,
particularly with athletes who might abuse them for rapid weight loss or to conceal the presence
of other banned drugs. The use of diuretics is prohibited in athletes. (Athletes require a prior
exemption for therapeutic use in athletes) and is routinely screened for by the world anti-doping
agency. If it persists chronically, such abuse can lead to detrimental effects on CV and
thermoregulatory functions, which could lead to death when combined with excessive physical
activity as encountered in athletes.[176] People with bulimia nervosa can misuse diuretics (when
they try to purge the food), and such use can lead to pseudo-Bartter syndrome.[177] Psychotic
patients also can abuse diuretics, along with laxatives [178].

Diuretics in Diagnosis

Furosemide/Fludrocortisone test (FFT): Furosemide, combined with the

mineralocorticoid fludrocortisone, has gained popularity as a diagnostic screening tool for
distal renal tubular acidosis (dRTA). dRTA is a condition where there is a defect in urinary
acidification due to the failure of alpha-intercalated cells to secrete H+ ions in the distal
tubules (refer to the mechanism of action of PSDs). There are four different types of
dRTA, usually diagnosed by ammonium chloride (NH4Cl) loading test, but due to
disturbing GI symptoms after administration, the test is sometimes abandoned. NH4Cl
combines with HCO3+ ions to form urea in the liver, thus decreasing the HCO3+ levels in
the blood stressing the kidneys to reabsorb more HCO3+ ions in exchange for H+ ions,
thus acidifying the urine. In patients with dRTA, this test can lead to systemic metabolic
acidosis as kidneys cannot reabsorb HCO3+ ions due to H+ ion secretion defect. If the
urine pH is greater than 5.3, then the test is considered positive for dRTA. FFT is a
palatable alternative that is better tolerated. Furosemide increases the distal delivery of
Na+ ions, and fludrocortisone being a mineralocorticoid, enhances the Na+ reabsorption
via ENaCs and increases H+ ion secretion via the alpha-intercalated cells. This
combination thus can acidify the urine without the metabolic acidosis induced by NH4Cl.
In people without dRTA, the urine pH is lower than 5.3 with FFT, whereas patients with
dRTA cannot lower their pH leading to its diagnosis.[179][180][181]

Mannitol challenge test (MCT): Mannitol can be an agent in a challenge test in the
diagnosis of asthma. In this test, dry powder of mannitol is inhaled, which leads to
hyperosmolality of bronchial periciliary liquid inducing cell shrinkage to equilibrate the
osmolality. This further results in the release of pro-inflammatory mediators from
inflammatory cells (particularly mast cells), resulting in smooth muscle constriction. A
15% decrease in forced expiratory volume in the first second (FEV1) is a positive result,
suggesting an easily elicited active airway inflammation, indicating airway
hyperresponsiveness. Though MCT is a very safe test, it has only a moderate sensitivity to
detect asthma but high specificity. In comparison, direct bronchial challenge tests such as
histamine or methacholine challenge tests have less specificity when compared to MCT.
[182]

Toxicity
:
 Reversible ototoxicity (manifested as sensory neural hearing loss, tinnitus) can be caused by
ischemia in stria vascularis and by inhibiting NKCC1 channels in stria vascularis by loop
diuretics, which improves with discontinuation of the drug. Deafness and tinnitus from loop
diuretics most frequently occur when administering large bolus doses in an acute setting, such as
when using furosemide in acute kidney injury. The resulting ototoxicity is, therefore, due to the
higher serum concentrations of the drug achieved. Ethacrynic acid is the most ototoxic drug in
this group.[183][57][184]

There are reports of hydrochlorothiazide, furosemide, spironolactone, and triamterene, causing

hepatotoxicity, but there is no suggestion of diuretic class effect.[185][186][187]

Diuretic-induced kidney injury has been reported, and it is most severe in elderly patients due to
their decreased sensitivity of thirst response. Diuretics are also associated with increased risk
when the renal blood flow is compromised in conditions such as congestive heart failure, hepatic
cirrhosis, and nephrotic syndrome and can cause acute renal failure. Dose dependency also plays
a factor as higher diuretic doses are associated with pathological injury of the glomerular
basement membrane. Diuretics can lead to vacuolar degeneration of tubular epithelial cells, and
hence their use with other nephrotoxic drugs should be contraindicated.[188]

Enhancing Healthcare Team Outcomes

Diuretic therapy, while typically well-tolerated, requires the comprehensive effort of an
interprofessional medical team, including clinicians, specialists, NPs and PAs, nurses, and
pharmacists. Patient education plays a crucial role and adequate knowledge of the adverse
effects, dietary, and lifestyle modifications necessary while on diuretics. Patients (especially in
an outpatient setting) must understand to report any changes in their compliance pattern or any
adverse effect thereof. Adherence to strict treatment protocols and timely intake of the drug, and
avoiding any overdosing when the patients miss their dosing will significantly improve the
clinical course and the effectiveness of the diuretic agent.

Nurses, as immediate caregivers, should be cognizant of the adverse effects of diuretics and
should be able to alert the treating clinician if a patient’s condition worsens. This situation is
particularly true in hospitalized patients in intensive care units where updating urine output
charts, daily body weight measurements, and periodic arterial blood gas analysis ensures patient
safety. Pharmacists play an essential role in an outpatient setting and should be vigilant to check
any drug-drug interactions or incorrect dosage in the prescriptions. Diuretics are prescription-
only drugs, and any over-the-counter request of these drugs should be refused and, if needed, be
reported to avoid damage to health by suspected misusers of diuretics. Several health
professionals, including clinicians and specialists like cardiologists, otorhinolaryngologists, plus
clinical pharmacists, nurses, and other healthcare workers, form part of the interprofessional
team to operate in collaboration to avert any adverse outcome with diuretic therapy.[189] [Level
5]

Review Questions

Access free multiple choice questions on this topic.

Comment on this article.

Figure

Table 1: Classification of diuretic agents. Created and Contributed by Vijay

Arumugham, MD, PhD
:
 Figure

Table 2: Dosages for specific indications of Loop diuretics.

Created and Contributed by Vijay Arumugham, MD, PhD

Figure

Table 3: Dosages for specific indications of thiazide diuretics.

Created and Contributed by Vijay Arumugham, MD, PhD

Figure

Table 4: Dosages for specific indications of potassium-

sparing diuretics. Created and Contributed by Vijay
Arumugham, MD, PhD

Figure

Table 5: Dosages for specific indications of carbonic

anhydrase inhibitors and osmotic diuretics. Created and
Contributed by Vijay Arumugham, MD, PhD

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