DIURETICS

Dr. ASHLEY M. STOKES

INTRODUCTION
General considerations

Diuretics, agents that increase the renal excretion of sodium and water, are some of the most
widely used therapeutic agents. Their primary use is the mobilization of edema fluid, although
some agents (i.e. mannitol) are not used for this purpose. It is, therefore, relevant to begin with a
review of the pathophysiology of edema formation. This will be followed by a review of normal
renal physiology since it is important to fully understand the effects, uses, and contraindications
of the various classes of diuretics. The pharmacological classification of diuretics can be based
on many factors including structure and potency, but classification based on site of action is the
most common system utilized. Agents that have primary actions in the proximal tubules include
the carbonic anhydrase inhibitors (i.e. acetazolamide) and the osmotic diuretics (i.e. glycerin and
mannitol). The loop diuretics (i.e. furosemide) have primary actions within the ascending
segment of the loop of Henle. Thiazide diuretics (i.e. chlorothiazide) act principally in the early
distal tubules. The potassium sparing diuretics (i.e. spironolactone) have primary actions within
the late distal tubules and the collecting ducts. The site or mechanism of action of these agents
also predicts the potential complications (i.e. risk of volume depletion and/or electrolyte
disorders) associated with their use. The chapter is concluded with two tables that summarize the
mechanisms, sites of action, potency, uses, side effects, and overall effects on electrolytes for
each class of diuretics (Tables 29.1 and 29.2).

Pathophysiology of edema formation

About one third of total body water is found within the extracellular space, which is comprised
of the intravascular plasma volume and the extravascular interstitial space. Normally, forces
within the capillaries and interstitial tissues are balanced to prevent the formation of edema.
Capillary hydrostatic pressure (capillary blood pressure), capillary oncotic pressure (plasma
proteins), interstitial hydrostatic pressure (interstitial tissue pressure), and interstitial oncotic
pressure (interstitial proteins) are the four basic forces held in balance within tissue beds to
prevent edema formation (Figure 29.1). Capillary permeability and the rate of lymphatic return
also greatly influence the formation of edema.1 Edema is a condition where an imbalance in
these forces leads to an abnormal interstitial fluid volume.
 Capillary Permeability

Capillary Plasma Colloid

Pressure
Capillary Pressure Flow

Interstitial Interstitium Interstitial Colloid

Pressure Pressure

Figure 1. Imbalances in capillary and interstitial pressure, colloid pressures, and capillary
permeability play the greatest roles in the formation of interstitial edema. Increased lymph flow
from the interstitium can aid in the prevention of edema until fluid accumulation overcomes
lymphatic capabilities.

Although diuretic therapy is useful in the treatment of edema, treatment of the underlying disease
process needs priority consideration. The location of edema dictates the prioritization of
treatment and the rate of movement of the fluid from the interstitial space into the vascular space.
Diuretics that move fluid rapidly from the body must be used with careful monitoring. Edema
due to lymphatic or venous obstruction is typically only mildly responsive to diuretic therapy and
the risk of diuretic-induced intravascular volume depletion is increased in these cases with
continued or increased diuretic administration. Generalized peripheral edema is very responsive
to diuretic therapy with quick movement from the interstitium into the vasculature. This form of
edema is usually not life-threatening and does not require immediate attention unless there is
respiratory compromise. Edema in the form of ascites or pleural effusion is mobilized more
slowly with diuretic therapy, thus requiring a more gradual diuresis to prevent excessive
intravascular volume depletion. Pulmonary congestion, a more life-threatening form of edema,
does require immediate attention, although the rapid rate of fluid removal may lead to
compromised plasma fluid volume. As expected, careful monitoring of the patient is imperative
in these cases.

The following is a review of the forces involved in the formation of edema and common
disorders associated with their dysfunction. An understanding of the dynamics of these forces
enhances identification of the underlying cause of edema formation and aids in the selection of
proper therapeutics.

Increased capillary pressure

There are three main causes of increased capillary pressure. One cause is excessive kidney
retention of salt and water, thereby increasing the volume of blood in the vascular system. A
second cause is high venous pressure, often due to heart failure, local venous occlusion, or
failure of the venous valve/pump system from muscle paralysis or immobilization. The third
cause is decreased arteriolar resistance, or increased blood flow, due to excessive body heat,
paralysis of the sympathetic nervous system, or the effects of vasodilator substances. In most
cases, increases in systemic arterial pressure can be regulated by opening and closing of
precapillary sphincters thereby protecting the capillary bed.2 However, during states that elevate
the capillary pressure, fluid is forced out of the capillary into the interstitium.

Decreased plasma proteins

The three most common causes of decreased plasma proteins are loss of proteins in the urine,
loss from burns or wounds of the skin, protein losing enteropathy, and from the decreased
production of proteins due to hepatic dysfunction or malnutrition.3 The net result of decreased
plasma protein concentration is a decrease in the osmotic colloid attraction of fluid into the
capillary. As the plasma colloid concentration of the interstitial tissues becomes greater than that
of the capillary, fluid is pulled osmotically into the tissues.

Increased capillary permeability

Factors that influence the integrity of the endothelial layer of the capillary bed will alter capillary
permeability. Examples of insults to this integrity include exposure to toxins, vasodilators,
inflammatory mediators, bacterial infections, immune reactions, vitamin deficiency, ischemia,
and burns.4 Increases in capillary permeability allow for unrestrained movement of fluid into and
out of the interstitium.

Blockage of lymph return

During normal physiological states in most tissues, there is a very small net efflux of fluid from
the capillary that filters through the interstitial tissues (i.e. bathing these tissues), and is returned
to the circulatory system by way of the lymphatics. The capabilities of the lymphatic vessels in
transporting excess fluid vary depending on anatomic location. Edema formation occurs with
blockage of tissues surrounding lymphatics, or by obstructing structures within the lymphatic
system.

Review of renal physiology

The human kidney contains over 1 million nephrons, which are made up of the glomerulus and
the tubule.5 Filtration by the human kidneys’ glomeruli amounts to 180 L/day and 1.7 kg of
sodium; however, a majority of this filtrate must be conserved by the body through reabsorption
in the tubules.6 The main function of the glomerulus is to filter the blood, retain cells and large
proteins, and produce an ultrafiltrate. The tubules are highly specialized in various segments and
are responsible for reabsorbing or secreting substances as needed to maintain hemostasis. The
primary mechanisms of renal excretion are filtration, reabsorption, and secretion of mostly water,
minerals, electrolytes, and hydrogen ions.5 Urinary excretion is finely tuned during normal states
to maintain hemostasis with usually less than 3% and 15% of filtered sodium and water,
respectively, excreted.6 The kidney also plays a major role in the maintenance of normal body
pH. Bicarbonate reclamation and regeneration, through the actions of the enzyme carbonic
anhydrase, maintains plasma levels of bicarbonate thus preventing minute-to-minute and day-to-
day pH fluctuations in blood and tissues7
The different mechanisms of action within each of the segments of the nephron and their serial
arrangement provide an amazing capacity for absorption. Diuretics have very similar
mechanisms of action across species and this is due in part to the similarities in renal physiology
between veterinary species. The following is a brief review of general renal physiology with
concentration on the specific processes altered by various classes of diuretics (Figure 29.2).

Figure 2. Locations of mechanisms of action (active sites) of the various classes of diuretics
within a generalized nephron.

Proximal tubule

Following filtration from the glomerulus, the proximal tubule is the site of a majority of
reabsorption of sodium (60 – 70%), bicarbonate (90%), and water (Figure 29.3).6 A sodium-
potassium active transport pump located abluminally creates the sodium gradient responsible for
the reabsorption of such a large amount of sodium. Bicarbonate is also reclaimed in the proximal
tubule in exchange for hydrogen ions through a process involving the dehydration of carbonic
acid by the enzyme carbonic anhydrase resulting in the production of water and carbon dioxide.8
Carbon dioxide freely diffuses across the luminal membrane and then combines with cellular
water to produce carbonic acid. Carbonic acid dissociates spontaneously, and is translocated to
the interstitial fluid via symporters responsible for sodium conservation. Thus, the bicarbonate
filtered by the glomerulus is conserved. Blockade of this mechanism reduces the amount of
hydrogen ion available for exchange with sodium by the luminal antiporters, and bicarbonate is
lost to the urine. Some of the factors that influence the reabsorption within the proximal tubules
are angiotensin II, endothelin, sympathetic innervation, acid-base status, dopamine, and the
glomerulotubular balance.6
 Figure 3. The proximal tubule is a major site of reabsorption for sodium (Na+), bicarbonate
(HCO3-), and water (H2O). The enzyme carbonic anhydrase (CA) participates to convert between
carbonic acid (H2CO3; by way of interaction between HCO3- and hydrogen ion (H+)) and carbon
dioxide (CO2) + H2O. This conversion takes place in the luminal membrane (CO2 + H2O
produced) and in the proximal tubular cells (H2CO3 produced). An antiporter (A) exchanges Na+
for H+ in the luminal membrane to participate in CA conversion of HCO3- to CO2 + H2O.
Potassium (K+) is also involved in the reabsorption of Na+ through an ATP-dependent transport
pump. Na+ is also absorbed with HCO3- through a symporter (S) located on the abluminal
membrane of the cell. The circled crosses denote the location of action of the carbonic anhydrase
inhibitors.

Thick ascending limb of the loop of Henle

The next major site of sodium transport (15 – 25% of filtered load), and therefore the next major
site of diuretic action, is the thick ascending limb of the loop of Henle (Figure 29.4).6 Sodium,
potassium, and two chlorides are transported across the luminal border by a single symporter and
are then transported into the interstitium by multiple mechanisms. Calcium and magnesium are
also reabsorbed in this segment of the nephron. Electrolyte absorption is greater than water
absorption within this segment, creating hypotonic lumen fluid. Control within this segment is
predominantly by β–adrenergic receptor agonists, parathyroid hormone, and prostaglandin E2.6
As the fluid within the tubules moves up the ascending limb of the loop of Henle, the cells of the
macula densa sense the sodium and chloride content of the lumen fluid and regulate glomerular
filtrate through the tubuloglomerular feedback loop and by way of renin production.6 If the
electrolyte concentration of the lumen fluid is increased, then the glomerular filtration rate of that
nephron is reduced to decrease loss of these electrolytes in the urine. The actions of the synporter
and this feedback mechanism are important mechanisms since these are the targets of the loop
diuretics.
 Figure 4. Thick ascending limb of the loop of Henle demonstrating the processes involved in the
reabsorption of Na+, K+, chloride (Cl-), calcium (Ca2+), and magnesium (Mg+). The symporter (S)
located in the luminal membrane is responsible for the transport of Na+, K+, and 2 Cl- into the cell
for absorption. The circled crosses and the crosses located between the cells denote the location of
action of the loop diuretics. The loop diuretics reduce the activity of the symporter in the luminal
membrane and alter the absorption of Na+, K+, and Cl- in addition to blocking the absorption of
Ca2+ and Mg+.

Early distal tubule and collecting duct

Approximately 5 – 8% of filtered sodium is reabsorbed within the early distal tubule primarily
by symport with chloride (Figure 29.5). Potassium conductance channels are involved in the
transport of sodium into the interstitial space along the abluminal membrane.9 Two of the factors
that regulate the processes within this segment are the sympathetic nervous system and
bradykinin.6
 Figure 5. Na+ and Cl- are the primary electrolytes reabsorbed by way of a symporter (S) in the
luminal membrane in the distal convoluted tubule. The circled cross denotes the site of action of
the thiazide diuretics to decrease absorption of Na+ and Cl-. Thiazides also decrease the absorption
of K+ since Na+ is not available for exchange through the ATP-dependent transport pump in the
abluminal membrane.

Late distal tubule and collecting duct

Only about 2 – 3% of filtered sodium is reabsorbed in the late distal tubules and collecting ducts.
The mechanisms by which this sodium is reabsorbed involves several processes resulting in the
absorption of sodium in exchange for potassium and hydrogen ions (Figures 29.6 and 29.7).6
Together they represent a “fine-tuning” mechanism for maintaining normal sodium
concentrations in the body. There are two main cell types in this region of the nephron. The
principal cell is responsible for the reabsorption of sodium in exchange for potassium. The
intercalated cells secrete hydrogen ions by way of active transport. The processes of the late
distal tubule and collecting duct cells are further divided into those that are influenced by the
mineralocorticoid aldosterone, and those that are not. Aldosterone is the main mineralocorticoid
secreted by the adrenal cortex and promotes the retention of sodium and water and the excretion
of potassium. Stimulation of the renin-angiotensin-aldosterone system can result in almost
complete reabsorption of sodium; however, potassium is traded for sodium and results in
increased potassium loss in the urine in exchange for enhanced sodium retention.10
Figure 6. This figure denotes only the late distal tubule and collecting duct processes not
influenced by mineralocorticoids. The principal cell (top) is responsible for the reabsorption of
Na+ in exchange for K+. The circled cross denotes the action of the potassium sparing diuretics
which results in the decreased absorption of Na+ and retention of K+. The intercalated cells contain
carbonic anhydrase (CA) activity producing carbonic acid (H2CO3) with subsequent bicarbonate
(HCO3-) + H+ production and secretion of H+ by way of active transport (ATP-dependent pump).

Figure 7. This figure denotes only the late distal tubule and collecting duct processes influenced
by mineralocorticoids. Within the cytosol of the principle cell, aldosterone (ALDO) normally
binds to the mineralocorticoid receptor (MR), then translocates to the nucleus and upregulates the
 synthesis of the Na+ pump proteins. The circled cross denotes the action of one group of potassium
sparing diuretics (those such as spironolactone that resembles aldosterone) that blocks the binding
of ALDO with the MR.

WATER AND SALTS AS DIURETICS

The kidney plays a major role in the homeostatic mechanisms for water and electrolyte balance.
If water is administered in excess of needs, increased excretion will occur resulting in diluted
urine. Common salt (sodium chloride) can act as very fundamental diuretic. Inclusion of this salt
in the diet will increase water intake and will therefore result in increased urine output. Other
salts that can increase urine output include sodium bicarbonate and sodium sulfate, although
these are not used as frequently. Administration of water and salts does not have the advantage
of decreasing vascular or extravascular fluid volume; therefore, they are not useful in mobilizing
edema and other classes of diuretics must be utilized for that purpose.

OSMOTIC DIURETICS

Introduction

The principal mechanisms of osmotic diuretics are 1) to shift water from the extracellular space
to the plasma, or 2) to increase renal excretion of water by way of increasing tubular osmotic
pressures. These diuretics are freely filtered by the glomerulus since they are of small molecular
weight. Since a majority of sodium and water reabsorption takes place in the proximal tubules,
this is the site of primary action of the osmotic diuretics, although they may act throughout the
entire nephron.11 One of the most important functions of osmotic diuretics is to increase renal
tubular fluid movement to prevent or reverse tubular collapse. An example of an osmotic effect
is that caused by freely filtered sugars, and the diuresis produced by glucose in patients with
untreated diabetes mellitus. It should be noted that osmotic diuretics are not preferred agents for
the reduction of generalized edema. Glycerin and mannitol, two commonly used osmotic
diuretics, have the ability to cross into the extracellular space and carry the potential to worsen
generalized edema, especially in inflamed and compromised tissues. Glycerin and mannitol are
most beneficial in reducing ocular and cerebral edema, respectively. Also, since these tissues are
less likely to accumulate the administered drug, they are not prone to increase osmotic pressure
and actually promote edema. The ideal osmotic diuretic is one which is poorly bound to plasma
proteins and is therefore freely filtered, is poorly metabolized, and is not reabsorbed as it travels
down the tubule.

Specific agents

Glycerin (Osmoglyn®)

Glycerin (Figure 29.8), also known as glycerol, increases the osmotic pressure of plasma to
draw water from the extracellular compartment. This fluid shift can decrease cerebrospinal fluid
pressure, but the most substantial effect is a decrease in intraocular pressure.12 In the small
animal patient, glycerin is most commonly used to treat increased intraocular pressure associated
with acute glaucoma.13
 Mannitol

Figure 8. Structure of glycerin and mannitol, two osmotic diuretics.

Glycerin administered orally as a 50% solution is rapidly absorbed from the gastrointestinal tract
within 90 minutes. Depending on the dose, the effects on intraocular pressure typically appear
within 1 hour of oral administration and persist for approximately 8 hours. Glycerin undergoes
hepatic metabolism with only 10% excreted in the urine unchanged. The elimination half-life is
about 30 – 45 minutes in humans. Dosages for use of glycerin to decrease intraocular pressure
have been published for the small animal patient.14

Glycerin administration is contraindicated in patients with anuria or severe renal disease, severe
dehydration, congestive heart failure and pulmonary edema, and diabetes. The most common
adverse effect in the small animal patient is vomiting after oral administration. Reduction of the
dose administered often alleviates this adverse effect.

Mannitol (Mannitol Injection)

Mannitol (Figure 29.8), a 6-carbon sugar alcohol, is freely filtered through the glomerulus and is
not reabsorbed in the tubules. Mannitol acts as an osmotic diuretic by increasing the osmotic
pressure of the filtrate, preventing water from being reabsorbed in the tubules. Some electrolytes,
including sodium, are also excreted at a higher rate in concert with the increased excretion of
water. It has been suggested that mannitol may be nephro-protective by increasing renal blood
flow through vasodilation, by decreasing blood viscosity, and by increasing flow through the
nephrons preventing their collapse.15

Development of other diuretics has now relegated the use of mannitol to conditions other than
diuresis. The primary uses for mannitol are to increase renal excretion of toxins and to reduce
intracerebral and intraocular pressures.13, 16 Mannitol is highly effective in the treatment of
cerebral edema, although careful monitoring of trauma patients is necessary since plasma volume
depletion has the potential for serious detrimental effects.17 With regard to increasing renal
excretion of toxins, it has been reported that administration of isotonic saline provides more
effective elimination of toxins than does mannitol 18, 19 Intravenous administration provides
distribution to the extracellular compartment, though mannitol does not cross the blood-brain
barrier or distribute into the eye. Approximately 90% of mannitol is excreted unchanged in the
urine with an elimination half-life of 40 – 60 minutes in domestic species. Dosages for varied
uses in dogs, cats, horses, cattle, swine, sheep, and goats have been reported. Due to the rapid
elimination of mannitol, it is often administered as a continuous intravenous infusion.

Mannitol administration is contraindicated in patients with anuria or severe renal disease, severe
dehydration, congestive heart failure and pulmonary edema. Since it can increase the
extracellular fluid space by drawing water from cells, it can increase cardiac pre-load and after-
load. Thus, instead of reducing edema and cardiac work associated with heart failure, it could
increase cardiac work load. As normally used, electrolyte imbalance is the most common
adverse effect encountered with the use of osmotic diuretics. Monitoring electrolyte
concentrations is recommended.

METHYLXANTHINES

The common methylxanthines caffeine, theobromine, and theophyllin, have long been known for
their mild to moderate diuretic activity. It is thought that they increase renal blood flow thereby
increasing glomerular filtration rate (theophyllin > caffeine).20 The unwanted effects of their
administration, such as CNS stimulation, and cardiovascular and gastrointestinal alterations,
limit their use as diuretics in veterinary medicine.

CARBONIC ANHYDRASE INHIBITORS

Introduction

Carbonic anhydrase is a zinc-containing enzyme that catalyzes the interconversion of CO2 and
water with HCO3- and H+ and is found chiefly in red blood cells, secretory cells (i.e. found in the
aqueous humor of the eye), and especially the epithelial cells lining the renal tubules.8 The
kidneys reabsorb almost all of the filtered bicarbonate. Approximately 80% is reabsorbed in the
proximal tubules (principal site of action of the carbonic anhydrase inhibitors). The carbonic
anhydrase inhibitors are derivatives of the sulfonamide antimicrobials and the sulfamoyl group
(SO2NH2-) in their structure is required for activity. This group behaves like an acid, in the same
manner as a carboxyl moiety. The inhibition of the enzyme carbonic anhydrase within the
proximal tubule results in impaired sodium, potassium, and bicarbonate reabsorption (Figures
29.2 and 29.3). The inhibition of carbonic anhydrase also alters the pH status leading to
alkalization of the urine and metabolic acidosis. Administration of systemically (orally)
administered carbonic anhydrase inhibitors is associated with clinically apparent metabolic
acidosis evidenced as panting, diarrhea, vomiting, and anorexia.

Carbonic anhydrase also plays a role in the production of aqueous humor by the ciliary body
epithelium of the eye. For this purpose, they may be administered orally, systemically, or
topically. Topical use of carbonic anhydrase inhibitors in ophthalmic preparations, such as
dorzolamide, is very beneficial in the treatment of glaucoma and usually avoids the undesired
side effects of systemic use.21
Specific agents

Acetazolamide (Diamox®)

Acetazolamide (Figure 29.9) is a noncompetitive, reversible carbonic anhydrase inhibitor; which

reduces the production of hydrogen and bicarbonate ions within renal tubular cells. This
increases the excretion of sodium, potassium, and bicarbonate resulting in alkalization of urine as
well as an increased volume of urine excretion.

Figure 9. Structures of acetazolamide and dichlorphenamide, two carbonic anhydrase inhibitors.

The primary uses of acetazolamide in veterinary medicine include diuresis, treatment of

metabolic alkalosis, and the treatment of glaucoma (through decreased production of aqueous
humor). The inevitable metabolic acidosis that occurs with systemic acetazolamide
administration has decreased its use as a diuretic. In fact, the acidosis that results from the loss of
bicarbonate overcomes the reduction in sodium resorption, so that the diuresis produced is self-
limited. The principal use of this agent is for the treatment of glaucoma.17 Acetazolamide is
typically administered orally as tablets or capsules and acetazolamide sodium is the injectable
form. Following oral administration, acetazolamide is well absorbed with wide distribution and
maximal effects occur within 2 - 4 hours. Acetazolamide is also well absorbed when
administered orally to horses, has although the bioavailability is lower than for some other
species.22 The pKas are 7.4 and 9.1 and the pH of the injectable form is 9.2. Acetazolamide
crosses the placenta and is found in the milk of lactating animals. It is transported for its diuretic
activity into the proximal tubule via the organic acid secretory pathway.23-25 The duration of
action is approximately 4 – 6 hours and within 24 hours 90% is eliminated by renal tubular
secretion as the unchanged drug.

As with all carbonic anhydrase inhibitors, acetazolamide is contraindicated in animals with

hyponatremia, hypokalemia, acidosis, decreased pulmonary function (inability to ventilate for
proper carbon dioxide balance), and renal insufficiency. Electrolyte, blood gases, and
hematologic parameters should be monitored for detection of hyponatremia, hypokalemia, and
acidosis. Since the pH of the urine is increased (alkalinization), the excretion of other drugs may
be effected.

Dichlorphenamide (Daranide®)

Dichlorphenamide (Figure 29.9) is also a noncompetitive, reversible carbonic anhydrase

inhibitor. It has very similar actions, uses, contraindications, and monitoring considerations as
acetazolamide. Although the primary use of dichlorphenamide is the treatment of glaucoma, it is
also used as a diuretic and for the treatment of alkalosis.26 This drug is currently administered
orally in the form of tablets. The pKas of dichlorphenamide are 7.4 and 8.6 with similar timing of
maximal effects and duration of action as acetazolamide. Electrolyte and acid-base status should
be evaluated before use and should be monitored with repeated administration.

Dorzolamide (Trusopt®)

Dorzolamide is a topical ophthalmic preparation related to the orally administered carbonic

anhydrase inhibitor dichlorphenamide. Dorzolamide is used primarily for the treatment of
glaucoma in small animals, where it produces a significant reduction in intraocular pressure.21

THIAZIDES

Introduction

The first thiazide diuretic, chlorothiazide, was discovered in 1957. The thiazides are of moderate
potency compared to the loop diuretics since they result in excretion of 5 – 8 % of the filtered
sodium load compared with the 20 – 25% rate of excretion of loop diuretics.27 Like the carbonic
anhydrase inhibitors, they are also sulfonamide derivatives (Figure 29.10). All of the thiazides
contain a chlorine or trifluromethyl group at position 6 and a sulphamoyl group at position 7
(Figure 29.10).28 The thiazides are considered to bind to the luminal surface of the early distal
convoluted tubule acting through a thiazide-sensitive ion transporter to block the transport of
sodium and chloride (Figure 29.5).29, 30 The results of thiazide administration are principally the
increased excretion of sodium, chloride, potassium, magnesium, and phosphate. Some of these
agents also produce a degree of carbonic anhydrase inhibition, resulting in some loss of
bicarbonate. Potassium loss is attributed to an increase in sodium delivery to the sodium-
potassium exchange mechanism in the distal tubule. The over-excretion of these substances
produces hypokalemic, hypochloremic, metabolic alkalosis. The hypokalemia associated with
their use increases the propensity for cardiac arrhythmias associated with the use of quinidine
and glycoside inotropes. The thiazides have also been linked to glucose intolerance.31 Because of
the potential for these side effects to occur, they are often used in combination with the
potassium sparing diuretics. Thiazides are very effective for the treatment of hypertension in
humans. Initially, these agents decrease blood volume and blood pressure. Homeostatic
mechanisms (i.e. renin-angiotensin-aldosterone system and the sympathetic nervous system)
increase proximal tubule sodium reabsorption leading to the restoration of blood volume, but
long term use of thiazides retains antihypertensive effectiveness by reducing peripheral vascular
resistance.17, 32

Figure 10. Structures of the thiazide diuretics. Note the substitutions in the R-groups for each of
the thiazides listed.

Specific agents

Chlorothiazide (Diuril®)

Chlorothiazide (Figure 29.10) was one of the first highly effective and useful diuretics. As with
others in this class, it enhances the excretion of water by decreasing the movement of sodium
across the renal tubular cells of the cortical diluting segment of the nephron. This results
principally in the increased excretion of sodium, chloride, potassium, magnesium, and
phosphate. Following chlorothiazide administration, plasma renin and aldosterone concentrations
increase, resulting in enhanced hypokalemia and hyperglycemia that can be exaggerated in
diabetic patients.

The primary indications for chlorothiazide are generalized edema, hypertension, and, in cattle,
post-parturient udder edema.15, 33 Although only 10 – 20% of orally administered chlorothiazide
is absorbed, tablets, boluses, and oral suspensions are the most common preparations used. Some
preparations contain a potassium sparing diuretic to reduce potassium loss. An injectable form,
chlorothiazide sodium, is also available. The pKas are 6.7 and 9.5 and the pHs of the oral
suspension and injectable form are 3.2 and 9.2, respectively. In humans, the maximal effect
occurs about 4 hours after oral administration with a serum half-life of 1 – 2 hours and a duration
of action of 6 – 12 hours. The thiazides are found in the milk and hypersensitivity reactions have
been known to occur in humans; therefore, milk withdrawal times should be carefully followed.
Chlorothiazide is transported for its diuretic activity into the proximal tubule via the organic acid
secretory pathway.23-25

Since chlorothiazide is structurally similar to the sulfonamides and its use is therefore
contraindicated in patients hypersensitive to the sulfas. Also, thiazides should be used with
caution in patients with renal insufficiency, electrolyte imbalances, and diabetes mellitus.
Monitoring of electrolytes, especially potassium, chloride, and sodium, is warranted.

Hydrochlorothiazide (Hydrozide or HydroDiuril)

Hydrochlorothiazide (Figure 29.10) is another thiazide diuretic with very similar mechanisms
of action, uses, contraindications, and monitoring considerations as chlorothiazide.
Hydrochlorothiazide is used as a diuretic as a treatment of systemic hypertension and udder
edema and for treatment of nephrogenic diabetes insipidus.34, 35 The injectable form is sometimes
used as an initial treatment but the oral preparation is the one most commonly used. The pKas are
7.9 and 9.2. The absorption of the oral preparation is better than that of chlorothiazide and is
about 65 – 75%.36 The peak action is 4 – 6 hours, the serum half-life is 5 – 15 hours, and the
duration of action is 6 – 12 hours in humans. Hydrochlorothiazide is also transported for its
diuretic activity into the proximal tubule via the organic acid secretory pathway.23-25 It is poorly
metabolized and is excreted in the urine largely unchanged. Thiazides are also excreted in the
milk with a current withdrawal time of 72 hours listed for lactating dairy cattle. As with other
thiazide diuretics, monitoring of serum electrolytes, especially potassium, is an important
consideration.

POTASSIUM SPARING DIURETICS

Introduction

Potassium sparing diuretics are much less potent than the loop diuretics and the thiazides since
they affect the excretion of only 2 – 3% of the filtered sodium load.27 Under normal conditions
within the late distal tubules and the collecting ducts, sodium is exchanged with potassium and
hydrogen ions. The exchange of sodium for potassium and hydrogen can also be stimulated by
aldosterone. The fundamental action of the potassium sparing diuretics is to alter the exchange of
sodium for potassium and hydrogen ions even though the two groups of agents within this class
have differing operating mechanisms.17 These differences are based on the influence of
mineralocorticoids within the cellular processes. Resembling the mineralocorticoid aldosterone,
one group of potassium sparing diuretics (prototype= spironolactone) compete with the hormone
for its receptor within the distal nephron.11 Within the cytosol of the principle cell, aldosterone
normally binds to the mineralocorticoid receptor, then translocates to the nucleus and upregulates
the synthesis of the sodium pump proteins.37, 38 Spironolactone blocks this receptor and prevents
the subsequent events.17 The other group of potassium sparing diuretics act through mechanisms
independent of mineralocorticoid influence. This group (i.e. amiloride and triamterene) contains
a pyrazine nucleus and act by altering sodium reabsorption independent of aldosterone
concentrations. The end result of both of these groups of potassium sparing diuretics is the
increased urinary excretion of sodium and the increased retention of potassium and hydrogen
ions. Due to their weaker diuretic effects, and the retention of potassium, this class of diuretics is
often used in combination with other diuretics for prevention or correction of hypokalemia, or
for the treatment of hyperaldosteronism.31

The potassium sparing diuretics are only mildly natriuretic and are less likely to lead to volume
depletion. However, proton excretion is limited that may lead to metabolic acidosis and
hyperkalemia is a leading complication due to its potassium sparing activity.31

Potassium sparing diuretics act on cells of the distal tubule and collecting duct to prevent or
reduce the loss of potassium through exchange with sodium. There are two groups of agents, and
they act at different receptors. All are only mildly natriuretic because the mechanisms involved
are responsible for controlling only 1-3% of the filtered load. One group act to block the sodium
channel on the luminal side of the principal cell. The other gains access to the cell from the
basolateral side to block the binding of aldosterone to a mineralocorticoid receptor in the
cytosol.16

By the time that filtrate reaches the distal tubule more than 95% of the sodium has been
reabsorbed and conserved. This can be greatly reduced by the action of diuretics, such that the
sodium load presented to the sodium channels of the principle cells may now be increased
several fold. This is a rather porous channel, and the high extracellular concentrations of sodium
can increase transport through the channel. This is aided by the creation of an electrochemical
gradient across the cell that results from the active pumping of sodium out through the
basolateral membrane in exchange for potassium (Figure 29.6). The latter exits the cell through a
luminal channel to maintain the electrochemical balance within the cell. Hydrogen ion can also
be exchanged for sodium, causing an acidification of the urine. Amiloride and triamterene are
two commonly used diuretics that act in this manner. Their principle use is in reduction of
potassium loss caused by more potent diuretics. They also complement and enhance the diuretic
action of other agents.

The second group of potassium sparing diuretics are the aldosterone antagonists. There is only
one such agent in common use in the United States, and that is spironolactone. Activation of the
rennin-angiotensin system leads to the synthesis and excretion of aldosterone, which enters the
distal tubular cell through the basal membrane to bind to a cytosolic mineralocorticoid receptor.
This receptor is similar to other steroid receptors, and the complex enters the nucleus to bind to
specific sites on DNA that control the production of a number of so called aldosterone-induced
proteins. There are two basic sets-one that controls the synthesis of sodium channel receptors,
their translocation to the luminal membrane, and their activation, and another which increases
the synthesis, translocation, and activation of Na+-K+ATPase in the basal membrane (Figure
29.7). Aldosterone then acts to upregulate channels for the absorption of sodium at the luminal
membrane and its pumping out of the cell in exchange for potassium at the basolateral
membrane36,37. As sodium and chloride flux is increased, an electrochemical gradient is created
that drives potassium and hydrogen into the tubular lumen. This action is blocked when
spironolactone binds to the receptor to prevent the formation of the receptor-aldosterone
complex. In contrast to the sodium channel blockers discussed above, spironolactone will be
effective as a diuretic only when aldosterone levels are high.
Both of these types of agent have similar effects on sodium, potassium, and hydrogen ion
excretion. They are primarily used for their weaker diuretic effect, their ability to conserve
potassium, and their ability to counter the effect of aldosterone. The latter use can be of value in
the treatment of hyperaldosteronism.30

The potassium sparing agents are less likely to lead to volume depletion than more potent
diuretics. However, proton excretion is limited, and may result in a degree of metabolic acidosis.
In addition, hyperkalemia is a leading complication from their potassium sparing activity.30

Specific agents

Spironolactone (Aldactone®)

Spironolactone (Figure 29.11) is a competitive inhibitor of aldosterone in the distal renal

tubules, as discussed above. It is currently the drug of choice for ascites or in patients susceptible
to hypokalemia with use of other classes of diuretics. Spironolactone is administered orally and
is also available in combination with hydrochlorothiazide. When used alone, spironolactone is
90% absorbed and peak plasma levels are reached within 1 – 2 hours.36 It is rapidly metabolized
into several products, including the active form canrenone, which are capable of crossing the
placenta and are also found in milk. Spironolactone is the only diuretic that does not have to
reach the lumen of the renal tubules, either by passive or active processes, to cause an effect.23-25
Spironolactone and canrenone are highly protein bound (98%) and canrenone has a half-life of
about 20 hours.36 Approximately three days of use are required to attain adequate diuretic
mechanisms of action, and because of this slow onset, the dose should not be increased more
frequently than every 3 or 4 days.39

Figure 11. Structure of the potassium sparing diuretic spironolactone.

Spironolactone should be used with caution in patients with electrolyte imbalances, especially
hyperkalemia, and in patients with renal impairment which may lead to the development of
hyperkalemia. Electrolytes should be monitored and combination therapy with another diuretic,
other than another potassium sparing diuretic, should be considered.

Amiloride (Midamor® and Triamterene (Dyrenium®, Maxzide®))

Amiloride and triamterene (Figure 29.12) are potassium sparing diuretics whose diuretic
function is independent of aldosterone levels. Amiloride and triamterene are transported for their
diuretic activity into the proximal tubule via the organic base secretory pathway.23-25 These
agents are shorter acting, allowing for more frequent adjustment of dosing than is the case for
spironolactone.17 Of these two agents, triamterene has a shorter half-life and requires
administration multiple times per day. Triamterene also requires hepatic metabolism for diuretic
effect whereas amiloride does not. In patients with impaired liver function, amiloride is
preferable if spironolactone is not an option.17 The uses, contraindications, and monitoring
parameters are similar to those of spironolactone since they produce the same overall effects
within this segment of the nephron. Amiloride is often used in combination with
hydrochlorothiazide.

Figure 12. Structure of the potassium sparing diuretics amiloride and triamterene.

LOOP OF HENLE (HIGH-CEILING) DIURETICS

Introduction

The loop diuretics furosemide and ethacrynic acid were developed in the 1960s in Germany and
the United States, respectively. Not only did the development of these diuretics provide rapid-
acting and potent diuretics, but it also provided tools that led to a better understanding of
electrolyte transport within the nephron.28 The loop diuretics are the most potent diuretics and
this is due to the high excretion of sodium (20 – 25% of filtered sodium) associated with their
use.27

The loop diuretics have different structures, but have very similar mechanisms of action.
Furosemide contains an unsubstituted sulfonamido group, like the carbonic anhydrase inhibitors,
yet its main action is inhibition of the sodium-potassium-chloride symporter found within the
thick limb of the ascending loop of Henle (Figure 29.4). Ethacrynic acid is a phenoxyacetic acid
derivative that works via the same mechanism. . Although not fully understood, it is thought that
the loop diuretics alter the synporter by binding to the chloride site of the transport mechanism.40
Recall from earlier discussion that the synporter and the tubuloglomerular feedback mechanism
play a major role in regulation of lumen sodium and chloride concentrations as well as
glomerular filtration rate. Loop diuretics inhibit ion transport by the synporter, thereby increasing
lumen electrolyte concentrations and creating hypotonicity of the medullary interstitium,
paralyzing the feedback mechanism. This results in a high glomerular filtration rate in spite of
increased lumen electrolyte concentrations.17, 41, 42 If loop diuretics did not block the
tubuloglomerular feedback mechanism, as the electrolyte concentrations increased within the
ascending loop of Henle, the glomerular filtration rate would be decreased and the diuretic
activity of the drug would be minimal.6 The loop blockers are short-acting diuretics and require
frequent administration; therefore, they are often used for rapid reduction of edema, short-term
reduction of blood pressure, and some electrolyte abnormalities (i.e. hypercalcemia). Other
longer acting agents are typically selected for chronic conditions such as hypertension.27

Loop diuretics have the highest potential for producing hyponatremia, which can lead to
permanent neurological damage without careful monitoring.31 Loop diuretics have also been
associated with reversible and irreversible ototoxicity, especially in dogs and cats. It has been
suggested that reducing the infusion rate (slow bolus infusion or administration of dose as a
constant rate infusion) or oral administration of the agent may decrease the probability of
ototoxicity since the toxicity is directly related to the blood level of the drug.31 Ethacrynic acid is
most often associated with irreversible hearing loss and is typically used only when patients
demonstrate hypersensitivity to other loop diuretics.43 The ototoxicity of other agents, such as
aminoglycoside antibiotics, may be potentiated by the administration of loop diuretics.44

Specific agents

Furosemide (Lasix®, Salix®, Diuride®)

Furosemide (Figure 29.13) is classified as a loop diuretic and is one of the most commonly used
diuretics across veterinary species. Furosemide has effects in multiple areas of the renal tubules
and loop of Henle with the following as the major actions: 1) within the proximal tubule,
electrolyte transport is altered; 2) within the ascending section of the loop of Henle, electrolyte
absorption is decreased; 3) within the distal tubule, reabsorption of sodium and chloride are
decreased and excretion of potassium is increased; and 4) glomerular filtration rate is increased
by renal vasodilation and increased renal blood flow. The result is increased excretion of sodium,
chloride, water, potassium, calcium, magnesium, ammonium, bicarbonate, and hydrogen ions.
The use of furosemide in veterinary species is widespread including therapy for generalized
edema, pulmonary edema, congestive heart failure, dilated cardiomyopathy, acute renal failure
and uremia, ascites, hypercalcemia, hypertension, post-parturient udder edema in cattle, and
exercise induced pulmonary hemorrhage (EIPH) in horses.17, 45 Currently, spironolactone is the
drug of choice for the treatment of ascites, but if an animal is non-responsive to this agent,
furosemide is the next drug usually chosen, because of its potency. The mechanism for reduction
of EIPH in horses is hypothesized to be due to a generalized reduction in pulmonary arterial
pressure and pulmonary vascular resistance that has the potential to lead to capillary rupture
found with strenuous exercise in some performance horses. Some researchers, however, have
postulated that high doses of furosemide immediately proceeding exercise would be required to
have beneficial action on arterial pressure reduction. Rules governing the use of pharmacological
agents during many equine sporting events ban the use of furosemide in this manner. The
potential for decreased ability, due to furosemide administration, to rehydrate and replenish
electrolyte loss after strenuous exercise have been studied and should be considered with its
use.46 This issue is discussed further in Chapter 57.

Figure 13. Structure of the loop diuretics furosemide and ethacrynic acid.

Furosemide is available in tablet form, oral solutions, and as an injectable. The dose of
furosemide should be small initially, then adjusted upward in increments until an adequate effect
is seen or until the maximal dose is attained. In addition, alterations in sodium intake are
positively correlated with the dose requirement of furosemide.17 The pKa is 3.9 and the pH of the
injectable form is 8 – 9.3. Following oral administration in dogs, bioavailability is 77% with a
half-life of approximately 1 – 1.5 hours. The diuretic effects of furosemide are evident within 5
minutes of intravenous administration, with maximal effects seen around 30 minutes after
dosing. Furosemide is transported for its diuretic activity into the proximal tubule via the organic
acid secretory pathway.23-25 It is highly protein bound (95%), which may affect it’s filtration but
not it’s active tubular excretion into the proximal tubule.

Furosemide is often used in patients with congestive heart failure that are also treated with
cardiac glycosides. The electrolyte status of the patient should be carefully monitored because
low magnesium and potassium concentrations, partially due to furosemide use, increase cardiac
glycoside toxicity.47, 48 Although furosemide is used in patients with anuria, it should be used
with caution and discontinued with prolonged anuria. The hydration status of the patient should
be monitored, especially when used in performance animals. Due to its effects on electrolyte
excretion, the electrolyte status of the patient should be determined and should be monitored
during diuretic use. Furosemide has been associated with ototoxicity, especially in cats, and may
cause gastrointestinal disturbances. The ototoxicity of other agents, such as aminoglycoside
antibiotics, may be potentiated by the administration of loop diuretics.

Ethacrynic Acid (Edecrin®)

Ethacrynic acid (Figure 29.13) is another loop diuretic that has very similar mechanisms of
action, indications, contraindications, and monitoring parameters as furosemide. Although it is
structurally dissimilar to furosemide, its location of action and the results are similar. It is
available in both oral and injectable forms. The oral form has high bioavailability and has a
duration of effect of about 6 -8 hours. The injectable form, ethacrynate sodium, has a half-life of
approximately 1 hour and a duration of effect of 2 hours. Ethacrynic acid is transported for its
diuretic activity into the proximal tubule via the organic acid secretory pathway.23-25 It
undergoes hepatic metabolism and is also excreted renally. The contraindications and monitoring
parameters, especially monitoring of electrolytes, are the same as for furosemide. Ototoxicity
and gastrointestinal disturbances associated with loop diuretic use are considered to be more
common with ethacrynic acid use than with furosemide.

Tables 29.1, 29.2 and Figure 29.2 summarize the mechanisms, sites of action, potency, uses, side
effects, and overall effects on electrolytes for each class of diuretics.

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Heart J 96: 389-400.
40. Fanestil, D.D., Tran, J.M., Vaughn, D.D., Maciejewski, A.R., and Beaumont, K. (1990).
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Greenberg, A., Eds. pp 195-204, Elsevier, New York.
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44. Pickrell, J.A., Oehme, F.W., and Cash, W.C. (1993) Ototoxicity in dogs and cats. Semin
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SUGGESTED READINGS

1. Brater, D.C. (2000) Pharmacology of diuretics. Am J Med Sci 319: 38-50.

2. Greenberg, A. (2000) Diuretic complications. Am J Med Sci 319: 10-24.

3. Greger, R. (2000) Physiology of renal sodium transport. Am J Med Sci 319: 51-62.

4. Lant, A. (1985) Diuretics. Clinical pharmacology and therapeutic use (Part I). Drugs 29:
57-87.

5. Lant, A. (1985) Diuretics. Clinical pharmacology and therapeutic use (Part II). Drugs 29:
162-88.

6. Puschett, J.B. (1994) Pharmacological classification and renal actions of diuretics.

Cardiology 84 Suppl 2: 4-13.
 Table 1. Important characteristics of the classes of diuretics
Diuretic Mechanism Site of Action Potency Primary Uses Most Common Side Effects
Osmotic diuretics • Freely filtered • Primarily proximal • Moderately • Increase urine • Mostly associated with rapid
• Cause water to be retained within nephron although potent volume administration
proximal tubule and descending entire nephron • 3 – 10% of • Decrease intracranial • Vomiting
limb of loop of Henle involved filtered sodium pressure • Volume expansion too rapid
excreted • Decrease intraocular leading to pulmonary edema
pressure • Hypovolemia
Methylxanthine • Dilates afferent arteriole • Glomerulus • Mildly potent • Diuretic activity is • Tachycardia
diuretics • May constrict efferent arteriole considered
• Increase glomerular filtration secondary to other • Cardiac vasoconstriction
• Decreases sodium reabsorption primary uses • Gastrointestinal effects
Carbonic anhydrase • Inhibit bicarbonate reabsorption • Luminal membrane of • Mildly potent • Decrease intraocular • Altered renal excretion of other
inhibitor diuretics by inhibiting carbonic proximal tubule • 3 - 5% of filtered pressure pharmacologic agents
anhydrase sodium excreted • Treatment of
• Increase tubular pH metabolic alkalosis • Hyperchloremic metabolic
• Increase sodium in tubule to attract acidosis
water • Hypokalemia
Thiazide diuretics • Inhibit sodium / potassium / • Early distal tubule • Moderately • Hypertension • Hyponatremia (may be severe)
chloride cotransport potent • Udder edema in • Hypokalemic metabolic alkalosis
• Results in increased sodium • 5 - 8% of filtered cattle
chloride within the tubule sodium excreted • Edema due to heart • Hyperglycemia
failure
• Nephrogenic diabetes • Hypersensitivity reactions
insipidus
Potassium-sparing • Block sodium channels and • Distal tubule • Mildly potent • Treat or prevent • Hyperkalemia (may be severe)
diuretics – Sodium increases tubular sodium • 2 – 3% of filtered hypokalemia
channel blockers • Results in decreased potassium sodium excreted associated with
secretion other diuretic use
Potassium-sparing • Compete with aldosterone for • Distal tubule • Mildly potent • Treat or prevent • Hyperkalemia (may be severe)
diuretics – receptor • 2 – 3% of filtered hypokalemia
Aldosterone receptor • Decreases activity of sodium / sodium excreted associated with
antagonists potassium pump other diuretic use
• Results in increased sodium in the
tubule and decreased potassium
secretion
Loop diuretics • Inhibit sodium / chloride / • Ascending limb of loop • Very potent • Edema due to heart • Hypovolemia (may be severe)
potassium transport of Henle • 20 – 25% of failure • Hyponatremia
• Inhibit sodium chloride filtered sodium • Short-term • Hypokalemia
reabsorption excreted treatment of • Hypotension
• Increase calcium / magnesium hypertension • Metabolic acidosis
excretion • Exercise induced
pulmonary
hemorrhage?
• Hypercalcemia
• Acute renal failure
 Table 2. Excretion of electrolytes associated with diuretic use.
Diuretic Sodium Chloride Potassium Calcium Magnesium Bicarbonate
Carbonic anhydrase
inhibitor diuretics No change
Thiazide diuretics

Potassium-sparing
diuretics No change

Loop diuretics
No change