DIURETICS

Diuretics are the drugs that increase the urinary output by increasing the excretion of water and
sodium from the body. They are considered as the most important therapeutic agents in the
treatment of numerous diseases, especially those associated with volume overload such
as edema. The sodium takes water with it from your blood decreasing the amount of fluid
flowing through your blood vessels hence lowering blood pressure. Diuretics are used effectively
in the management of hypertension, and are typically prescribed because of their efficacy, low
cost, and low side effects profile. Diuretics are known for their ability to increase the formation
and excretion of urine. The increase in excretion allows for more water and sodium to be
removed, and ultimately affects the vascular system by leading to a decrease in fluid volume.
The decrease in fluid volume affects blood pressure directly, which is why they are effective in
reducing high blood pressure.

PRINCIPLES OF DIURETIC USE

Overview

The current therapeutic goal of diuretic use is increased excretion of sodium followed by water.
The degree of sodium loss in the urine (referred to as natriuresis or, in combination with
chloride, saluresis) varies with the mechanism of action of the drug. All except osmotic diuretics
inhibit specific enzymes, transport proteins, hormone receptors, or ion channels that function,
directly or indirectly, in renal tubular sodium reabsorption. Although saluresis is the primary
clinical goal, diuretics also alter elimination of other ions to varying degrees (e.g., K +, H+, Ca2+,
Mg2+, Cl−, HCO3−, phosphates) and may affect renal hemodynamics. Diuretic-induced depletion
of circulating blood volume may lead to adverse effects such as electrolyte imbalances and
dehydration if therapy is not well monitored. Older animals and those with cardiac or renal
disease are also at increased risk for adverse effects if diuretic-induced hypovolemia goes
untreated. Because these groups are also the primary target groups for diuretic use, rational use
of diuretic drugs is essential. Table 24.1 summarizes selected features of diuretic drugs most
commonly used in veterinary medicine.
 The effect of diuretics on water and electrolyte elimination

H20 Na+ K+ Cl− Mg2+ Ca2+ HCO3− H2PO4 H+

Carbonic anhydrase inhibitors + + + 0−+ +/− 0 ++ ++ −

+

Osmotic diuretics ++ ++ + + ++ + + + ?

Loop diuretics (Na+K+2Cl− symport) ++ ++ + ++ ++ ++ 0−+ 0−+ +

+

Thiazide diuretics (Na+/Cl− symport) + + + + + -(chronic) 0−+ 0−+ +

+

K+-sparing (Na+ channel) + + − + − − + 0 −

Aldosterone antagonists + + − + 0 ? + ? −

++, large increase in elimination; +, increase in elimination; 0, little to no change in elimination;

− decreased elimination; +/− variable effect; ? Effect unknown.

TYPES
There are three different groups of diuretics; these include thiazide diuretics, loop diuretics, and
potassium-sparing diuretics. Potassium diuretics are used in congestive heart failure and are
discussed 

Thiazide refers to both a class of sulfur-containing organic molecules and a class

of diuretics based on the chemical structure of benzothiadiazine. The thiazide drug class was
discovered and developed at Merck and Co. in the 1950s. The first approved drug of this
class, chlorothiazide, was marketed under the trade name Diuril beginning in 1958. In most
countries, thiazides are the least expensive antihypertensive drugs available.

Thiazide organic molecules are bi-cyclic structures that contain adjacent sulfur and nitrogen
atoms on one ring. Confusion sometimes occurs because thiazide-like diuretics such
as indapamide are referred to as thiazides despite not having the thiazide chemical
structure. When used this way, "thiazide" refers to a drug which acts at the thiazide receptor. The
thiazide receptor is a sodium-chloride transporter that pulls NaCl from the lumen in the distal
convoluted tubule. Thiazide diuretics inhibit this receptor, causing the body to release NaCl and
water into the lumen, thereby increasing the amount of urine produced each day. An example of
a molecule that is chemically a thiazide but not used as a diuretic is methylchloroisothiazolinone,
often found as an antimicrobial in cosmetics.
Thiazide diuretics act on the distal tubule of the nephron by inhibiting sodium reabsorption. With
this inhibition, more sodium stays within the nephron creating an osmotic force that allows for
water retention in the nephron, and ultimately water excretion. Thiazide diuretics are considered
the drug of choice for long term treatment of hypertension by many physicians.

LOCATION OF THIAZIDE DIURETIC EFFECTS.

Thiazide diuretics control hypertension in part by inhibiting reabsorption of sodium (Na+)

and chloride (Cl−) ions from the distal convoluted tubules in the kidneys by blocking the
thiazide-sensitive Na+-Cl− symporter

Examples of oral thiazide diuretics include:

Chlorothiazide (Diuril)

Chlorthalidone

Hydrochlorothiazide (Microzide)
Indapamide

Metolazone

LOOP DIURETICS: also called high ceiling diuretics are one of the most commonly used
classes of drug in clinical practice, and exert their action by acting on the thick ascending loop of
Henle, hence called “Loop diuretics”.

Mechanism of Action

movement in the thick ascending loop, the primary location of furosemide effects.
The thick ascending limb of Henle’s loop is the site of action of loop diuretics.

This Henle’s loop is characterized by being impermeable to water, although it powerfully and
actively transports the sodium, chloride and potassium ions via the apical membrane Na+-K+-
2Cl− cotransporter. This makes the water in early distal tubular fluid hypotonic (about 100
mOsm/kg H2O).

Sodium first binds to the cotransporter, promoting the binding of potassium and chloride ions,
followed by binding with a second chloride ion.

Loop diuretic is a powerful inhibitor of Na +-K+-2Cl− cotransporter in the luminal membrane of

the thick ascending limb of Henle’s loop, which acts by competing with the chloride site
(seemingly the second chloride binding site).

This inhibitory effect of loop diuretics results in a decreased rate of sodium, chloride, potassium
and other electrolytes reabsorption from these tubules into the medullary interstitium, thus
inhibiting the formation of hypertonic medullary fluid. This leads to high osmotic pressure inside
the renal tubules associated with a low osmolarity of the medullary interstitial fluid, which
results in:

An increased sodium excretion (natriuresis) and increased excretion of other electrolytes, such as
chloride and potassium. Magnesium and calcium reabsorption is also inhibited because their
absorption in the thick ascending limb depends mainly on the positive lumen voltage gradient,
which is lost with loop diuretics usage.

A decreased in the reabsorption of water from the collecting ducts and descending loop of Henle
into the hypotonic medullary fluid, due to the loss of the osmotic driving force of water into the
hypotonic medullary interstitium → resulting in an increase in the urine output (diuresis) as great
as 25 times of normal urine output.

Thus, loop diuretics aims to increase sodium excretion from the body with a subsequent increase
in urine output resulting in a decrease in the extracellular fluid (ECF) volume in the clinical
conditions that are associated with extracellular fluid (ECF) expansion, such as hypertension
and edema.

Adverse Effects

Acute Hypovolemia

Large doses of diuretics can lead to volume depletion, with the following subsequent
consequences:

Early symptoms: Postural dizziness, easily fatigability and thirst

More severe cases can lead to decreased organ perfusion such as:

Brain: Confusion and drowsiness

Kidney: Acute kidney insult (elevation of blood urea nitrogen “BUN” and creatinine)

Heart: Myocardial ischemia

Hypovolemic shock: It is associated with tachycardia, hypotension, cold extremities, cyanosis

and oliguria

Electrolyte Disturbances

Hyponatremia

(Usually develops within the first 1–2 weeks of therapy.)

In the presence of the antidiuretic hormone (ADH), the high osmotic pressure in the medullary
interstitium allows NaCl reabsorption through collecting ducts via the osmotic gradient between
the lumen and hypertonic interstitium, resulting in the formation of concentrated urine. Loop
diuretics inhibit this normal physiological process resulting in increased sodium and water
excretion.

Diuretic-induced volume depletion stimulates ADH secretion from the posterior pituitary, but its
effect on the kidneys is limited because of the impairment of lumen-medullary osmotic gradient.

Hyponatremia (serum sodium level of less than 135 mEq/L) occurs usually in the cases of high
water intake, especially if associated with impaired water excretion as in elderly patients, and
patients with renal diseases.

Important: Thiazides cause severe hyponatremia as compared to loop diuretics; this is due to

their action on different sites at the nephron.

Hypokalemia

Loop diuretics cause potassium depletion by the following mechanisms:

Increased distal delivery of sodium to the collecting duct results in an increased tubular exchange
of sodium for potassium with subsequently increased excretion of potassium resulting
in hypokalemia.

Diuretic-induced volume depletion stimulates mineralocorticoids (aldosterone) release from the

adrenal gland. Aldosterone increases the rate of potassium secretion by:

Stimulating the activity of Na/K ATPase in the basolateral membrane, resulting in increased
intracellular potassium concentration, which is then secreted into the tubular lumen.
Directly increase the permeability of the luminal membrane to potassium.

Hypokalemia can be avoided by:

Using potassium-sparing diuretics (e.g. spironolactone).

Dietary supplementation of potassium.

Hypocalcemia and hypomagnesemia

Most of the reabsorbed potassium from the ascending limb of the loop of Henle via Na-K-
2Cl cotransporters is recycled again back to the tubular lumen to drive further absorption of
NaCl. Also, the reabsorbed chloride ions move back into the tubular lumen via chloride
channels. The cationic potassium and chloride ions generate a net positive voltage gradient
which allows the passive absorption of cations: sodium, calcium, and magnesium, via
the paracellular pathway between cells.

Loop diuretics inhibit the Na reabsorption, and thus decrease the rate of potassium leakage into
the tubular lumen and the generation of this positive voltage gradient, and thus decreasing the
rate of absorption of calcium and magnesium and increasing the rate of their excretion.

Loop diuretics mnemonics: Loop all (loop diuretics loop most of the electrolytes)

Hyperuricemia

Loop diuretics can lead to hyperuricemia and gouty arthritis by two mechanisms:

Loop diuretics increase the uric acid level in the plasma by competing with the same organic
anion transporter (both uric acid and loop diuretics are secreted by the same transporter on
proximal tubule of nephron).

Both loop and thiazide diuretics decrease the uric acid excretion by increasing the reabsorption
process of uric acid.

Hyperuricemia: Plasma uric acid level greater than 6.8 mg/dL at normal body temperature.

Acid-Base Disturbance (Metabolic alkalosis)

Loop diuretics can lead to metabolic alkalosis (elevation of the serum bicarbonate) by different
mechanisms:

Diuretic-induced volume depletion results in the reduction of the extracellular fluid (ECF)
resulting in concentrating the bicarbonate (HCO3) in the plasma. This mild rise in HCO3 is
buffered by the release of H ions from cells and the uptake of HCO3 into the bone, making this
mechanism less effective.
Aldosterone released as a result of decreased extracellular fluid, increases the distal H ions
secretion resulting in increased acid excretion (acidification) in distal nephrons, thereby
increasing the new input of HCO3 by kidneys into the venous blood.

Decreased effective arterial blood volume (EABV) decreases the renal perfusion and

thus glomerular filtration rate (GFR) leading to the decreased filtration of HCO3 and its
excretion by the kidneys.

Hypersensitivity

Loop diuretics are sulfa drugs that might lead to hypersensitivity reaction, ranging from a rash to
acute interstitial nephritis (rare).

Ototoxicity

Loop diuretics (especially ethacrynic acid and furosemide) can affect hearing temporarily or
permanently based on the dose, duration, and route of administration. Ethacrynic acid is the most
ototoxic drug in loop diuretics. It causes hearing loss by:

Morphological alterations in the cochlea and loss of outer hair cells.

Disturbances in endolymph potassium concentration.

Decease in the electrical potentials of the cochlea.

Loop diuretics and other ototoxic drugs, such as aminoglycosides, should be used cautiously
together.

Osteoporosis: Increase the risk of osteoporosis and incidence of fractures due to the diuretics-
induced hypocalcemia

Potassium-sparing diuretics: refers to drugs that cause diuresis without

causing potassium loss in the urine and leading to hypokalemia. They are typically used as
an adjunct in management of hypertension, cirrhosis, and congestive heart failure.

Examples: Amiloride, Eplerenone (Inspra), Spironolactone (Aldactone, Carospir), Triamterene

(Dyrenium)

MECHANISM OF ACTION

Normally, sodium is reabsorbed in the collecting tubules of a renal nephron. This occurs via

epithelial sodium channels or ENaCs, located on the luminal surface of principal cells that line
the collecting tubules. Positively-charged Na+ entering the cells during reabsorption leads to an
electronegative luminal environment causing the secretion of potassium (K+) into the lumen/
urine in exchange. Sodium reabsorption also causes water retention. When the kidneys detect
low blood pressure, the renin–angiotensin–aldosterone system (RAAS) is activated and
eventually, aldosterone is secreted. Aldosterone binds to aldosterone receptors
(mineralocorticoid receptors) increasing sodium reabsorption in an effort to increase blood
pressure and improve fluid status in the body. When excessive sodium reabsorption occurs, there
is an increasing loss of K+ in the urine and can lead to clinically significant decreases,
termed hypokalemia. Increased sodium reabsorption also increases water retention.

Potassium-sparing diuretics act to prevent sodium reabsorption in the collecting tubule by either
binding ENaCs (amiloride, triamterene) or by inhibiting aldosterone receptors (spironolactone,
eplerenone). This prevents excessive excretion of K+ in urine and decreased retention of water,
preventing hypokalemia.

Because these diuretics are weakly natriuretic, they do not cause clinically significant blood
pressure changes and thus, are not used as primary therapy for hypertension.  They can be used in
combination with other anti-hypertensives or drugs that cause hypokalemia to help maintain
a normal range for potassium. For example, they are often used as an adjunct to loop
diuretics (usually furosemide) to treat fluid retention in congestive heart
failure and ascites in cirrhosis.

ADVERSE EFFECTS

On their own this group of drugs may raise potassium levels beyond the normal range,
termed hyperkalemia, which risks potentially fatal arrhythmias. Triamterene, specifically, is a
potential nephrotoxin and up to half of the patients on it can have crystalluria or urinary casts.
Spironolactone can cause gynecomastia, menstrual abnormalities, impotence, and decreased
libido by binding non-selective estrogen and progesterone receptors.

Inhibitors of Carbonic Anhydrase

This class of drugs was discovered as a result of the observation that sulfanilamide
chemotherapeutic agents were capable of causing metabolic acidosis by inhibition of carbonic
anhydrase (CA). Screening of sulfanilamides resulted in identification of compounds whose
predominant mechanism of action was CA inhibition. These drugs have been used sparingly in
veterinary medicine as diuretics and are more commonly used for ophthalmic purposes as topical
formulations. The prototype drug in this class, acetazolamide (Diamox®, Dazamide®), is
available in tablets (125 and 250 mg), extended-release capsules (500 mg), and injectable
(500 mg per vial). Other CA inhibitors include preparations for oral use, dichlorphenamide
(Daranide®) and methazolamide (Neptazane®), and a topical drug, dorzolamide (Trusopt®), for
ophthalmic use.

Mechanisms and Sites of Action

Renal Mechanisms

Drugs in this class are active in the CA-rich segments of the nephron, in particular the proximal
tubule. Noncompetitive, reversible inhibition of CA located in the luminal and basolateral
membranes (type IV CA) as well as in the cytoplasm (type II CA) results in decreased formation
of carbonic acid from CO2 and H2O,

Reduction in the amount of carbonic acid yields fewer H+ within proximal tubular cells. Because
H+ is normally exchanged for Na+ from the tubular lumen by the Na+/H+ antiporter (also referred
to as a Na+/H+ exchanger or NHE), less Na+ is reabsorbed and more is available to combine with
urinary HCO3−. The NHE maintains a low proton concentration in the cell so that H 2CO3− ionizes
spontaneously to form H+ and HCO3−. This, in turn, creates an electrochemical gradient for
HCO3− across the basolateral membrane that drives movement of HCO 3− into the interstitial
space. Diuresis is established when water is excreted with sodium bicarbonate that accumulates
due lack of CA activity. As sodium bicarbonate is trapped in the urine and eliminated, less
HCO3− is returned to plasma, and a systemic acidosis eventually develops. As a result of the
systemic acidosis, H+ becomes available, Na+ reabsorption is reestablished, and diuresis
decreases. Continual use of CA inhibitors is therefore self-limiting in terms of diuretic action.
Diuresis induced by CA inhibitors is mild due to incomplete inhibition of CA, redundancy of
Na+ transporting systems in the proximal tubule, and rescue of Na+ by reabsorption later in the
distal tubule. Because intracellular K+ can, to some extent, substitute for H + in the
Na+ reabsorption step, CA inhibitors cause enhanced K+ excretion. As more Na+ is presented to
the distal tubule, the potential for K + wasting increases. CA inhibitors also decrease secretion of
titratable acids and ammonia in the collecting duct. For this reason, and due to the increased
excretion of sodium bicarbonate, urine pH increases despite the decreasing systemic pH
associated with CA inhibitor induced acidosis. This class of drugs has little, if any, effect on
excretion of Ca2+ and Mg2+ but does enhance phosphate elimination.

Osmotic Diuretics

Osmotic diuretics contain simple solutes of low molecular weight that are typically freely filtered
by the glomerulus, undergo limited tubular reabsorption, and are pharmacologically inert. They
increase serum and tubular fluid osmolarity resulting in fluid shifts. The most common osmotic
diuretic is mannitol, a six-carbon nonmetabolized polyalcohol with a molecular weight of 182.
Other agents include glycerin, isosorbide, urea, and hypertonic saline solutions.

Mechanisms and Sites of Action

Hyperosmolar solutions exert part of their effects by establishing an osmotic gradient between
plasma and extravascular fluid compartments resulting in fluid movement into the plasma. Acute
effects of this gradient include decreases in hematocrit, blood viscosity, plasma sodium, plasma
pH, and, to some degree, the volume of solid organs. Hence, parenchymal dehydration and acute
hemodilution are theoretically related as long as the osmotically active particles are effectively
separated by a relatively solute-impermeable barrier.

Renal Mechanisms

Initially, osmotic diuretics were thought to act primarily at the level of the proximal tubule by
limiting the movement of water from the lumen into the interstitial space. Water retained in the
tubular lumen diluted concentrations of sodium and other ions, reduced ion reabsorption, and
promoted diuresis. It is now held that osmotic diuretics, in particular mannitol, have effects
throughout the length of the tubule, with the most prominent action occurring in the loop of
Henle. Sodium reabsorption is markedly reduced in the descending and thin limbs of the loop of
Henle, Sodium load to the thick ascending limb of the loop of Henle and to the distal tubule is
consequently increased, but the nephron fails to recapture the increased loads of salt and water.
As demonstrated in the dog, sodium reabsorption is also thought to be directly inhibited in
medullary collecting ducts.

Other reported renal effects of mannitol include increases in cortical and medullary blood flow
due to a decrease in renal vascular resistance, impairment of urinary concentration, reduction in
medullary tonicity (also known as medullary washout), an increase in GFR during renal
hypoperfusion (may vary according to species), and an increase in urinary excretion of other
electrolytes (e.g., K+, Ca2+, Mg2+, phosphate, bicarbonate) \Mannitol may also prompt the release
of atrial natriuretic factor and vasodilatory prostaglandins and inhibition of renin release.