Download Diuretics

Introduction
Diuretics are chemicals that increase the rate of urine formation. By increasing the urine flow
rate, diuretic usage leads to increased excretion of electrolytes (especially sodium and chloride
ions) and water from the body without affecting protein, vitamin, glucose, or amino acid
reabsorption. These pharmacological properties have led to the use of diuretics in the treatment
of edematous conditions resulting from a variety of causes (e.g., congestive heart failure,
nephrotic syndrome, and chronic liver disease) and in the management of hyper tension.
Diuretic drugs also are useful as the sole agent or as adjunct therapy in the treatment of a wide
range of clinical conditions, including hypercalcemia, diabetes insipidus, acute mountain
sickness, primary hyperaldosteronism, and glaucoma.
Normal Physiology of urine formation
Normal Physiology of Urine Formation
Two important functions of the kidney are 1) to maintain a homeostatic balance of electrolytes
and water and 2) to excrete water -soluble end products of metabolism. The
kidney accomplishes these functions through the formation of urine by the nephrons. Each
kidney contains approximately 1 million nephrons and is capable of forming urine
independently. The nephrons are composed of a specialized capillary bed called the glomerulus
and a long tubule divided anatomically and functionally into the proximal tubule, loop of Henle,
and distal tubule. Each component of the nephron contributes to the normal functions of the
kidney in a unique manner; thus, all are targets for different classes of diuretic agents.
Urine formation begins with the filtration of blood at the glomerulus. Approximately 1,200 mL
of blood per minute flows through both kidneys and reaches the nephron by way of afferent
arterioles. Approximately 20% of the blood entering the glomerulus is filtered into Bowman's
capsule to form the glomerular filtrate. The glomerular filtrate is composed of blood
components with a molecular weight less than that of albumin (~69,000 daltons) and not bound
to plasma proteins. The glomerular fil tration rate (GFR) averages 125 mL/min in humans but
can vary widely even in normal functional states.
The glomerular filtrate leaves the Bowman's capsule and enters the proximal convoluted tubule
(S1, S2 segments, Fig 27.1), where the majority (50–60%) of filtered sodium is reabsorbed
osmotically. Sodium reabsorption is coupled electrogenetically with the reabsorption of glucose,
phosphate, and amino acids and nonelectrogenetically with bicarbonate reabsorption. Glucose
and amino acids are completely reabsorbed in this portion of the nephron, whereas phosphate
reabsorption is between 80 and 90% complete. The early proximal convoluted tubule also is the
primary site of bicarbonate reabsorption (80–90%) , a process that is mainly sodium dependent
and coupled to hydrogen ion secretion. The reabsorption of sodium and bicarbonate is
facilitated by the enzyme carbonic anhydrase, which is present in proximal tubular cells and
catalyzes the formation of carbonic acid from water and carbon dioxide. The carbonic acid
provides the hydrogen ion, which drives the reabsorption of sodium bicarbonate. Chloride ions
are reabsorbed passively in the proximal tubule, where they follow actively transported
sodium ions into tubular cells.
Clinical significance
Diuretics have a variety of uses. Thiazide diuretics may be used either alone or in combination
with other pharmacotherapy for the treatment of hyper tension. Loop diuretics can provide
immediate diuresis and are used for heart failure and in lieu of thiazides in patients with
compromised renal function. In addition to more traditional uses, certain potassium-sparing
diuretics provide added benefit to other pharmacotherapy in patients with primary
hyperaldosteronism, heart failure, or post–acute myocardial infarction. Carbonic anhydrase
inhibitors have limited use for diuresis; however, they may be used to reduce intraocular
pressure and treat acute mountain sickness.
The reabsorption of electrolytes and water also occurs isosmotically in the proximal straight
tubule or pars recta (S3 segment, Fig. 27.1) . By the end of the straight segment, between 65
and 70% of water and sodium, chloride, and calcium ions; 80 to 90% of bicarbonate and
phosphate; and essentially 100% of glucose, amino acids, vitamins, and protein have been
reabsorbed from the glomerular filtrate. The proximal tubule also is the site for active secretion
of weakly acidic and weakly basic organic compounds. Thus, many of the diuretics can enter
luminal fluid not only by filtration at the glomerulus but also by active secretion.
The descending limb of the loop of Henle is impermeable to ions, but water can freely move
from the luminal fluid into the surrounding medullary interstitium, where the
higher osmolality draws water into the interstitial space and concentrates luminal fluid. Luminal
fluid continues to concentrate as it descends to the deepest portion of the loop of Henle, where
the fluid becomes the most concentrated. The hyper tonic luminal fluid next enters the waterimpermeable, thick ascending limb of the loop of Henle.
In this segment of the nephron, approximately 20 to 25% of the filtered sodium and chloride
ions are reabsorbed via a cotransport system (Na+/K+/2Cl -) on the luminal membrane.
Reabsorption of sodium and chloride in the medullary portion of the thick ascending limb is
important for maintaining the medullary interstitial concentration gradient. Reabsorption of
sodium chloride in the cortical component of the thick ascending limb of the loop of Henle and
the early distal convoluted tubule contributes to urinary dilution, and as a result, these two
nephron sections sometimes are called the cortical diluting segment of the nephron.
Luminal fluid leaving the early distal tubule next passes through the late distal tubule and
cortical collecting tubule (collecting duct) , where sodium is reabsorbed in
exchange for hydrogen and potassium ions. This process is partially controlled by
mineralocorticoids (e.g., aldosterone) and accounts for the reabsorption of between 2
and 3% of filtered sodium ions. Although the reabsorption of sodium ions from these segments
of the nephron is not large, this sodium/potassium/hydrogen ion exchange
system determines the final acidity and potassium content of urine. Several factors, however,
can influence the activity of this exchange system, including the amount of
sodium ions delivered to these segments, the status of the acid-base balance in the body, and
the levels of circulating aldosterone.
Normal Regulation of Urine Formation
The body contains several control mechanisms that regulate the volume and contents of urine.
These systems are activated by changes in solute or water content of the body, by changes in
systemic or renal blood pressure, and by a variety of other stimuli. Activation of one or more of
these systems by diuretic drugs can modify the effectiveness of these drugs to produce their
therapeutic response and may require additional therapeutic measures to ensure a maximal
response.
The kidney has the ability to respond to changes in the GFR through the action of specialized
distal tubular epithelial cells called the macula densa. These cells are in close contact with the
glomerular apparatus of the same nephron and detect changes in the rate of urine flow and
luminal sodium chloride concentration. An increase in the urine flow rate at this site (as can
occur with the use of some diuretics) activates the macula densa cells to communicate with the
granular cells and vascular segments of the juxtaglomerular apparatus. Stimulation of the
juxtaglomerular apparatus causes renin to be released, which leads to the formation of
angiotensin II and subsequent renal vasoconstriction. Renal vasoconstriction leads to a decrease
in GFR and, possibly, a decrease in the effectiveness of the diuretic. Renin release also
can be stimulated by factors other than diuretics, including decreased renal per fusion pressure,
increased sympathetic tone, and decreased blood volume.
Another important regulatory mechanism for urine formation is antidiuretic hormone (ADH),
also known as vasopressin, which is released from the posterior pituitary in response to reduced
blood pressure and elevated plasma osmolality. In the kidney, ADH acts on the collecting tubule
to increase water permeability and reabsorption. As a result, the urine becomes more
concentrated, and water is conserved in the presence of ADH.
Disease States
The diuretic drugs are used primarily to treat two medically important conditions, edema and
hypertension. Both conditions are common, although some patients exhibit refractory disease
states that require additional modification of the drug regimen to include alternative diuretics or
addition of nondiuretic drugs.
Diuretic drugs may be administered acutely or chronically to treat edematous states. When
immediate action to reduce edema (e.g., acute pulmonary edema) is needed,
intravenous administration of a loop diuretic often is the approach of choice. Thiazide or loop
diuretics normally are administered orally to treat nonemergency edematous states. The
magnitude of the diuretic response is directly proportional to the amount of edema fluid that is
present. As the volume of edema decreases, so does the magnitude of the diuretic response
with each dose. If concern exists about diuretic-induced hypokalemia developing, then a
potassium supplement or potassium-sparing diuretic may be added to the drug regimen. The
development of hypokalemia is particularly important for patients with congestive heart failure
who also are taking cardiac glycosides, such as digitalis. Digitalis has a narrow therapeutic index,
and developing hypokalemia can potentiate digitalis- induced cardiac effects with potentially
fatal results.
Diuretic drugs (thiazide and loop diuretics) are administered orally to help control blood
pressure in the treatment of hyper tension. Diuretics often are the first drugs used
to treat hyper tension, and they also may be added to other drug therapies used to control
blood pressure with beneficial effects.
Structure Classification
The diuretics currently in use today are classified by their chemical class (thiazides) , mechanism
of action (carbonic anhydrase inhibitors and osmotics), site of action (loop diuretics), or effects
on urine contents (potassium-sparing diuretics) . These drugs vary widely in their efficacy ( i.e.,
their ability to increase the rate of urine formation) and their site of action within the nephron.
Efficacy often is measured as the ability of the diuretic to increase the excretion of sodium ions
filtered at the glomerulus (i.e., the filtered load of sodium) and should not be confused with
potency, which is the amount of the diuretic required to produce a specific diuretic response.
Efficacy is determined, in part, by the site of action of the diuretic. Drugs (e.g., carbonic
anhydrase inhibitors) that act primarily on the proximal convoluted tubule to induce diuresis are
weak diuretics because of the ability of the nephron to reabsorb a significant portion of the
luminal contents in latter portions of the nephron.
Likewise, drugs (potassium-sparing diuretics) that act at the more distal segments of the
nephron are weak diuretics, because most of the glomerular filtrate has already been
reabsorbed in the proximal tubule and ascending limb of the loop of Henle before reaching the
distal tubule.
Thus, the most efficacious diuretics discovered so far, the high-ceiling or loop diuretics, interfere
with sodium chloride reabsorption at the ascending limb of the loop of Henle, which is situated
after the proximal tubule but before the distal portions of the nephron and collecting tubule.
Classification of diuretics
1. Mercurials e.g. Mersalyl, Mercurophylline
2. Thiazide (Benzothiaziazines) e.g. Chlorthiazide, Hydrochlorthiazide, Benzthiazide
3. Sulphonamides e.g.Carbonic anhydrase inhibitors (Acetazolamide)
4. Water and Osmotic agents e.g. Water, Mannitol, Urea, Isosorbide
5. Sulphamyl Benzoic acid derivatives e.g. Furosimide, Clopamide
6. Endocrine antagonists e.g. Spironolactone, aldosterone, cortisone
7. Purines and related compounds e.g. caffeine, theophylline
8. Acidifying salts e.g. NH4Cl, NH4NO2
9. Phenoxyacetic acids e.g. Ethacrynic acid
Carbonic Anhydrase Inhibitors
Mechanism of Action
In 1937, it was proposed that the normal acidificat ion of urine was caused by secretion of
hydrogen ions by the tubular cells of the kidney. These ions were provided by
the action of the enzyme carbonic anhydrase, which catalyzes the formation of carbonic acid
(H2CO3) from carbon dioxide and water .
It also was observed that sulfanilamide rendered the urine of dogs alkaline because of the
inhibition of carbonic anhydrase. This inhibition of carbonic anhydrase resulted
in a lesser exchange of hydrogen ions for sodium ions in the kidney tubule. Sodium ions, along
with bicarbonate ions, and associated water molecules were then excreted, and a diuretic effect
was noted. The large doses required and the side effects of sulfanilamide prompted a search for
more effective carbonic anhydrase inhibitors as diuretic drugs.
It was soon learned that the sulfonamide portion of an active diuretic molecule could not be
monosubstituted or disubstituted. It was reasoned that a more acidic sulfonamide would bind
more tightly to the carbonic anhydrase enzyme. Synthesis of more acidic sulfonamides produced
compounds more than 2,500- fold more active than sulfanilamide. Acetazolamide was
introduced in 1953 as an orally effective diuretic drug. Before that time, the organic mercurials,
which commonly required intramuscular injection, were the principal diuretics available.
Carbonic anhydrase inhibitors induce diuresis by inhibiting the formation of carbonic acid within
proximal (proximal convoluted tubule; S2) and distal tubular cells to limit the number of
hydrogen ions available to promote sodium reabsorption. For a diuretic response to be
observed, more than 99% of the carbonic anhydrase must be inhibited. Although carbonic
anhydrase activity in the proximal tubule regulates the reabsorption of approximately 20 to 25%
of the filtered load of sodium, the carbonic anhydrase inhibitors are not highly efficacious
diuretics. An increased excretion of only 2 to 5% of the filtered load of sodium is seen with
carbonic anhydrase inhibitors because of increased reabsorption of sodium ions by the
ascending limb of the loop of Henle and more distal nephron segments.
Therapeutic Applications
With prolonged use of the carbonic anhydrase inhibitor diuretics, the urine becomes more
alkaline, and the blood becomes more acidic. When acidosis occurs, the carbonic anhydrase
inhibitors lose their effectiveness as diuretics. They remain ineffective until normal acid-base
balance in the body has been regained. For this reason, this class of compounds is limited in its
diuretic use. Today, they are most commonly used in the treatment of glaucoma, in which they
reduce the rate of aqueous humor formation and, subsequently, reduce the intraocular
pressure. These compounds also have found some limited use in the treatment of absence
seizures, to alkalinize the urine, to treat familial periodic paralysis, to reduce metabolic alkalosis,
and prophylactically, to reduce acute mountain sickness.
ACETAZOLAMIDE
Synthesis
Acetazolamide is 5-acetamido-1,3,4-thiadiazole-2-sulfonamide (9.7.5) The synthesis of
acetazolamide is based on the production of 2-amino-5-mercapto-1,3, 4-thiadiazole (9.7.2),
which is synthesized by the reaction of ammonium thiocyanate and hydrazine, forming
hydrazino-N,N_-bis-(thiourea) (9.7.1), which cycles into thiazole (9.7.2) upon reaction with
phosgene. Acylation of (9.7.2) with acetic anhydride gives 2-acetylamino-5-mercapto-1,3,4thiadiazol (9.7.3). The obtained product is chlorinated to give 2-acetylamino-5-mercapto-1,3,4thiadiazol-5-sulfonylchloride (9.7.4), which is transformed into acetazolamide upon reaction
with ammonia (9.7.5)
Structure activity relationship
•Sulfamoyl group is essential for the carbonic anhydrase inhibitory activity in vitro and diueresis in Vivo
•Substitution at sulfamoyl nitrogen leads to loss in activity
Benzothiadiazine or Thiazide Diuretics
Further study of the benzene disulfonamide derivatives was undertaken to find more efficacious
carbonic anhydrase inhibitors. These studies provided some compounds with a high degree of
diuretic activity. Chloro and amino substitution gave compounds with increased activity, but
these compounds were weak carbonic anhydrase inhibitors. When the amino group was
acylated, an unexpected ring closure took place. These compounds possessed a diuretic activity
independent of the carbonic anhydrase inhibitory activity, and a new series of diuretics called
the benzothiadiazines was discovered.
Mechanism of Action
The mechanism of action of the benzothiadiazine diuretics is primarily related to their ability to
inhibit the Na+/Cl - symporter located in the distal convoluted tubule. These diuretics are
actively secreted in the proximal tubule and are carried to the loop of Henle and to the distal
tubule. The major site of action of these compounds is in the distal tubule, where these drugs
compete for the chloride binding site of the Na+/Cl - symporter and inhibit the reabsorption of
sodium and chloride ions. For this reason, they are referred to as saluretics. They also inhibit the
reabsorption of potassium and bicarbonate ions, but to a lesser degree.
Structure–Activity Relationship
The thiazide diuretics are weakly acidic with a benzothiadiazine 1,1-dioxide
nucleus.
Chlorothiazide is the simplest member of this series, having a pKa of 6.7 and
9.5. The hydrogen atom at the 2-N is the most acidic because of the electron-withdrawing
effects of the neighboring sulfone group. The sulfonamide group that is
substituted at C-7 provides an additional point of acidity in the molecule but is less acidic than
the 2-N proton. These acidic protons make possible the formation of a
water -soluble sodium salt that can be used for intravenous administration of the diuretics.
An electron-withdrawing group is necessary at posit ion 6 for diuretic activity. Little diuretic
activity is seen with a hydrogen atom at position 6, whereas compounds with a
chloro or trifluoromethyl substitution are highly active. The trifluoromethyl -substituted
diuretics are more lipid-soluble and have a longer duration of action than their
chloro-substituted analogues. When electron-releasing groups, such as methyl or methoxyl , are
placed at position 6, the diuretic activity is markedly reduced.
Replacement or removal of the sulfonamide group at position 7 yields compounds with little or
no diuretic activity. Saturation of the double bond to give a 3,4-dihydro derivative produces a
diuretic that is 10- fold more active than the unsaturated derivative. Substitution with a
lipophilic group at position 3 gives a marked increase in the diuretic potency. Haloalkyl , aralkyl ,
or thioether substitution increases the lipid solubility of the molecule and yields compounds
with a longer duration of action. Alkyl substitution on the 2-N position also decreases the
polarity and increases the duration of diuretic action. Although these compounds do have
carbonic anhydrase activity, there is no correlation of this activity with their saluretic activity
(excretion of sodium and chloride ions) .
Adverse Effects
Thiazide diuretics may induce a number of adverse effects, including hypersensitivity reactions,
gastric irritation, nausea, and electrolyte imbalances, such as hyponatremia, hypokalemia,
hypomagnesemia, hypochloremic alkalosis, hypercalcemia, and hyperuricemia. Individuals who
exhibit hypersensitivity reactions to one thiazide are likely to have a hypersensitivity reaction to
other thiazides and sulfamoyl-containing diuretics (e.g., thiazide-like and some high-ceiling
diuretics). Potassium and magnesium supplements may be administered to treat hypokalemia or
hypomagnesemia, but their use is not always indicated.
Combination preparation of hydrochlorothiazide or a potassium-sparing diuretic are available
(e.g., Diazide and Moduretic). Long- term use of thiazide diuretics also may result in decreased
glucose tolerance and increased blood lipid (low-density lipoprotein cholesterol , total
cholesterol, and total triglyceride) content.
High-Ceiling or Loop Diuretics
Mechanism of Action
This class of drugs is characterized more by its pharmacological similarities than by its chemical
similarities. These diuretics produce a peak diuresis much greater than that observed with the
other commonly used diuretics, hence the name high-ceiling diuretics. Their main site of action
is believed to be on the thick ascending limb of the loop of Henle, where they inhibit the luminal
Na+/K+/2Cl - symporter . These diuretics are commonly referred to as loop diuretics. Additional
effects on the proximal and distal tubules also are possible. High-ceiling diuretics are
characterized by a quick onset and short duration of activity. Their diuretic effect appears in
approximately 30 minutes and lasts for approximately 6 hours.
Structure–Activi ty Relationships
Furosemide is an example of a high-ceiling diuretic and may be regarded as a derivative of
anthranilic acid or o-aminobenzoic acid. Research on 5-sulfamoylanthranilic acids at the Hoechst
Laboratories in Germany showed them to be effective diuretics. The most active of a series of
variously substituted derivatives was furosemide.
The chlorine and sulfonamide substitutions are features also seen in previously discussed
diuretics. Because the molecule possesses a free carboxyl group, furosemide is a stronger acid
than the thiazide diuretics (pKa = 3.9) . This drug is excreted primarily unchanged. A small
amount of metabolism, however, can take place on the furan ring, which is substituted on the
aromatic amino group
Therapeutic Applications
Furosemide has a saluretic effect 8- to 10-fold that of the thiazide diuretics; however, it has a
shorter duration of action (~6–8 hours). Furosemide causes a marked excretion of sodium,
chloride, potassium, calcium, magnesium, and bicarbonate ions, with as much as 25% of the
filtered load of sodium excreted in response to initial treatment. It is effective for the treatment
of edemas connected with cardiac, hepatic, and renal sites. Because it lowers the blood
pressure similar to the thiazide derivatives, one of its uses is in the treatment of hypertension.
Furosemide is orally effective but may be used parenterally when a more prompt diuretic effect
is desired, such as in the treatment of acute pulmonary edema. The dosage of furosemide, 20–
80 mg/day, may be given in divided doses because of the short duration of action of the drug
and carefully increased up to a maximum of 600 mg/day.
Adverse Effects
Clinical toxicity of furosemide and other loop diuretics primarily involves abnormalities of fluid
and electrolyte balance. As with the thiazide diuretics, hypokalemia is an important adverse
effect that can be prevented or treated with potassium supplements or coadministration of
potassium-sparing diuretics.
Synthesis
Furosemide, 4-chloro-N-furfuryl-5-sulfamoylanthranylic acid (21.4.11), is synthesized in a relatively simple manner from
2,4-dichlorobenzoic acid, which is converted into 5-aminosulfonyl-4,6-dichlorobenzoic acid (21.4.10) during subsequent
reaction with chlorosulfonic acid and ammonia. Reacting this with furfurylamine gives furosemide
Potassium-Sparing Diuretics (Mineralocorticoid Receptor Antagonists)—Antihormone Diuretics
Mechanism of Action
The adrenal cortex secretes a potent mineralocorticoid called aldosterone, which promotes salt
and water retention and potassium and hydrogen ion excretion.
Other mineralocorticoids have an effect on the electrolytic balance of the body, but aldosterone
is the most potent. Its ability to cause increased reabsorption of sodium and chloride ion and
increased potassium ion excretion is approximately 3,000- fold that of hydrocortisone. A
substance that antagonizes the effects of aldosterone could conceivably be a good diuretic drug.
Spironolactone is such an antagonist.
Metabolism
On oral administration, approximately 90% of the dose of spironolactone is absorbed and is
significantly metabolized during its first passage through the liver to its major active metabolite,
canrenone, which is interconvertible with its canrenoate anion. Canrenone is an antagonist to
aldosterone.
Specific Drugs
Spironolactone
Spironolactone is a competitive antagonist to the mineralocorticoids, such as aldosterone. The
mineralocorticoid receptor is an intracellular protein that can bind aldosterone. Spironolactone
binds to the receptor and competitively inhibits aldosterone binding to the receptor. The
inability of aldosterone to bind to its receptor prevents reabsorption of sodium and chloride
ions and the associated water. The most important site of these receptors is in the late distal
convoluted tubule and collecting system (collecting duct).
The canrenoate anion is not active per se but acts as an aldosterone antagonist because of its
conversion to canrenone, which exists in the lactone form. Canrenone has been suggested to be
the active form of spironolactone as an aldosterone antagonist. The formation of canrenone,
however, cannot fully account for the total activity of spironolactone. Both canrenone and
potassium canrenoate are used as diuretics in other countries, but they are not yet available in
the United States.
Therapeutic Applicat ions
Spironolactone is useful in treating edema resulting from primary hyperaldosteronism and
refractory edema associated with secondary hyperaldosteronism.
Spironolactone is considered to be the drug of choice for treating edema resulting from cirrhosis
of the liver . The dose of spironolactone is 100 mg/day given in single or divided doses. Another
use of spironolactone is coadministration with a potassium-depleting diuretic (e.g., a thiazide or
loop diuretic) to prevent or treat diuretic-induced hypokalemia. Spironolactone can be
administered in a fixed-dose combination with hydrochlorothiazide for this purpose, but optimal
individualization of the dose of each drug is recommended.
Adverse Effects
The primary concern with the use of spironolactone is the development of hyperkalemia, which
can be fatal. Spironolactone may cause hypersensitivity reactions, gastrointestinal disturbances,
peptic ulcer, gynecomastia, decreased libido, and impotence. It also has been implicated in
tumor production during chronic toxicity studies in rats, but human risk has not been
documented.