Diuretics

Dr. Majdi Bkhaitan

Department of Pharmaceutical Chemistry

www.medchem1432.pbworks.com

www.uqu.edu.sa/mmbakhaitan

Clinical Significance

It is important for the clinician to understand the medicinal chemistry of the diuretics to appropriately use

them in individual patients. This diverse group of medications is classified in many ways: mechanism of

action, site of action, chemical class, and effect on urine contents. Knowledge of structureactivity

relationships helps to predict indications, possible off- label uses, magnitude of diuresis, potency, and side

effect profile.

Consequently, 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 postacute

myocardial infarction. Carbonic anhydrase inhibitors have limited use for diuresis; however, they may be

used to reduce intraocular pressure and treat acute mountain sickness.

A thorough understanding of the medicinal chemistry, mechanisms of action, and pharmacokinetics helps

the clinician to use available diuretics appropriately. As new medications are developed, the clinician will

rely on these basic concepts to continue tailoring therapy to the individual patient with the goals to

maximize outcomes, improve quality of life, and minimize adverse events.

Kimberly Birtcher Pharm.D.

Clinical Assistant Professor, Department of Clinical Sciences and Administration,

University of Houston College of Pharmacy

Diuretics Primary target of diuretics is the kidney, where these compounds interfere with the

re-absorption of sodium and other ions from the Lumina of nephrons.

Definition

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.

Functions of the kidney

To maintain a homeostatic balance of electrolytes and water.

To excrete water-soluble end products of metabolism.

Uses

Treatment of different edematous conditions, resulting from a variety of

causes (e.g. congestive heart failure, nephrotic syndrome, and chronic

liver disease).

Management of hypertension.

Adjunctive therapy in the treatment of a wide range of clinical conditions,

including hypercalcemia, acute mountain sickness, primary

hyperaldosterism, glaucoma and mountain sickness.

Physiology

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 filtration 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 where the majority (5060%) of filtered sodium is reabsorbed

osmotically. Sodium reabsorption is coupled electrogenetically with the

reabsorption of glucose, phosphate, and amino acids and non-electrogenetically

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 (8090%) , 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.

There are four Anatomical sites for diuretic action in the nephron: Site 1: proximal convoluted tubule.

Site 2: thick ascending Henles loop (TAL)

Site 3: distal tubule

Site 4: connecting tubule and collecting duct.

Site 1 diuretics Carbonic anhydrase inhibitors CA inhibitors:

These are infrequently used as diuretics, because of their low efficacy and

the early development of tolerance. They played, however, an important

role in the development of other major classes of diuretics that are

currently largely used.

There are two groups of CA inhibitors:

Simple heterocyclic sulfonamides

Metadisulfamoylbenzene derivatives.

SAR

In case of the simple heterocyclic compounds:

The unsubstituted sulfonamide is essential for the diuretic activity.

This sulfonamide group has to be attached directly to an aromatic group.

The derivative with the highest Pc partition coefficient and the lowest

ionization pKa has the greatest CA inhibitory and diuretic activities.

In case of metadisulfamoylbenzene derivatives series:

The parent 1,3 metadisulfamoylbenzene lacked diuretic activity.

Key substitutions in 4 and 5 positions lead to compounds with diuretic

activity.

Site and Mechanism of action

CA is located both intracellularly and in the luminal brush border membrane of

proximal convoluted tubule cells; these two sites are targets of CA inhibitors.

During the first 4-7 days of treatment, we observe an excretion in sodium and

bicarbonate. We observe also an increase in potassium excretion, because the

proximal tubule actions of CA inhibitors present a greater percentage of the

Cl

S

O

O

H2N

Cl

S

O

O

NH2

Dichlorphenamide Chloraminophenamide

NH2Cl

S

O

O

H2N S

O

O

NH2

NN

S N H C

O

C H 3S

O

O

H 2 N

A c e t o z o l a m i d e

NN

S N C

O

C H 3S

O

O

H 2 N

C H 3

M e t h a z o l a m i d e

filtered load of sodium at site 4, this with other factors increases the exchange of

the luminal fluid sodium for intracellular potassium at site 4.

T

Therefor CA inhibitors are considered:

Natriuretic(increse the execretion of Sodium)

Bicarbonaturetic (increse the execretion of bicarbonate)

Kaluretic (increse the execretion of Potassium)

Toward the end of the first week of continuous therapy with CA inhibitors,

resistance to its diuretic effect develops. This is due primarily to two factors. First,

there is a marked reduction in the filtered load of Bicarbonate because CA

inhibitors produce both a reduction in the plasma concentration of Bicarbonate

and a 20% reduction in the GFR (glomerular filtration rate).

When there is less bicarbonate present in the luminal fluid, there is less

bicarbonate reabsorption to inhibit.

Second, the metabolic acidosis created by these diuretics provides a sufficient

amount of non-CA generated intracellular hydrogen ions to exchange for the

luminal fluid sodium. Sodium reabsorption at site1 progressively returns to

normal and the diuresis disappears.

Uses:

Primarily in the treatment of glaucoma, by inhibiting CA in the eye,

reducing the formation of aqueous humor in the eye.

In the prophylaxis of mountain sickness, Adjuvant in the treatment of

epilepsy, to create alkaline urine when it is needed.

Adverse effects:

Metabolic acidosis, Hypokalemia, Typical sulfonamide-associated

hypersensitivity reactions, such as urticaria, drug fever, blood dyscrasias,

and interstitial nephritis.

Products

Simple heterocyclic sulfonamides: Acetozolamide ,Methazolamide

Metadisulfamoylbenzene derivatives: Dichlorphenamide: Given orally

Chloraminophenamide: Doesnt possess oral

bioavailability. It is a precursor for site 3

diuretics

Site 3 diuretics: Thiazide and Thiazide-like derivatives

Chloraminophenamide became a logical key intermediate in the development of a

new class of Diuretics.

In fact, when

Chloraminophenami

de was treated with

an acylating reagent,

cyclization occured,

with the result of

formation 1,2,4-

thiadiazine-1,1-

dioxide thiazide

derivatives.

On the other hand,

when

Chloraminophenamide is treated with aldehyde or ketone, in place of the acylating

reagent, this produces the corresponding hydrothiazide derivatives.

SN H

N R

O O

X

S

O

O

N H 2

SN H

N R

O O

X

S

O

O

N H 2

H

H

T h i a z i d e

H y d r o t h i a z i d e

C h l o r a m i n o p h e n a m i d e

N H 2C l

S

O

O

H 2 N S

O

O

N H 2

RC

OC l

RC

OR

These represent the first oral active saluretic agents (increase the excretion of NaCl).

Site and Mechanism of action

These agents block the reabsorption of sodium (and thereby the reabsorption of

chloride) in the distal convoluted tubules by inhibiting the luminal membrane

bound Na+/Cl- cotransport system.

Thus, all diuretics in this class are responsible for the urinary loss of about (5-

8%) of the filtered load of sodium. Although they differ in their potencies, they

are equally efficacious.

As a result of their action, these diuretics deliver more sodium to site 4, resulting

in an increase exchange between Na and K, producing also K elimination.

On the other hand this family possesses a residual CA inhibition producing a very

mild elimination of HCO3-.

Site 3 diuretics are considered

Natriuretic chloruretic, saluretic kaliuretic and extremely weak

bicarbonaturetic agents.

SAR

Position 2 can tolerate the presence of a small alkyl group (such as a CH3 or

better an H)

Position 3 is an extremely important site of

molecular modification. In fact, substituents at

position 3 play an important role in determining

the potency, duration of action, and other

pharmacokinetic properties of the derivative.

Loss of double bond between C3-C4 increases the

potency approximately of 3-10 folds this means

that in general, hydrothiazide derivatives are more

potent than thiazide derivatives.

Direct substitution for the 4,5, and 8 position results in an activity decrease.

Substitution at position 6 with a deactivating group such as Cl, Br, CF3,

CHCl3, i.e. electron withdrawing groups is essential for the activity.

The unsubstituted sulfonamide group in position 7 is a prerequisite for the

activity.

SN H

N

O O

H

1

2

3

4

5

6

7

8

Substitution of the sulfone group in position 1 with another similar electrophilic

group (carboxyl, carbamoyl) can produce an activity increase.

Products

Thiazide derivatives

Chlorthiazide ( X= Cl, R=H)

Benthizide (X= Cl, R= CH2-CH2-Ph)

Hydrothiazide derivatives Hydrochlorthiazide ( X= Cl, R=H)

Hydroflumethiazide ( X= CF3, R=H)

Trichlomethiazide ( X= Cl, R=CHCl2)

Thiazide like derivatives

Meta disulfamoyl benzens

Mefruside

Salicylanilide

xipamide

Benzhydrazides

Indapamide

Phthalimidines

Chlorthalidone

Others

Metolazone,etc.

These diuretics were developed as an outgrowth of the thiazide research that involved molecular

modification of aromatic sulfamoyl-containing compounds.

SNH

N R

O O

X

S

O

O

NH2

SNH

N R

O O

X

S

O

O

NH2

H

H

Uses

Treatment of edema associated with mild to moderate congestive heart

failure, hepatic cirrhosis, and nephrotic syndrom. This after treating the

underlying cause of the disease.

In the treatment of hypertension, either alone or in combination with other

drugs depending on the severity of the condition.

An advantage in their use as antihypertensive agents is that their diuretic

effect is weakened after one week of use but their antihypertensive effect

remains.

Treatment of type II renal tubular acidosis.

Adverse effects

Typical sulfonamide-associated hypersensitivity reactions, such as

urticaria, drug fever, blood dyscrasias, and interstitial nephritis. This is

usually a crossed hypersensitivity, even with other agents of other sites

diuretics, containing sulfonamide groups

Hypokalemia.

Acute reduction in GFR, and Hyperglycemia.

Site 2 Diuretic High ceiling loop diuretics

The diuretics that belong to this class are of diverse chemical structure. And these

are:

5-sulfamoyl-2-aminobenzoic acid derivatives anthranilic acid

derivatives. E.g. Furosemide, Azosemide.

5-sulfamoyl-3-aminobenzoic acid derivatives metanilic acid

derivatives. E.g. Bumetanide, Piretanide.

Phenoxyacetic acid derivatives. E.g. ethacrynic acid.

4-amino-3-pyridine sulfonylurea. E.g. Torsemide.

Organomercurials not in use because not available orally and for other

unfavorable conditions.

Site and mechanism of action

These diuretics have a tremendous efficacy because they inhibit the Na/K/2Cl co-

transport system located on the luminal membrane of cells of the thick ascending

limb of Henles loop. Importantly, the carboxylate moieties of Furosemide and

Bumetanide are thought to be responsible for their competing with Cl- for the Cl-

binding site on the Na/K/2Cl co-transport system.

Because site 2 is such a high capacity site for Na reabsorption, up to (20-25%) of

the filtered load of Na that normally is absorbed in this nephron segment may be

excreted in the urine. On the other hand this inhibition destroys the hypertonicity

of the medullar interstitium preventing the reabsorption of water at the descending

limb of Henles loop.

Other factors and mechanisms participate also to make of this class the most

efficacious of all diuretics.

All diuretics acting on site 2 are

equally efficacious (20-25%), and are

more efficacious than any other

diuretic acting on other sites. Site 2

diuretics are referred to according to

the site of action or efficacy as loop

or High ceiling diuretics.

The high ceiling diuretics enhance

the urinary loss of K+ and H+,

because they block the reabsorption

of K+ at site 2, and they deliver

more of the filtered load of sodium

at a faster rate to site 4. This leads to an enhanced exchange of the luminal fluid

sodium ions for the potassium ions and the hydrogen atoms.

When the loop diuretics are used in submaximal doses for the treatment of

hypertension, they produce diuresis comparable of thiazide diuretics with little

effect upon potassium elimination, on the other hand their use in their maximum

potency they produce serious hypokalemia.

Uses

Treatment of edema that may accompany congestive heart failure,

cirrhosis of the liver and nephrotic syndrome.

In particular high ceiling diuretics are agents of choice in the treatment of

pulmonary edema. No other group of diuretics is more effective than the

loop diuretics in this situation.

Treatment of symptomatic hypercalcemia.

In the treatment of hypertension, even though thiazides are more advised

because of their longer duration of action and their less toxicity.

Adverse effects

Hypokalemia. Caution should be taken in case of combined treatment with

cardiac glycosides, because hypokalemia intensifies the toxicity of the

cardiac glycosides.

Reduction in GFR, observed only in long term therapies.

Typical sulfonamide-associated hypersensitivity reactions, such as

urticaria, drug fever, blood dyscrasias, and interstitial nephritis. This is

usually a crossed hypersensitivity, even with other agents of other sites

diuretics, containing sulfonamide groups.

Ototoxicity, usually transient.

SAR

Regarding the anthranilic acid and metanilic acid derivatives

The substituent at C1 must be acidic, the best possible acidic group is the

carboxyl group (COOH), other acidic functions (such as the tetrazole

ring), however, maintain the diuretic activity.

A sulfamoyl group in position 5 is a prerequisite for the high ceiling

diuretic activity.

The electron withdrawing group at C4 can be Cl, CF3, or yet better a

phenoxy, alkoxy, anilino, benzyl, or benzoyl group.

Only furfyryl, benzyl, thienylmethyl groups are allowed in position 2 in

the anthranilic acid derivative, however we can observe decreased activity

going from the furfyl and on.

In case of metanilic acid derivatives a wide range of substituents are

tolerated.

Regarding the anthranilic acid and metanilic acid derivatives

The substituent at C1 must be acidic, the best possible acidic group is the

carboxyl group (COOH), other acidic functions (such as the tetrazole

ring), however, maintain the diuretic activity.

A sulfamoyl group in position 5 is a prerequisite for the high ceiling

diuretic activity.

The electron

withdrawing group at

C4 can be Cl, CF3, or

yet better a phenoxy,

alkoxy, anilino,

benzyl, or benzoyl

group.

Only furfyryl, benzyl,

thienylmethyl groups

are allowed in

position 2 in the

anthranilic acid

derivative, however we can observe decreased activity going from the

furfyl and on. In case of metanilic acid derivatives a wide range of

substituents are tolerated.

Site 4 diuretics Potassium sparing or Antikaluretic Diuretics.

A negative feature of all previous diuretic classes is that they induce an

increase in the renal excretion rate of potassium. Potassium sparing

diuretics increase sodium and chloride secretion without causing an

increase in potassium excretion.

Potassium sparing diuretics are derived from different chemical roots, they

have however, similar anatomic site of action in the nephron, efficacy, and

electrolyte excretion pattern. They even share certain adverse effects.

The Potassium sparing diuretics include

Spirolactones Spironolactone Canrenone

The 2,4,7-triamino-6- arylpteridine Ttrimeteren

The pyrazinoylguanidine Amiloride

Bumetanide

COOHS

O

O

H2N

O

NH

C4H9

Furosemide

COOH

NH CH2O

Cl

S

O

O

H2N

NH CH2O

Cl

S

O

O

H2N

N N

NN

COOHS

O

O

H2N

ON

Azosemide

Piretinide

1

23

4

56

65

4

3

2

1

Spirolactones (e.g. spironolactone)

Spironolactone is a structural similar of progesterone. Progesterone was observed to possess an antialdosteronic activity, inhibiting the

antitinatriuretic and kaluretic activity.

Phramacokinetic Spironolactone is absorbed well after oral administration (>90%);

biotransformed rapidly and extensively by the liver (about 80%) to

canrenone, an active

metabolite and excreted

primarily as metabolites in

urine.

Phramacokinetic

Spironolactone is absorbed well after oral administration

(>90%); biotransformed

rapidly and extensively by

the liver (about 80%) to

canrenone, an active

metabolite and excreted

primarily as metabolites in

urine. Spironolactone metabolism

Site and Mechanism of action

Spironolactone inhibits the reabsorption of (2-3%) of the filtered load of sodium at site 4 by competitively inhibiting the actions of aldosterone.

This inhibition prevents the biosynthesis of transport proteins such as

Na,K ATPase, luminal membrane channels that are involved in the

exchange of sodium for potassium, and the H+ ATPase that actively

pumps H+ into the luminal fluid at site 4.

Thus inhibiting the passage of luminal fluid sodium into and potassium and H+ out of the late distal convoluted tubule and early collecting tubule

cells.

O

O

O

S C

O

CH3

O

O

O

Metabolism in liver

Spironolactone is Natriuretic, chloruretic, saluretic and Antikaluretic agent. It is considered to

be a very weak diuretic and of low efficacy (2-3%)

Uses

It may be used for the following indications

To remove edema from individuals suffering Congestive heart failure, cirrhosis, or nephrotic syndrome

Antihypertensive agent. Primarily it is used in combination with diuretics that act at site 2 or 3 in

an attempt to reduce the urinary potassium loss associated with these latter

groups of diuretics.

The principal side effect is hyperkalemia and mild metabolic acidosis.

2,4,7-triamino-6-arylpteridine Trimeteren & The pyrazinoylguanidine Amiloride.

These agents are both well absorbed orally and act by the plugging the sodium

channel in the luminal membrane of the principal cells at site 4. And thereby

inhibits the electrogenic entry of 2-3% of the filtered load of sodium into these

cells.

Because the secretion of potassium and H+ at site 4 is linked to sodium

reabsorption, a concomitant reduction in the excretion rate of potassium and H+

occurs. The presence of aldosterone is not a prerequisite for the activity of these

agents.

They are considered mild diuretics. They are Natriuretic, chloruretic, saluretic

and Antikaluretic agent.

N

N N

N

H2N

H2N

H2NN

N

H2NH2N

Cl C

O

C

NH

NH2NH

Amiloride Trimeterene