Diuretics •

Dr. Majdi Bkhaitan

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Department of Pharmaceutical Chemistry

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www.medchem1432.pbworks.com

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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 structure–activity 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 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. 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

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To maintain a homeostatic balance of electrolytes and water.

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To excrete water-soluble end products of metabolism.

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Treatment of different edematous conditions, resulting from a variety of causes (e.g. congestive heart failure, nephrotic syndrome, and chronic liver disease).

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Management of hypertension.

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Adjunctive therapy in the treatment of a wide range of clinical conditions, including hypercalcemia, acute mountain sickness, primary hyperaldosterism, glaucoma and mountain sickness.

Uses

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.

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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.

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The glomerular filtration rate (GFR) averages 125 mL/min in humans but can vary widely even in normal functional states.

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The glomerular filtrate leaves the Bowman's capsule and enters the proximal convoluted tubule 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 non-electrogenetically with bicarbonate reabsorption.

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Glucose and amino acids are completely reabsorbed in this portion of the nephron, whereas phosphate reabsorption is between 80 and 90% complete.

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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.

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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.

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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.

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There are four Anatomical sites for diuretic action in the nephron: •

Site 1: proximal convoluted tubule.

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Site 2: thick ascending Henle’s loop (TAL)

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Site 3: distal tubule

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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 •

H

2

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.

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The derivative with the highest Pc “partition coefficient” and the lowest ionization “pKa” has the greatest CA inhibitory and diuretic activities.

N

O N S O

C H

N S

N H

O C

C H

H

3

2

N

O S O

N

Ace t ozol am i de

3

N S

N

O C

C H

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

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. Cl

Cl

Cl O H2N S O

O S NH2 O

Dichlorphenamide

O H2N S O

NH2 O S NH2 O

Chloraminophenamide

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

3

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)

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Bicarbonaturetic (increse the execretion of bicarbonate)

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Kaluretic (increse the execretion of Potassium)

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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).

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When there is less bicarbonate present in the luminal fluid, there is less bicarbonate reabsorption to inhibit.

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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:

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Primarily in the treatment of glaucoma, by inhibiting CA in the eye, reducing the formation of aqueous humor in the eye.

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In the prophylaxis of mountain sickness, Adjuvant in the treatment of epilepsy, to create alkaline urine when it is needed.

Adverse effects:

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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: Doesn’t 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 1,2,4thiadiazine-1,1dioxide “ thiazide derivatives”.

X O C l H

2

Chl or a m i n op h e n am i d e

N

O S O

N H O S O

2

C l

C

R

N H

O S O

2

R N H

S O

O

Thi az i de N H

2

R

C O

R

H N

X

N H

•

N

2

O S O

On the other hand, Hy dr o t h i a z i d e when Chloraminophenamide is treated with aldehyde or ketone, in place of the acylating reagent, this produces the corresponding hydrothiazide derivatives.

S O

R N H O

H

These represent the first oral active saluretic agents (increase the excretion of NaCl). Site and Mechanism of action

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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.

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Thus, all diuretics in this class are responsible for the urinary loss of about (58%) of the filtered load of sodium. Although they differ in their potencies, they are equally efficacious.

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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.

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On the other hand this family possesses a residual CA inhibition producing a very mild elimination of HCO3-.

Site 3 diuretics are considered

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Natriuretic chloruretic, saluretic kaliuretic and extremely weak bicarbonaturetic agents.

SAR

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

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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.

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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”.

4

H N

5 6

3

N H

7

S

8

O

1

O

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

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Substitution at position 6 with a deactivating group “ such as Cl, Br, CF3, CHCl3, i.e. electron withdrawing groups” is essential for the activity.

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

2

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Substitution of the sulfone group in position 1 with another similar electrophilic group (carboxyl, carbamoyl) can produce an activity increase.

Products

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Thiazide derivatives

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Chlorthiazide ( X= Cl, R=H)

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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

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Meta disulfamoyl benzens •

•

S O

X

H N

O NH2 S O

S O

Mefruside

xipamide

Indapamide

Chlorthalidone

Others •

R NH O

Phthalimidines •

•

O S O

Benzhydrazides •

•

N

Salicylanilide •

•

NH2

X

Metolazone,etc.

These diuretics were developed as an outgrowth of the thiazide research that involved molecular modification of aromatic sulfamoyl-containing compounds.

R H NH O

Uses

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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.

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In the treatment of hypertension, either alone or in combination with other drugs depending on the severity of the condition.

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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.

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Treatment of type II renal tubular acidosis.

Adverse effects

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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

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Hypokalemia.

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Acute reduction in GFR, and Hyperglycemia.

Site 2 Diuretic “High ceiling” “loop” diuretics

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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.

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5-sulfamoyl-3-aminobenzoic acid derivatives “metanilic acid derivatives”. E.g. Bumetanide, Piretanide.

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Phenoxyacetic acid derivatives. E.g. ethacrynic acid.

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

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Organomercurials “not in use because not available orally and for other unfavorable conditions”.

Site and mechanism of action

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These diuretics have a tremendous efficacy because they inhibit the Na/K/2Cl cotransport system located on the luminal membrane of cells of the thick ascending limb of Henle’s loop. Importantly, the carboxylate moieties of Furosemide and Bumetanide are thought to be responsible for their competing with Cl- for the Clbinding site on the Na/K/2Cl co-transport system.

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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 Henle’s loop.

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Other factors and mechanisms participate also to make of this class the most efficacious of all diuretics.

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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.

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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.

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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

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Treatment of edema that may accompany congestive heart failure, cirrhosis of the liver and nephrotic syndrome.

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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.

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Treatment of symptomatic hypercalcemia.

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In the treatment of hypertension, even though thiazides are more advised because of their longer duration of action and their less toxicity.

Adverse effects

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Hypokalemia. Caution should be taken in case of combined treatment with cardiac glycosides, because hypokalemia intensifies the toxicity of the cardiac glycosides.

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Reduction in GFR, observed only in long term therapies.

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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.

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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.

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

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The electron withdrawing group at C4 can be Cl, CF3, or yet better a phenoxy, alkoxy, anilino, benzyl, or benzoyl group.

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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.

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

Regarding the anthranilic acid and metanilic acid derivatives

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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.

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

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The electron withdrawing group at C4 can be Cl, CF3, or yet better a phenoxy, alkoxy, anilino, benzyl, or benzoyl group.

•

3

Cl

2 4

O H2N S O

5

1 6

NH CH2

O

COOH

Furosemide

Cl

NH CH2

O H2N S O

N N

N N

Azosemide

C4H9 NH O

N

3 2

O

4 Only furfyryl, benzyl, O O thienylmethyl groups 5 1 H N S COOH H2N S COOH 2 6 are allowed in O O position 2 in the Bumetanide Piretinide 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.

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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.

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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



O

Spirolactones  Spironolactone  Canrenone  The 2,4,7-triamino-6- arylpteridine  Ttrimeteren  The pyrazinoylguanidine  Amiloride

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

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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

O O

O

O M etabolism in liver O S

C

CH3

O

O

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.

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.

O Cl

N

NH H2N

C NH C NH2

N

N H2N

N

H2N

Amiloride

H2N

N

N

H2N

Trimeterene