DIURETICS

Diuretics (“water pills”) are the drugs which

increase the urine out put (or) urine volume .

What is natreuretic agent ?

Any drug when introduce into the body

increases the out put of sodium

ie., loss of sodium in urine.

DIURETICS

General knowledge about kidney

1 cardiac output -5 lit/min.

Out of that 20% goes to kidneys i.e.1 lit/min.

Only 20% can enter into glomerelus that is 120 ml.

This 120 ml/min makes glomerular filtrate.

98 Percent water and electrolyte reabsorb

1-2 percent urine formation

Approximately 1200 ml of blood per minute flows through both kidneys.

Ions such as sodium, chloride,calcium are reabsorbed. Total amount of glucose, amino acids, vitamins,

proteins are reabsorbed. If the urine contains above it represents the disorders. For example proteins such as albumin in higher amounts causes

albuminaria.

NORMAL PHYSIOLOGY / FUNCTIONS OF KIDNEY

Important functions of the kidney are:-

Water Reabsorption

To maintain a homeostatis balance of electrolytes and water.

To excrete water soluble end products of metabolites.

Filteration

Urine formation

KIDNEY STRUCTURAL UNIT ---THE NEPHRON

Each kidney contains approximately one million

nephrons and is capable of forming urine

independently.

The nephrons are composed of glomerulus,

proximal tubule, loop of henle, distal tubule.

NORMAL PHYSIOLOGY OF KIDNEY (URINE FORMATION)

Diuretics are very effective in the treatment of conditions like:-

chronic heart failure

nephrotic syndrome

chronic hepatic diseases

hypertension

Pregnancy associated oedema

Cirrhosis of the liver.

Therapeutic approaches

Types of urine

Oliguria

PolyuriaNormal

CLASSIFICATION OF DIURETICS

Non Mercurial Diuretics Mercurial Diuretics

CLASSIFICATION OF DIURETICS

A. Weak Diuretics :-

i. Osmotic Diuretics: Electrolytes: Sodium Chloride, Potassium chloride,Mannitol

Nonelectrolytes: Isosorbide, Sucrose, Urea, Glycerol.ii. Xanthine derivatives: Aminophylline, Theophyllineiii. Carbonic anhydrase inhibitors: Acetazolamide,

Dichlorphenamide, Ethozolamide, Methazolamide

Moderately potent Diuretics:-i. Thiazide Diuretic

Chlorthiazide, Hydrochlorthiazide.Very Potent Diuretics:-

ii. Loop Diuretics: Furosemide, Ethacrynic acid, Torsemide,Bumetamide,

Mercurial: Mersalyl, Mercaptomerin,Meralluride, Chlormerodin, Mercurous chloride (Mersalyl).

Potassium sparing Diuretics:-Triamterene, Spironolactone, Amiloride.

MERCURAL DIURETICS

MERCURIAL DIURETICS Mercuric diuretics contains mercuric ion

in their structure and it combine with SH Group containing enzyme and inactivate.

These enzymes control reabsorption of water and Na/Cl Ion exchange.

Block reabsorption of sodium in proximal tubules and Ascending loop of Henle.

They enhance the excretion of potassium.

MERCURIAL DIURETICS Due to there pronoun and serious

complications not mostly used Merculism Hypersenstivity Excessive diuresis Administered through intramuscular

route and orally less common

SAR OF MERCURIAL DIURETICS Diuretic activity of mercurial diuretic

require hydrophilic group e.g RCONH attach not less than 3 carbon from Hg.

Compounds with shorter chain activity little or short.

Diuretic activity/toxicity determined by fuctional group attached at X,Y,R Position

Y more , R less activity influence and X not imp activity

SAR OF MERCURIAL DIURETICS Theophylline instead of X improve

activity Enhanced diuretic activity Reduce tissue irritation Increase absorption from site of

action

MERALLURIDE

SYNTHESIS OF MERALLURIDE

SYNTHESIS OF MERALLURIDE

USES OF MERALLURIDE EDEMA CHF NEPHROTIC SYNDROME HEPATIC CIRRHOSIS

MERCAPTOMERIN SODIUM

SYNTHESIS OF MERCAPTOMERIN SODIUM

USES OF MERCAPTOMERIN SODIUM

MERETHOXYLLINE PROCAINE

NON MERCURIAL DIURETICS

CLASSIFICATION OF NON MERCURIAL DIURETICS

THIAZIDE

SAR OF THIAZIDES

The position 2 can tolerate the presence of small alkyl

groups such as methyl.

Substituents in 3 position determines the

potency,duration of action.

SN

NR1

SO2NH2

R

OO

43

21

87

6

5

SAR OF THIAZIDES Loss of c-c double bond between 3&4 positions of nucleus

increases diuretic potency approximately three to ten fold.

Direct substitution of the 4,5 or 8 position with an alkyl group

usually results in diminished diuretic activity.

Substitution of the 6-position with an activating group is essential

for diuretic activity . The best substituent's include Cl,Br,CF3 and

No2 groups.

The sulphamoyl group in the7-position is a prerequisite for diuretic

activity.

SN

NR1

SO2NH2

R

OO

43

21

87

6

5

MECHANISM OF ACTION OF THIAZIDES

These drugs compete for the chloride binding site of the

sodium/chloride symporter and inhibit the re-absorption of

sodium &chloride.

SYNTHESIS OF CHLORTHIAZIDE

Uses HEART FAILURE

HYPERTENSION

NEPHROTIC SYNDROMES

Alkalizing the urine.

These are given in combination with amiloride,allopurinol to

prevent the formation of calcium stones in hyper calciuric

patients.

ADVERSE EFFECTS

GI effects -Anorexia

CNS effects -Dizziness, vertigo.

CVS effects-Ortho static hypotension.

HYPOKALEMIA, HYPONATREMIA,

ALLERGIC REACTIONS

chlorothiazide R1 =H

hydrochlorothiazide R1=H,R=Cl

trichlormethiazide R1=CHCl2,R=Cl

methyclothiazide R1=CH2Cl,R=Cl

hydroflumethiazide R1=H,R=CF3

DRUGS SUBSTITUENTS

HYDROCHLOROTHIAZIDE

CARBONIC ACID INHIBITORS

CH3 C NH

NN

S

S

O

O

N

H

H

O

Acetazolamide

SAR OF ACETAZOLAMIDE

Presence of sulphonamide moiety necessary for diuretic activity

N group of sulphonamide remain unsubstituted for its activity

If methyl group on N position attachment to retain its activity

CH3 C NH

NN

S

S

O

O

N

H

H

O

CARBONIC ANHYDRASE INHIBITORS Carbonic anhydrase is present in many

sites but predominent location of this enzyme is the luminal membrane of the proximal tubules cells.

It catalyzes the dehydration of H2CO3 . By blocking Carbonic anhydrase,

inhibitors block sodium bicarbonate reabsorption and cause diuresis.

MECHANISM OF ACTION OF ACETAZOLAMIDE

It is a sulfonamide derivative which is a non competitive

reversible inhibitor of “carbonic anhydrase enzyme”.

This enzyme is responsible for catalytic reversible hydration of

carbon dioxide and dehydration of carbonic acid.

MECHANISM OF ACETAZOLAMIDE

SYNTHESIS OF ACETAZOLAMIDE Reaction between hydrazine hydrate and ammonium

thiocyanate yields 1, 2-bis (thiocarbamoyl) hydrazine which on treatment with phosgene

undergoes molecular rearrangement through loss of ammonia to yield 5-amino-2-mercapto-1, 3, 4-thiadiazole. This on acylation gives a corresponding amide which on oxidation with aqueous chlorine affords the 2-sulphonyl chloride. The final step essentially consists of amidation by treatment with ammonia.

USES OF ACETAZOLAMIDEHTN, GLUCOMA ,URINARY ALKALINIZATION, ADJUVANT FOR

TREATMENT OF EPILEPSY

ADVERSE EFFECTS: Hypo kalaemia. Renal calculi. Nausea, loss of hearing, loss of apetite, Drowsiness, paresthesia

LOOP DIURETICS

Loop diuretics selectively inhibit NaCl reabsorption in the thick ascending limb of the loop of

Henle. Due to the large NaCl absorptive capacity of this

segment and the fact that diuresis is not limited by development of acidosis, as it is with the

carbonic anhydrase inhibitors, these drugs are the most efficacious diuretic agents available. The two prototypical drugs of this group are

furosemide and ethacrynic acid

SYNTHESIS OF FUROSEMIDE

MECHANISM OF ACTION OF LOOP DIURETICS

These agents produce a peak diuresis much greater than observed

with other commonly used diuretics.

They act by inhibiting the luminal Na/K/2Cl symporter.

Furosemide is preferred usually to ethacrynic acid for a

number of reasons:

It is less ototoxic.

It has broader dose response curve.

It is more convenient for i.v. use.

It causes fewer git side effects.

ETHACRYNIC ACID

SYNTHESIS OF ETHACRYNIC ACID

USES

ADVERSE EFFECT OF LOOP DIURETIC

ALDOSTERONE ANTAGONIST

Mechanism of action of SPIRONOLACTONE

Aldosterone,by binding to its receptor in the cytoplasm increases

expression &function of Na channel and sodium pump.

Spironolactone competitively inhibits the binding of aldosterone and

abolishes its biological effect.

O

O

H3C

CH3

O S C CH3

O

Spironolactone-

17-hydroxy-7-α-mercapto-3-oxo-17αpreg-4-ene-21-carboxlic acid-ϒ-lactone

acetate

POTASSIUM SPARING DIURETIC

USES Acute renal failure HTN HypokalemiaADVERSE EFFECTS:OtotoxicityHyperuricemiaHypomagnesiaAllergic reactions

PURINE DIURETICS

OSMOTIC DIURETIC

MECHANISM OF ACTION OF OSMOTIC DIURETICS.

Osmotic agents such as Mannitol are low molecular weight

compounds that are freely filtered through bowmans capsule.

They have limited reabsorption because of high water solubility.

Osmotic diuretics increase the volume of water and almost all of

the electrolytes.

TRIAMTERENE

SYNTHESIS OF TRIAMETRENE

DRUG BRAND NAME DOSEAcetazolamide Diamex 125/250mg orallyAmiloride Midamor 5mg orallyBumetanide Bumex 0.5,1,2mg / I.V

0.5mg/2mlFurosemide Lasix 20,40,80mg OR

I.V/I.M 10mg/mlEthacrynic acid Edecrin 25/50mg I.V 50mgChlorothiazide Diuril 250/500mg or

250mg/5ml oral suspens

Hydrochlorthiazide Diucardin 50mg orallyMannitol Osmitrol 5,10,15,20,25% for injSpironolactone Aldactone 25,50,100 mg tabletsTorsemide Demadex 5,10,20,100mg tabletsTriamterene Dyrenium 50/100mg orally

Medicinal chemistry by Austoshkar www.slideshare.net

Lipponcot’s chapter# 22 diuretic agents

Katzung

73