diuretics by p.ravisankar

104/08/2023

DIURETICSPresented by B.RAVALI

Reg.no:11AB1R0008

Under the guidance of Mr. P.RAVI SANKAR M. Pharm

Department of Pharmaceutical chemistryVadlamudi, Guntur Dt, A.P, INDIA.

PIN:522213

CONTENTS

Introduction to diuretics.

Therapeutic approaches.

Normal physiology of urine formation.

Classification of drugs .

Mechanism of action of Acetazolamide.

Mechanism of action of Thiazides.

Mechanism of action of Loop diuretics.

Mechanism of action of potassium sparing diuretics

&aldosterone antagonists.

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

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

NORMAL PHYSIOLOGY OF URINE FORMATION

Two important functions of the kidney are:-

To maintain a homeostatis balance of electrolytes and water.

To excrete water soluble end products of metabolites.

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.

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.

Types of urine

Oliguria

PolyuriaNormal

LOOP DIURETICS

FurosemideS

Cl

O

O

H2N COOH

NH

O

CARBONIC ACID INHIBITORS

Acetazolamide CH3 C NH

NN

S

S

O

O

N

H

H

O

CLASSIFICATION OF DRUGS

POTASSIUM SPARING DIURETICS

Aldosterone antagonist

O

O

H3C

H3C

O S C CH3

O

N

NNH NH2

NH2H2N

Cl

O NH

Amiloride

Spironolactone

Hydrochlor thaizideH2NO2S

Cl NH

NHS

O O

H2NO2S

ClN

NHS

O O

Chlorothiazide

THIAZIDE DIURETICS

Chlor thalidone

NH

OH

Cl

SO2NH2

O

N

HN

CH3

CH3Cl

H2NO2S

O

Metolazone

THIAZIDE LIKE DIURETICS

GFR FORMATION

1 cardiac output -5 lit/min.

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

1 lit of blood of has 40%of cells and 60%of plasma.

600 ml of plasma is not entered into glomerulus only a part of plasma

can enter into it and the rest pass through the efferent arteriole.

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

This 120 ml/min makes glomerular filtrate.

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.

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

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.

Uses

Treatment of glaucoma.

Reduces the intra occular pressure.

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.

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.

S

N

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.

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

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.

SYNTHESIS OF FUROSEMIDE

LOOP DIURETICS THIAZIDE DIURETICS

They inhibit Na/K/2Cl symporetr.

Acts at thick ascending loop of

henle.

These are Ca wasting drugs.

They cause heavy diuresis.

Para thyroid hormone

independent Ca absorption.

It can reabsorb 25%to 30% of Na.

They act by inhibiting Na/Cl

symporter.

Acts at distal convoluted tubule.

These are Ca retaining drugs.

They cause mild diuresis.

Para thyroid hormone dependent

Ca absorption.

It can reabsorb 8% of Na.

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.

Mechanism of action of potasssium sparing diuretic

They act by inhibiting sodium reabsorption in the late distal tubule and thus

indirectly spare potassium excretion.

USES:-

Liddle’s syndrome(pseudo-hyper aldosteronism).

Amiloride is used to treat lithium induced nephrogenic diabetes insipidus.

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

Generic name Trade name

Chlorothiazide Diuril

Metalazone Zaroxylon

Furosemide Lasix

Chlorthalidone Thalitone

Indapamide Lozol

Hydroflumethiazide Saluron

CONCLUSION

Diuretics are the first line agents to treat hypertension. When it

is not controlled it can be given in the form of combinations

with other anti hypertensive's.

Some of these agents has the capacity to reabsorb more

calcium so they can be prescribed for the patients suffering

from osteoporosis.

Thomas L Lemke /David A Williams –Foye’s principles of

Medicinal chemistry 6th edition pg.no:722-735.

Lippincott Williams & Wilkins – Remington The science

&practice of pharmacy 21st edition pg.no:1422-1431.

D. Sriram, P.Yogeeswari –Medicinal chemistry pg.no:171-

181.

REFERENCES

REFERENCES

Wilson & Gisvold’s Text book of Organic Medicinal &

Pharmaceutical chemistry 11th edition pg. no:596-621.

Bertram G.Katzung –Basic & Clinical pharmacology 12th

edition pg.no:251-269.

ACKNOWLEDGEMENTS

I oblige to pay my deep gratitude for the patience hearing of my presentation delivered by me with reference to power point.

I thank one and all.

I would like to thank my guide Mr. P.RAVI SANKAR for his

extreme support & guidance.

I would like to thank our principal Dr.P.SRINIVAS BABU I also would like to thank our organizing committee.

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