Class 4- LOOP DIURETICS High ceiling Diuretics Lec-4.

23
Class 4- LOOP DIURETICS High ceiling Diuretics Lec-4

Transcript of Class 4- LOOP DIURETICS High ceiling Diuretics Lec-4.

Page 1: Class 4- LOOP DIURETICS High ceiling Diuretics Lec-4.

Class 4- LOOP DIURETICSHigh ceiling Diuretics

Lec-4

Page 2: Class 4- LOOP DIURETICS High ceiling Diuretics Lec-4.

• The diuretics that belong to this class are of extremely

diverse chemical structure, such as:

• The organomercurial diuretics,

• The 5-Sulfamoyl-2- and -3-aminobenzoic acid

derivatives. Examples, furosemide and bumetanide

• Phenoxyacetic acid derivatives as ethacrynic acid

Page 3: Class 4- LOOP DIURETICS High ceiling Diuretics Lec-4.

Loop diuretics

• Act by inhibition of Na+, K+, and Cl- reabsorption from the ascending limb of the loop of Henle in the renal tubule.

• They also tend to reduce renal Ca+ reabsorption, thus

they are used in treatment of hypercalcemia.

• High efficiency diuretics.

• High ceiling diuretics.( what is mean? )

Page 4: Class 4- LOOP DIURETICS High ceiling Diuretics Lec-4.
Page 5: Class 4- LOOP DIURETICS High ceiling Diuretics Lec-4.

ATP

Na

K

Na

Luminal membrane Basolateral membrane

Urine Blood

K

K

K

Na

Cl

Na

ClH

2Cl

Mechanism of Action:They inhibit the 1Na+/1K+/2Cl- cotransport system located on the luminal membrane of cells of the thick ascending limb of Henle’s

loop

Adverse Effects:1. Hypokalemic alkalosis. 2. Fluid and electrolyte losses 3. Reduction in plasma volume

may result from long-term use of these diuretics.

4.Hypersensitivity reactions such as urticaria, fever, and interstitial nephritis.

Page 6: Class 4- LOOP DIURETICS High ceiling Diuretics Lec-4.

6

High-ceiling or loop diuretics

Results from structure-activity relationship studies that led to the development of furosemide.

Page 7: Class 4- LOOP DIURETICS High ceiling Diuretics Lec-4.

Loop Diuretics

active in “loop” of HenleFurosemide (prototype)BumetanideTorsemideEthacrynic acid

Page 8: Class 4- LOOP DIURETICS High ceiling Diuretics Lec-4.

8

Furosemide

Name:

5-(Aminosulfonyl)-4-chloro-2-[(2-furanylmethyl ) amino] benzoic acid

S

OO

H2N

Cl

O

OH

NH

O

Page 9: Class 4- LOOP DIURETICS High ceiling Diuretics Lec-4.

Synthesis of FurosemideCl Cl

COOH

Cl Cl

COOHH2NO2S

1) ClSO3H

2) NH3

Cl NH

COOHH2NO2S

CH2O

Furfurylamine

, 130 C

Page 10: Class 4- LOOP DIURETICS High ceiling Diuretics Lec-4.

H2NO2S

XHN

COOH

R

1

2

34

5

6 H2NO2S

X

COOH

N

R

5

4 3

2

1

6

1)  The substituent at the 1-position must be acidic, The carboxyl group provides optimal diuretic activity, but other groups, as tetrazole, may have respectable diuretic activity.2) A sulfamoyl group in the 5-position is essential for optimal high-ceiling diuretic activity.3)  The activating group (x-) in the 4-position can be Cl- or CF3-,

a phenoxy-, alkoxy-, anilino-, benzyl-, or benzoyl- group.4)  Substitutents that can be tolerated on the 2-amino group series: only furfuryl-, > benzyl-, > thienylmethyl. 5) Substituent, on the 3-amino group series: can very widely without affecting optimal diuretic activity.

SAR of 5-Sulfamoyl-2- and -3-aminobenzoic acid derivatives

Page 11: Class 4- LOOP DIURETICS High ceiling Diuretics Lec-4.

2,3-Dichloro-4-(2-methylene-1-oxobutyl) phenoxyacetic acid

Uses:

Ethacrynic acid is prescribed for individual who has a known

hypersensitivity to Sulfamoyl containing drugs.

Cl

OCl

C

CH2COOH

O

C

CH2

H3CH2C

Phenoxyacetic acids, Ethacrynic Acid, (Edecrin®).

Page 12: Class 4- LOOP DIURETICS High ceiling Diuretics Lec-4.

Cl

OCl

C

CH2COOH

O

C

CH2

H3CH2C

Phenoxyacetic acids, Ethacrynic Acid, (Edecrin®).

SARs:

Optimal diuretic activity is achieved when:1. An oxyacetic acid moiety is placed in the 1-position on

the benzene ring, 2. A sulfhydryl-reactive acryloyl moiety is located para to

the oxyacetic acid group,3. Activating groups (Cl- or CH3-) occupy either the 3-

position or the 2- and 3-positions.4. Alkyl substituent of two- to four-carbon atoms in length

occupy the position α to the carbonyl on the acryloyl moiety.

Page 13: Class 4- LOOP DIURETICS High ceiling Diuretics Lec-4.

Cl

Cl

ONa

ClCH2COOH

Cl

Cl

O CH2COOH AlCl3

Cl

Cl O

H3CH2CH2COC

CH2COOH

HCHO

(CH3)2NH

Cl

OCl

C

CH2COOH

O

Cl

OCl

C

CH2COOH

O

C

CH2

H3CH2C

CH3CH2CH

H2C

NCH3H3C

2,3-dichloro sodium phenolate

+CH3CH2CH2COCL

Cl

OCl

C

CH2COOH

OH

CH3CH2C

CH2

NCH3H3C

heat

-NH-(CH3)2

Synthesis of Ethacrynic acid

Page 14: Class 4- LOOP DIURETICS High ceiling Diuretics Lec-4.

Class 5:Potassium sparing diuretics

Page 15: Class 4- LOOP DIURETICS High ceiling Diuretics Lec-4.

three groups1- steroid aldosterone antagonists

as spironolactone,

2- triamterene

3- Pyrazinoylguanidines

amiloride

Page 16: Class 4- LOOP DIURETICS High ceiling Diuretics Lec-4.

Potassium-sparing diuretics

Competitivealdosteroneantagonists:•Spironolactone

Blockers of the amiloride-sensitiveNa+ channels:•Amiloride•Triamterene

Page 17: Class 4- LOOP DIURETICS High ceiling Diuretics Lec-4.
Page 18: Class 4- LOOP DIURETICS High ceiling Diuretics Lec-4.

18

Spirolactones

Page 19: Class 4- LOOP DIURETICS High ceiling Diuretics Lec-4.

Mechanism of Action

K+ sparing diuretics function in CCD decrease Na+ transport in collecting tubule

all previous-discussed diuretics is that they increase the renal excretion rate of K+ and thus can induce hypokalemia

Keep K+

Aldosterone-stimulated sodium reabsorption in exchange for potassium and hydrogen ion, in the distal, collecting tubules and ducts

Page 20: Class 4- LOOP DIURETICS High ceiling Diuretics Lec-4.

3%

AmilorideTriamterene

Spironolactone

5. Potassium- sparing diuretics

They have weakdiuretic actionand save K+.

Often they are usedin combination withdiuretics, causinghypokalemia.

Page 21: Class 4- LOOP DIURETICS High ceiling Diuretics Lec-4.

21

Mechanism and site of action:

• Triamterene and amiloride (organic bases) inhibit

sodium transport in nephron segments beyond the

distal convoluted tubule.

• They do not interact with aldosterone receptors.

Other potassium-sparing diuretics: triamterene and amiIoride:

Page 22: Class 4- LOOP DIURETICS High ceiling Diuretics Lec-4.

22

Interferes with cationic exchange by blocking

luminal Na+ channels in the late distal

convoluted tubule and collecting duct.

Triamterene & amiloride

amilorideTriamterene

Page 23: Class 4- LOOP DIURETICS High ceiling Diuretics Lec-4.

Activity

• Brain Storming