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

2. 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

3. 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? )

5. Mechanism of Action: Adverse Effects:
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.

6. High-ceiling or loop diuretics
Results from structure-activity relationship studies that led to the development of furosemide.

7. Loop Diuretics active in “loop” of Henle Furosemide (prototype)
Bumetanide
Torsemide
Ethacrynic acid

8. Furosemide
Name:
5-(Aminosulfonyl)-4-chloro-2-[(2-furanylmethyl）amino] benzoic acid

9. Synthesis of Furosemide

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

11. Phenoxyacetic acids, Ethacrynic Acid, (Edecrin®).
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.

12. 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.

13. Synthesis of Ethacrynic acid

14. Class 5:Potassium sparing diuretics

15. three groups 1- steroid aldosterone antagonists as spironolactone,
2- triamterene
3- Pyrazinoylguanidines
amiloride

16. Potassium-sparing diuretics
Competitive
aldosterone
antagonists:
Spironolactone
Blockers of the amiloride-sensitive
Na+ channels:
Amiloride
Triamterene

18. Spirolactones

19. Mechanism of Action Keep K+
Aldosterone-stimulated sodium reabsorption in exchange for potassium and hydrogen ion, in the distal, collecting tubules and ducts
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

20. 5. Potassium- sparing diuretics Amiloride Triamterene Spironolactone3%
Often they are used
in combination with
diuretics, causing
hypokalemia.
They have weak
diuretic action
and save K+.

21. Other potassium-sparing diuretics: triamterene and amiIoride:
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.

22. Triamterene & amiloride
Interferes with cationic exchange by blocking luminal Na+ channels in the late distal convoluted tubule and collecting duct.
amiloride
Triamterene

23. Activity
Brain Storming