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

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

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? )

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.

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

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

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

Synthesis of Furosemide

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.

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.

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.

Synthesis of Ethacrynic acid

Class 5:Potassium sparing diuretics

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

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

Spirolactones

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

5. Potassium- sparing diuretics Amiloride Triamterene Spironolactone 3% Often they are used in combination with diuretics, causing hypokalemia. They have weak diuretic action and save K+.

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.

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

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