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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: 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. Luminal membrane Basolateral membrane Na Na ATP 2Cl K K Na K H K Cl Cl Na Urine Blood High-ceiling or loop diuretics Results from structure-activity relationship studies that 6 led to the development of furosemide. Loop Diuretics active in “loop” of Henle Furosemide (prototype) Bumetanide Torsemide Ethacrynic acid Furosemide O O H2N O S Cl OH O N H Name: 5-(Aminosulfonyl)-4-chloro-2-[(2-furanylmethyl) amino] benzoic acid 8 Synthesis of Furosemide Cl Cl Cl Cl 1) ClSO3H COOH 2) NH3 H2NO2S COOH Furfurylamine , 130 C Cl NH CH2 O H2NO2S COOH SAR of 5-Sulfamoyl-2- and -3-aminobenzoic acid derivatives H N 3 X 4 R R 2 1 6 COOH 3 4 X 5 H2NO2S N 2 1 5 H2NO2S 6 COOH 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®). Cl Cl O CH2COOH CH2 C H3CH2C C O 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, Cl Cl Ethacrynic Acid, (Edecrin®). O CH2COOH CH2 C SARs: H3CH2C C O 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 3position 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 Cl Cl Cl Cl ONa Cl O + ClCH2COOH Cl AlCl3 CH3CH2CH2COCL O CH2COOH CH2COOH H3CH2CH2COC 2,3-dichloro sodium phenolate HCHO (CH3)2NH Cl Cl Cl O CH2COOH Cl OH O C CH3CH2C CH3CH2CH CH2 N H3C CH3 H2C heat -NH-(CH3)2 N H3C Cl Cl CH2 C H3CH2C C O O C CH2COOH CH3 O CH2COOH Class 5:Potassium sparing diuretics three groups 1- steroid aldosterone antagonists as spironolactone, 2- triamterene 3- Pyrazinoylguanidines amiloride Potassium-sparing diuretics Competitive aldosterone antagonists: Blockers of the amiloride-sensitive Na+ channels: •Spironolactone •Amiloride •Triamterene Spirolactones 18 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. Potassiumsparing diuretics Amiloride Triamterene Spironolactone 3% They have weak diuretic action and save K+. Often they are used in combination with diuretics, causing hypokalemia. 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. 21 Triamterene & amiloride Interferes with cationic exchange by blocking luminal Na+ channels in the late distal convoluted tubule and collecting duct. Triamterene amiloride 22 Activity • Brain Storming