The most powerful diuretic effect is provided by loop diuretics, which severely inhibit reabsorption of sodium and chloride ions from renal tubules in cortical and cerebral regions and the ascending region of Henle's loop. In both oral and intravenous introduction, they cause a rapid rise in excretion of sodium and chloride ions from the kidneys and an increase in secreted urine volume.
An increase in potassium, hydrogen, magnesium, and calcium ions is observed simultaneously with the increase of sodium and chloride ions being excreted. Urine becomes more acidic, and the concentration of ammonia ions falls. This can result in hypochloremic alkalosis. The most widely used loop diuretics are bumetanide (derivative of monosulfamoyl methanylamide), ethacrynic acid (a derivative of aryloxyacetic acid), and furosemide (derivative of monosulfamoylanthranylic acid), which have more diuretic efficacy than thiazides. Bumetanide, ethacrynic acid, and furosemide are used in treating edema associated with severe and chronic cardiac insufficiency, cirrhosis of the liver, nephrotic syndrome, and renal diseases. They are frequently used by patients unable to tolerate thiazides. They are also used to treat chronic hypertension both independently as well as in combination with other antihypertensive drugs. The efficacy and safety of bumetanide and ethacrynic acid in chronic hypertension has not been proven. Loop diuretics are effective in treating severe hyperkalemia.
Bumetanide: Bumetanide, 3-butylamino-4-phenoxy-5-sulfamoylbenzoic acid (21.4.6), is synthesized from 4-chlorobenzoic acid. In the first stage of synthesis, it undergoes sul-fonylchlorination by chlorosulfonic acid, forming 4-chloro-3-chlorosulfonylbenzoic acid (21.4.1), which is further nitrated with nitric acid to 4-chloro-3-chlorosulfonyl-5-nitroben-zoic acid (21.4.2). Reacting this with ammonia gives 5-aminosulfonyl-4-chloro-3-nitroben-zoic acid (21.4.3), which when reacted with sodium phenolate is transformed into 5-amino-sulfonyl-3-nitro-5-phenoxybenzoid acid (21.4.4). Reduction of the nitro group in this product by hydrogen using a palladium on carbon catalyst gives 3-amino-5-aminosul-fonyl-5-phenoxybenzoic acid (21.4.5). Finally, reacting this with butyl alcohol in the presence of sulfuric acid gives the desired bumetanide (21.4.6) [55-59].
Bumetanide is used for relieving edema associated with cardiac insufficiency, for liver and kidney diseases including nephrotic syndrome, for ascites, and hypertension. Synonyms of this drug are bumex and others.
Ethacrynic acid: Ethacrynic acid—[2,3-dichloro-4-(2-methylenbutyryl)phenoxy]acetic acid (21.4.9), is synthesized from 2,3-dichlorophenoxyacetic acid. This is acylated with buty-royl chloride, forming 4-butyroyl-2,3-dichlorophenoxyacetic acid (21.4.7), which is further aminomethylated under Mannich reaction conditions using dimethylamine and formaldehyde. The resulting product (21.4.8) undergoes further thermal degredation, forming an unsaturated ketone—ethacrynic acid (21.4.9) [60-62].
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Ethacrynic acid is a powerful diuretic prescribed for edema associated with cardiac insufficiency, renal edema that does not respond to other diuretics, and edema of the brain and lungs. Synonyms of this drug are uregit, edecrin, and others.
Furosemide: Furosemide, 4-chloro-N-furfuryl-5-sulfamoylanthranylic acid (21.4.11), is synthesized in a relatively simple manner from 2,4-dichlorobenzoic acid, which is converted into 5-aminosulfonyl-4,6-dichlorobenzoic acid (21.4.10) during subsequent reaction with chlorosulfonic acid and ammonia. Reacting this with furfurylamine gives furosemide (21.4.11) [63-66].
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Furosemide is a highly effective and quick-acting diuretic whose action, like all of the examined loop diuretics, is associated with blocking reabsorption of ions in the ascending bend of Henle's loop. It is used for edema syndrome of various origins, edema of the lungs and brain, chronic renal insufficiency, some forms of hypertonic crises, and poisoning by barbiturates and other compounds excreted mainly with urine.
In a number of cases, furosemide has proven more effective than other diuretics. Besides a diuretic effect, it also dilates peripheral vessels. It is frequently used in combination with other antihypertensive drugs. Synonyms of this drug are lazix, lazizix, franil, urosemide, and many others.
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