Saluretic activity

Replacement or removal of the sulfonamide group at position 7 yields compounds with little or no diuretic activity. Saturation of the double bond to give a 3,4-dihydro derivative produces a diuretic that is 10-fold more active than the unsaturated derivative. Substitution with a lipophilic group at position 3 gives a marked increase in the diuretic potency. Haloalkyl, aralkyl, or thioether substitution increases the lipid solubility of the molecule and yields compounds with a longer duration of action. Alkyl substitution on the 2-N position also decreases the polarity and increases the duration of diuretic action. Although these compounds do have carbonic anhydrase activity, there is no correlation of this activity with their saluretic activity (excretion of sodium and chloride ions). 

While these two classes of diuretics have effectively overcome the kaluretlc problem, and perhaps the disturbance of uric acid and glucose metabolism, it has been accomplished at the price of a greatly decreased saluretic activity, the activity that is the basis of diuretic agents. 

Sulfonamides derived from sulfanilamide (p-arninoben2enesulfonainide) are commonly referred to as sulfa dmgs. Although several dmg classes are characterized by the presence of a sulfonamide function, eg, hypoglycemics, carbonic anhydrase inhibitors, saluretics, and tubular transport inhibitors, the antibacterial sulfonamides have become classified as the sulfa dmgs. Therapeutically active derivatives are usually substituted on the N nitrogen the position is generally unsubstituted. These features are illustrated by the stmctures of sulfanilamide (1) and sulfadiazine (2)... 

Muzolimine (710), a 1-substituted 2-pyrazolin-5-one derivative, is a highly active diuretic, differing from the structures of other diuretics since it contains neither a sulfonamide nor a carboxyl group. It has a saluretic effect similar to furosemide and acts in the proximal tubule and in the medullary portion of the ascending limb of the loop of Henle. Pharmacokinetic studies in dogs, healthy volunteers and in patients with renal insufficiency show that the compound is readily absorbed after oral administration (B-80MI40406). 

Some saluretic-diuretic agents, like ethacrynic acid, are inactive in the rat, when given orally. Moreover, uricosuric activity in mice is less reliable than that in primates. 

Figure 2.5 In addition to its antibacterial activity, sulfanilamide 11 (Figure 2.4) inhibits the enzyme carbonic anhydrase. Acetazolamide 12 is much more potent as a carbonic anhydrase inhibitor but its clinical use as diuretic was impaired by some serious side effects. Hydrochlorothiazide 13 is the prototype of orally active saluretic sulfonamide diuretics. Furosemide (frusemide) 14 and bumetanide 15 are so-called loop diuretics .

The mechanism of action of the benzothiadiazine diuretics is primarily related to their ability to inhibit the Na /cr symporter located in the distal convoluted tubule. These diuretics are actively secreted in the proximal tubule and are carried to the loop of Henie and to the distal tubule. The major site of action of these compounds is in the distal tubule, where these drugs compete for the chloride binding site of the Na /cr symporter and inhibit the reabsorption of sodium and chloride ions. For this reason, they are referred to as saluretics. They also inhibit the reabsorption of potassium and bicarbonate ions, but to a lesser degree. 

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