Sulfonylurea hypoglycemic agents

The sulfonylurea hypoglycemic agents, as noted in Chapter 2, also trace their ancestry to the sulfonamides. It is of interest that activity is retained when a substituted 2-amino-1,3,4-thiadiazole replaces the urea function. Reaction of isobutyryl chloride (123-1) with thiosemicarbazone (123-2) leads initially to the transient 1,2-diacyUiydrazine (123-3). This apparently cyclizes spontaneously to thiadiazine (123-4) under reaction conditions. Acylation with p-methoxysulfonyl chloride (123-5) affords the oral hypoglycemic agent isobuzole (123-6) [134]. 

All sulfonamides, including antimicrobial sulfas, diuretics, diazoxide, and the sulfonylurea hypoglycemic agents, have been considered to be partially cross-allergenic. Flowever, evidence for this is not extensive. The most common adverse effects are fever, skin rashes, exfoliative dermatitis, photosensitivity, urticaria, nausea, vomiting, diarrhea, and difficulties referable to the urinary tract (see below). Stevens-Johnson syndrome, although relatively uncommon (ie, < 1% of treatment courses), is a particularly serious and potentially fatal type of skin and mucous membrane eruption associated with sulfonamide use. Other unwanted effects include stomatitis, conjunctivitis, arthritis, hematopoietic disturbances (see below), hepatitis, and, rarely, polyarteritis nodosa and psychosis. 

Cleveland JC Jr, Meldrum DR, Cain BS, Banerjee A, Harken AH. Oral sulfonylurea hypoglycemic agents prevent ischemic preconditioning in human myocardium. Two paradoxes revisited Circulation 1997 96(l) 29-32. 

Comparison of Orally Administered Sulfonylurea Hypoglycemic Agents... 

A A female patient with non-insulin-dependent diabetes has been maintained on an oral sulfonylurea hypoglycemic agent. She becomes pregnant. The doctor switches her to insulin. This is necessary for all of the following reasons EXCEPT ... 

TABLE 1 Comparison of Orally Administered Characteristics Tolbutamide Sulfonylurea Hypoglycemic Agents Acetohexamide Tolazamide Chlorpropamide Glipizide Glyburide... 

Following are structural formulas for two more widely used sulfonylurea hypoglycemic agents. 

Several studies on the synthesis and evaluation of new sulfonylurea hypoglycemic agents have been reported during the year. One such study involved the synthesis and testing of a series of N-benzyl-N -p-toluenesul-fonylureas related to I. Many of these compounds were found to be effective hypoglycemics in rats. Compound I was found to be the most active member of the series. It is comparable to tolbutamide in potency. 

Yet another example of a so-called pharmacophoric group is the biguanide functionality, a grouping associated with oral antidiabetic activity (see the section on sulfonylureas for a fuller discussion of this activity). Condensation of 2-phenethylamine with dicyanamide affords directly the orally active hypoglycemic agent phenformin (88). ... 

Nephropathy in type 2 diabetes-The usual starting dose is 50 mg once daily. Increase the dose to 100 mg once daily based on blood pressure response. Losartan may be administered with insulin and other commonly used hypoglycemic agents (eg, sulfonylureas, glitazones, glucosidase inhibitors). 

The history of pharmacology revealed that certain drugs have been developed from the observation of their side effects for example sulfonamide produce hypoglycemia and acidosis as side effect, which further gave an idea for developing a new compound related to sulfona-mide - sulfonylurea as hypoglycemic agent and acetazolamide as diuretic. 

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