First-Generation Sulfonylureas

Sulfonylureas. The hypoglycemic effect of sulfonylureas was first noted in the early 1940s when several patients died in hypoglycemic coma after testing glyprothia2ole, a synthetic sulfonamide used to treat typhoid. Chemical modifications which enhanced activity and lowered toxicity led to the development of the first-generation sulfonylureas. Carbutamide [339-43-5] the first commercial sulfonylurea, came onto the European... 

The sulfonylureas appear to lower blood glucose by stimulating the beta cells of the pancreas to release insulin. The sulfonylureas are not effective if the beta cells of the pancreas are unable to release a sufficient amount of insulin to meet the individual s needs. The first generation sulfonylureas (eg, chlorpropamide, tolazamide, and tolbutamide) are not commonly used today because they have a long duration of action and a higher incidence of adverse... 

The oral antidiabetic drugs are contraindicated in patients with known hypersensitivity to tiie drugs, DKA, severe infection, or severe endocrine disease. The first generation sulfonylureas (chlorpropamide, tolazamide, and tolbutamide) are contraindicated in patients with coronary artery disease or liver or renal dysfunction. Other sulfonylureas are used cautiously in patients with impaired liver function because liver dysfunction can prolong the drug s effect. In addition, the sulfonylureas are used cautiously in patients with renal... 

The first-generation sulfonylureas are not frequently used in the modem management of diabetes mellitus because of their relatively low specificity of action, delay in time of onset, occasional long duration of action, and a variety of side effects. They also tend to have more adverse drug interactions than the second-generation sulfonylureas. They are occasionally used in patients who have achieved previous adequate control with these agents. 

Mechanism of Action A first-generation sulfonylurea thatpromotesthereleaseof insulin from beta cells of pancreas. T herapeutic Effect Lowers blood glucose concentra-... 

The older first-generation sulfonylureas are extensively metabolized and primarily excreted renally. Tolbutamide is transformed by oxidation of the benzylic methyl group, yield-inga hydroxymethyl metabolite, (la), which is further oxidized to the corresponding carboxylic acid, (lb). These metabolites have little activity. 

Which drugs are considered first-generation sulfonylureas ... 

The first-generation sulfonylureas vary considerably in their half-lives and extents of metabo-hsm. The tj of acetohexamide is short, but it is reduced to an active compound whose tj is similar to those of tolbutamide and tolazamide (4-7 hours). These drugs may require divided daily doses. Chlorpropamide has a long (24-48 hours). The second-generation agents are approximately... 

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