Co Cd

sulfonylureas possess a lower binding affinity for the ATP-sensitive potassium channel and thus require higher doses to achieve efficacy. Second-generation sulfonylureas are much more potent compounds (Bl00-fold) with a rapid onset of action, shorter plasma half-lives, and longer duration of action compared with the first-generation agents57 (Table 7).

6.19.6.4.1.1 Pharmacokinetics

Both first-generation sulfonylureas (tolbutamide, chlorpropamide, tolazamide, and acetohexamide) and second-generation sulfonylureas (glyburide, glipizide, and glimepiride) are rapidly absorbed after oral administration. The half-lives are between 4 and 10 h with the duration of glycemic effect ranging from 6 to 24 h. The exception is chlorpropamide, which has a half-life of 25-60 h and a duration of glycemic effect of 24-72 h. Most sulfonylureas are hepatically metabolized and renally cleared. Active circulating metabolites may prolong the hypoglycemic effect, especially in individuals with acute or chronic renal impairment.

6.19.6.4.1.2 Mechanisms of action

The sulfonylurea receptor on the cell membrane of pancreatic b-cells is a component of the ATP-sensitive potassium (K+) channel (Figure 3). The K+-ATP channel is composed of two subunits: a cytoplasmic binding site for sulfonylureas

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