First-Gen Sulfonylureas



First-generation sulfonylureas include the drugs tolbutamide and chlorpropamide, and they are used in the management of type 2 diabetes. They work by closing potassium channels on beta cells of the pancreas, which leads to depolarization and an influx of calcium, eventually resulting in insulin release. Since the total amount of insulin is increased, these drugs have a tendency to cause hypoglycemia, which is especially relevant in kidney failure since these drugs are renally-cleared. Lastly, first generation sulfonylureas can also cause a disulfiram-like reaction after consuming alcohol.

Key Points

  • First-Generation Sulfonylureas
    • Drugs
      • Tolbutamide
      • Chlorpropamide
    • Mechanism
      • Close ATP-dependent potassium channels
      • → beta cell depolarization
      • → calcium influx
      • → insulin release
        • So C-peptide levels also increase
          • C-peptide is also in beta cell vesicles
          • This gives us a way to differentiate between endogenous and exogenous insulin exposure (esp. relevant in factitious hypoglycemia)
    • Clinical Use
      • Type II diabetes
        • Requires some islet function, so not useful in type I DM
    • Adverse Effects
      • Hypoglycemia
        • Insulin drives sugar into cells, which removes glucose from the bloodstream. If too much insulin is present, too much glucose can be driven into cells and blood glucose levels can get too low.
      • Weight gain
        • I like to think of this as insulin driving sugar into cells and fattening them up
      • Disulfiram-like effects
      • Side effects are worse in kidney disease
        • Sulfonylureas are renally-excreted, so in CKD patients they accumulate and can lead to worse side effects
        • Diabetes can cause kidney disease
        • The one to really watch out for is hypoglycemia
      • Sulfa allergies
        • Obvious because "sulfa" is in the drug class’ name
        • Symptoms range from mild to life-threatening
          • E.g. fever, urticaria (hives), Stevens-Johnson syndrome, etc.