Mechanism of Action of Sulfonylureas
Sulfonylureas work by binding to the sulfonylurea receptor (SUR1) on pancreatic beta cells, which closes ATP-sensitive potassium channels, leading to calcium channel opening and subsequent insulin release. 1
Primary Mechanism: Pancreatic Beta Cell Stimulation
Sulfonylureas bind to the SUR1 subunit of ATP-sensitive potassium (K-ATP) channels on pancreatic beta cell membranes, causing channel closure. 2, 3
The K-ATP channel is a complex of two proteins: a pore-forming subunit (Kir6.2) and the drug-binding subunit (SUR1), which functions as the receptor for sulfonylureas. 3
When potassium channels close, the beta cell membrane depolarizes, triggering voltage-dependent calcium channels to open. 2
The influx of calcium ions stimulates exocytosis of insulin-containing granules, resulting in insulin secretion. 1, 2
This mechanism is entirely dependent on functioning beta cells in the pancreatic islets—sulfonylureas cannot work if beta cells are absent or severely dysfunctional. 1
Timing and Duration of Action
The insulinotropic response to a meal occurs within 30 minutes after an oral dose of glipizide in diabetic patients. 1
Elevated insulin levels do not persist beyond the time of the meal challenge, though blood sugar control can persist for up to 24 hours after a single dose even as plasma drug levels decline. 1
Fasting insulin levels are not elevated even with long-term sulfonylurea administration, but the postprandial insulin response continues to be enhanced after at least 6 months of treatment. 1
Extrapancreatic Effects
Sulfonylureas may exert additional hypoglycemic effects beyond insulin secretion, including reducing hepatic insulin clearance, decreasing glucagon secretion, and enhancing peripheral tissue insulin sensitivity. 4
The mechanism by which sulfonylureas lower blood glucose during long-term administration has not been clearly established, and extrapancreatic effects may contribute to their overall glucose-lowering action. 1
Drug-Specific Receptor Binding
Different sulfonylureas have varying affinities for different SUR subtypes, which explains tissue-specific effects. 5
Tolbutamide and gliclazide selectively block channels containing SUR1 (beta-cell type) but not SUR2 (cardiac and smooth muscle types), whereas glibenclamide, glimepiride, repaglinide, and meglitinide block both types of channels. 5
This differential binding is clinically important because blocking cardiac K-ATP channels may theoretically affect the heart's response to ischemia. 2
Channel Dynamics and Drug Efficacy
Even when sulfonylureas are bound, K-ATP channels can still open to a limited extent, so high-affinity sulfonylurea inhibition is not complete even at saturating drug concentrations. 5
Sulfonylurea block is decreased by factors that increase K-ATP channel open probability, such as phosphatidylinositol bisphosphate or certain mutations. 5
MgADP produces an apparent increase in sulfonylurea efficacy on channels containing SUR1 but not SUR2, which relates to changes in channel gating and drug-binding site transduction. 5
Clinical Implications of Mechanism
Because sulfonylureas require functioning beta cells, some patients fail to respond initially, or gradually lose their responsiveness over time due to progressive beta cell dysfunction. 1
The progressive decrease in effectiveness with long-term use results from reduction in insulin-producing capacity by pancreatic beta cells, not from drug tolerance. 2
Sulfonylureas are particularly beneficial when combined with agents like metformin that decrease insulin resistance, since they address complementary defects in type 2 diabetes pathophysiology. 2