SULFONYLUREA – Ischemic Preconditioning

SULFONYLUREA – Ischemic Preconditioning

            Second generation sulfonylurea are potent drugs and should be used with caution especially in patients with cardiovascular disease and in elderly patients because of risk of dangerous hypoglycemia. All these drugs should be administered at least an hour before food for better absorption. Sulfonylurea metabolized in the liver to inactive products.

            Glimepiride has rapid onset and longer duration of action, lower insulin levels and reduced cardiovascular side effects. It has a unique extrapancreatice effect of reducing the IR. This decrease of IR is thought to be due to increased  levels of plasma adiponectin and decreased levels of TNF-a. Glimepiride is more heart friendly as it does not have dangerous interaction with the cardiac sulfonylurea receptor.

            Insulin secretion is regulated by ATP dependent K⁺ channel located in plasma membrane of b cells. Under fasting condition, most of the channels are open. K⁺ is actively extruded from b cells. When plasma glucose rises, glucose is transported into the b cells through a special transport molecule.

Ø      GLU T 2 transporter

Ø      Phosphorylated by glucokinase

Ø      Metabolized in the mitochondria

Ø      ATP is generated from ADP

            So high intracellular ATP and low ADP concentration cause ATP dependent K⁺ channel to close. K⁺ acculumate within cell membrane, thereby causing it to depolarize. A voltage dependent Ca⁺⁺ channel opens. Ca moves from extracellular space into b cell cytosol. A rising cytosolic Ca⁺⁺ concentration causes insulin granule to migrate to cell surface, where its contents are released by exocytosis.

            When sulfuonylurea bind to ATP dependent K⁺ channel, it closes. This then causes insulin secretion sulfonylureas therefore potentiates glucose mediated insulin secretion as well as stimulate basal insulin secretion. KATP channels are abundant in both cardiomyocytes and arterial smooth muscle cells. Thus, sufonylurea, which stimulate insulin secretion by binding to pancreatic b cells (KATP) channels, may also bind to KATP channels of cardiomyocytes and vascular smooth muscle cells.

            In response to ischemia, ATP K channels closed and opened to allow K⁺ to be released and Ca⁺⁺ to enter. This causes vasodilatation to occur and improve myocardial function. KATP channels mediate ischemic preconditioning in cardiomyocytes. Ischemic preconditioning is the condition in which exposure of cardiomyocytes to episodes of ischemia induce cellular adaptation that makes these cells resistant to damage during subsequent episodes of ischemia (i.e., delay of lethar cell injury in ischemic cardiomyopathy).

            The second generation sulfonylureas have a shorter duration of action and are increasingly becoming more preferred. Hypoglycemia is the major side effect. Glimepiride binds to different subunits of the sulfonylurea receptor, making its action short enough to prevent unnecessary hypoglycemia.

CONCLUSION:

            All sulfonylurea except glimepride interfere with ischemic preconditioning of heart. Glimepride does not interfere with ischemic preconditioning.

REFERENCE:

            RSSDI Text Book of Diabetes Mellitus