tolbutamide

Tolbutamide is a first-generation oral hypoglycemic agent in the sulfonylurea class, used to improve glycemic control in adults with type 2 diabetes mellitus when diet and exercise alone are insufficient. It was introduced in 1957 by Searle and marketed as Orinase, becoming one of the earliest sulfonylureas used in clinical practice.

Mechanism of action: Tolbutamide binds to the sulfonylurea receptor on pancreatic beta cells and inhibits the ATP-sensitive potassium channel, causing cell membrane depolarization and calcium influx that leads to the release of insulin. The effect depends on residual beta-cell function and tends to be reduced as diabetes progresses.

Pharmacokinetics: Tolbutamide is orally active with rapid absorption. Onset is typically within 30 minutes to an hour, and the duration of action is variable and generally shorter than that of later-generation sulfonylureas. It is largely metabolized in the liver and excreted in the urine, with individual half-life influenced by liver and kidney function.

Safety and contraindications: The major adverse effect is hypoglycemia, especially in older patients or those with renal or hepatic impairment or irregular meals. Weight gain is common. It is contraindicated in type 1 diabetes and diabetic ketoacidosis, and caution is advised during pregnancy. Drug interactions can modify hypoglycemic risk, including concomitant use of alcohol or other antidiabetic agents.

Status and legacy: As a first-generation sulfonylurea, tolbutamide has largely been supplanted by newer agents with more favorable pharmacokinetics and safety profiles, but it remains referenced in medical literature and is notable in the historical development of sulfonylurea therapy.