sulfonylurea

**Classes/Examples** - First generation: tolbutamide, chlorpropamide, tolazamide (rarely used now). - Second generation: glipizide, glyburide (glibenclamide), glimepiride (more potent, fewer side effects).

**Mechanism of action** - Bind the sulfonylurea receptor 1 (SUR1) on the K-ATP channel (Kir6.2 + SUR1) of pancreatic beta cells, which closes the channel. - Closing the channel causes membrane depolarization, opening of voltage-gated Ca2+ channels, Ca2+ influx, and insulin exocytosis. - This is an insulin secretagogue effect that is independent of glucose, so it increases insulin even when glucose is low. - It requires functional beta cells, so it is ineffective in type 1 DM. - Mnemonic: they "close the K channel", which is the same step that high glucose normally triggers. Meglitinides (repaglinide, nateglinide) act at the same channel but at a different site, with shorter action and a postprandial effect.

**Clinical use** - Type 2 diabetes mellitus, as an add-on to or alternative to metformin (cheap, effective at lowering HbA1c by about 1-1.5%). - Neonatal diabetes caused by activating Kir6.2/ABCC8 mutations (K-ATP channel mutations) can be treated with high-dose sulfonylureas instead of insulin. - Current ADA guidance favors SGLT2 inhibitors and GLP-1 agonists for patients with ASCVD, HF, or CKD. Sulfonylureas are lower-cost alternatives.

**Adverse effects (high yield)** - **Hypoglycemia**: most important. Risk is highest with long-acting agents (glyburide, chlorpropamide), renal impairment (reduced clearance of active metabolites), elderly patients, skipped meals, and alcohol. Glipizide is preferred in CKD and the elderly. Management is glucose, and for refractory cases, octreotide (inhibits insulin secretion). - **Weight gain** (from hyperinsulinemia). - **Disulfiram-like reaction** with alcohol (first-generation, especially chlorpropamide). - **SIADH/hyponatremia** (chlorpropamide, which potentiates ADH). - **Hemolytic anemia** in G6PD deficiency (sulfa moiety), and rare cross-reactivity with sulfonamide allergy (low). - Cholestatic jaundice and rash (rare), and possible increased CV mortality concerns with older agents (UGDP trial), now mostly unsupported for newer agents. - Contraindicated or used with caution in pregnancy (glyburide sometimes used in gestational DM, though insulin is preferred) and in severe hepatic or renal disease.

**Pharmacology pearls** - Hepatic metabolism, with renal excretion of metabolites (glyburide has active metabolites, so accumulation is a risk in CKD). - Drug interactions that increase hypoglycemia: beta-blockers (mask adrenergic symptoms), sulfonamide antibiotics and fluconazole (CYP2C9 inhibition), and warfarin competition for protein binding. - A frequent boards comparison is with metformin (does not cause hypoglycemia or weight gain, causes lactic acidosis), and with thiazolidinediones (PPAR-gamma, fluid retention).