Sulfonylureas are still the mainstay of oral antidiabetic therapy, in type-2 diabetes since the early 1950s. Sulfonylureas are of first generation (Chlorpropamide, Tolbutamide, Tolazamide etc.) and second generation (Glimepiride, Glipizide, Glyburide, Glibenclamide).

Sulfonylureas are most effective in individuals with type-2 diabetes of relatively recent onset (i.e. less than 5 years) with good residual endogenous insulin production. First generation sulfonylureas are similar in potency (at maximum doses,) to second-generation agents but have a longer half-life, a greater incidence of hypoglycemia, and more frequent drug interactions, so second-generation sulfonylureas are generally preferred. Second generation sulfonylureas have advantage of more rapid onset of action and better coverage of the postprandial glucose rise, although have shorter half-life and requires more than once-a-day dosing.

Sulfonylureas reduce both fasting as well as postprandial blood glucose. They should be started at low doses and increased at 1-2 weeks intervals based on self monitored blood glucose result. As sulfonylureas cause acute rise in insulin level, they should be taken 15-20 minutes before meal to prevent possible hypoglycemia. But on long term (chronic) use the insulin release by sulfonylureas is more sustained.

Mechanism of action of sulfonylureas:

Sulfonylureas cause brisk release of insulin from pancreas (insulin is present inside granules in pancreatic beta-cells). Sulfonylureas cause augmentation of insulin release in second phase of insulin release and have little or no effect on the first phase of insulin release. Sulfonylureas act on the “sulfonylurea receptors” (SUR1) which are present pancreatic beta-cell membrane. By acting on sulfonylurea receptors they reduce conductance of ATP (adenosine triphosphate) sensitive K⁺ channels and cause depolarization. Due to depolarization influx of Ca²⁺ increases which cause degranulation of insulin granules and release of insulin.

Sulfonylureas cause increase insulin secretion at any glucose level. Sulfonylureas can not increase insulin secretion in animal models if pancreas is removed. At least 30% of functional beta-cells are required for sulfonylureas to act. In type-2 diabetes the insulin release in response to glucose or meals is subdued or delayed, which can be overcome by sulfonylureas.

Side effects of sulfonylureas:

The incidence of side effects of sulfonylureas is low (3-7%). Side effects of sulfonylureas are hypoglycemia, hypersensitivity and non specific side effects.

Hypoglycemia:

Hypoglycemia is the commonest side effect of sulfonylureas. Sometimes hypoglycemia may be severe and very rarely it can be fatal. Hypoglycemia is more common among elderly type-2 diabetes patients, if patient has associated liver or kidney disease, or if any drug is added which can also cause hypoglycemia. Hypoglycemia is more common with chlorpropamide due to its long duration of action and less common with other short and medium acting sulfonylureas such as Glimepiride, Glibenclamide Glipizide etc.

Hypoglycemia should be treated with oral glucose, which should be given for few days as hypoglycemia may recur.

Hypersensitivity:

Photosensitivity, rashes, transient leucopenia etc. are some hypersensitivity reactions that can occur with sulfonylureas. Agranulocytosis is a rare problem.

Non specific side effects:

They include headache, nausea, vomiting, diarrhea or constipation, flatulence, weight gain etc.

Sulfonylureas and pregnancy:

The safety of sulfonylureas during pregnancy is not yet established and should not be given during pregnancy. During pregnancy type-2 diabetes patients should be switched over to insulin therapy. Sulfonylureas should not be given to nursing mothers as it is secreted in breast milk.

Medications that reduce action of sulfonylureas:

Rifampin (antitubercular antibiotic), phenobarbitone, phenytoin, ethyl alcohol etc. induce metabolism of sulfonylureas and reduce the action.

Corticosteroids, thiazides, furosemide, oral contraceptives etc. opposes the action of sulfonylureas or suppress insulin release.

Medication that increase action of sulfonylureas:

Phenylbutazone, salicylates, sulfonamides, sulfinpyrazone, PAS etc. displace sulfonylureas from protein binding sites and increase free level and potentiate action of sulfonylureas.

Cimetidine, warfarin, sulfonamides, alcohol, chloramphenicol etc. inhibit metabolism or excretion of sulfonylureas.

Salicylates, propranolol, alcohol, lithium, theophyllin etc. have synergistic action with sulfonylureas.