Glyburide (glyburide)

Glyburide is a sulfonylurea antidiabetic agent.

The precise mechanism(s) of hypoglycemic action of sulfonylurea antidiabetic agents has not been clearly established, but the drugs, including glyburide, initially appear to lower blood glucose concentration principally by stimulating secretion of endogenous insulin from the beta cells of the pancreas. Sulfonylureas bind to the sulfonylurea receptor in the pancreatic beta-cell plasma membrane, leading to closure of the ATP-sensitive potassium channel, thereby stimulating the release of insulin. Other mechanisms of the hypoglycemic action associated with short-term glyburide therapy appear to include reduction of basal hepatic glucose production and enhancement of peripheral insulin action at postreceptor (probably intracellular) site(s).

Following short-term administration of glyburide, an increase in insulin binding has been demonstrated in monocytes obtained from healthy individuals, but not in adipocytes obtained from diabetic patients. Like other sulfonylureas, glyburide alone is ineffective in the absence of functioning beta cells. On a weight basis, glyburide is one of the most potent of the sulfonylurea antidiabetic agents; although an exact dosage relationship does not exist, a daily glyburide dosage of 5 mg controls blood glucose concentration to approximately the same degree as daily dosages of glipizide 5-10 mg.

The mechanism(s) of action of glyburide during prolonged administration has not been fully established. Glyburide-induced improvement in glucose tolerance during long-term therapy persists despite a gradual decline in glucose- or meal-stimulated secretion of endogenous insulin towards pretreatment levels. During prolonged administration of sulfonylureas, including glyburide, extrapancreatic effects appear to substantially contribute to the hypoglycemic action of the drugs.

Many extrapancreatic effects of the drugs have been proposed and/or studied, but the principal effects appear to include enhanced peripheral sensitivity to insulin and reduction of basal hepatic glucose production; however, the nature of the long-term hypoglycemic effect and the mechanism(s) involved remain to be fully elucidated. There is evidence that glyburide enhances the peripheral action of insulin at postreceptor (probably intracellular) site(s) and reduces basal hepatic glucose production during long-term administration. An increase in insulin binding and/or number of insulin receptors has also been demonstrated in monocytes and adipocytes obtained from diabetic patients receiving long-term therapy with the drug.

Glyburide produces a mild diuresis by enhancing renal free water clearance. The diuretic effect has been demonstrated in healthy individuals, diabetic patients, and patients with neurohypophyseal diabetes insipidus; the drug apparently has no diuretic effect in patients with nephrogenic diabetes insipidus. The exact mechanism by which glyburide enhances renal free water clearance is not known.

The diuretic action apparently is not mediated through an effect on the release of vasopressin (antidiuretic hormone) from the posterior pituitary or on the action of vasopressin at the renal collecting ducts. It has been suggested that glyburide inhibits reabsorption of sodium in the proximal renal tubule or nonvasopressin-dependent reabsorption of water in the distal renal tubule.

Currently available tablet formulations of glyburide appear to be reliably and almost completely absorbed following oral administration. Bioavailability studies have demonstrated that micronized glyburide and nonmicronized (conventional) glyburide tablets are not bioequivalent; therefore, patients switching from micronized to nonmicronized tablets or vice versa should have their dosage retitrated. Food apparently does not affect the rate or extent of absorption of glyburide.

Following oral administration of a single 5-mg dose of glyburide, the drug appears in plasma or serum within 15-60 minutes and peak plasma concentrations are attained within 2-4 hours (range: 2-8 hours). The AUC for glyburide increases in proportion to increasing doses. Substantial interindividual variations in steady-state serum concentration have been reported in diabetic patients receiving the same dosage of glyburide.

Following single oral doses of glyburide in nonfasting diabetic or healthy individuals, plasma insulin concentration generally begins to increase within 15-60 minutes and is maximal within 1-2 hours; in diabetic patients, increases in plasma insulin concentration may persist for up to 24 hours. Following single oral doses of the drug in fasting healthy individuals, the degree and duration of lowering of blood glucose concentration are proportional to the dose administered and the AUC; the hypoglycemic action generally begins within 45-60 minutes and is maximal within 1.5-3 hours. In nonfasting diabetic patients, the hypoglycemic action of a single morning dose of glyburide may persist for up to 24 hours.

Distribution of glyburide into human body tissues and fluids has not been fully characterized. Following oral or IV administration in animals, highest concentrations of the drug are attained in the liver, kidneys, and small and large intestines, with lower concentrations in the stomach, pancreas, spleen, mesenteric lymph nodes, mesenteric and retroperitoneal fat, heart, lungs, gonads, skeletal muscle, and brain. In humans, glyburide is distributed in substantial amounts into bile.

Glyburide appears to cross the placenta, since prolonged hypoglycemia has occurred in neonates born to women who received the drug up to the time of delivery. It is not known if the drug is distributed into human milk. Glyburide is more than 99% bound to serum proteins and its major metabolite, 4-trans-hydroxyglyburide, is more than 97% bound to serum proteins.

Glyburide has a higher affinity for binding to serum albumin than does glipizide. The protein binding of glyburide is principally nonionic; consequently, glyburide may be less likely to be displaced from binding sites by, or displace from binding sites, other highly protein-bound drugs whose protein binding is ionic in nature.

Serum concentrations of glyburide appear to decline in a biphasic manner. In studies in healthy adults using assays relatively specific for unchanged glyburide, the terminal elimination half-life has reportedly averaged 1.4-1.8 hours (range: 0.7-3 hours); when assays that also measured metabolites of the drug were used, the terminal elimination half-life has averaged about 10 hours (range: 5-26 hours). Serum glyburide concentrations may be increased in patients with renal or hepatic insufficiency.

Data are limited, but the half-life may be prolonged in patients with severe renal impairment. In one study in patients with normal hepatic function and impaired renal function given a single oral dose of radiolabeled glyburide, the plasma half-life of total radioactivity was 2-5 hours in those with creatinine clearances of 29-131 mL/minute per 1.73 m2 and 11 hours in one patient with a creatinine clearance of 5 mL/minute per 1.73 m2; in those patients with creatinine clearances of 29-131 mL/minute per 1.73 m2, no relationship between plasma half-life and creatinine clearance was observed.

Glyburide appears to be completely metabolized, probably in the liver. The drug is metabolized at the cyclohexyl ring principally to-hydroxyglyburidetrans4-; the 4-trans-hydroxy metabolite has only 0.25% of the hypoglycemic activity of glyburide following oral administration in rabbits, but has about 15% of the hypoglycemic activity of the parent compound following intraperitoneal administration in rats. Glyburide is also metabolized to the 3-cis-hydroxy derivative and to another unidentified metabolite; the 3-cis-hydroxy metabolite has 2.5% of the hypoglycemic activity of glyburide following oral administration in rabbits.

The hypoglycemic activity of glyburide metabolites is generally considered clinically unimportant; however, results of studies in rats indicate that retention of the 4-trans-hydroxy metabolite in the presence of renal insufficiency may enhance and prolong the hypoglycemic effect of the drug.

Unlike other currently available sulfonylurea antidiabetic agents which are excreted principally in urine, glyburide is excreted as metabolites in urine and feces in approximately equal proportions. Fecal excretion appears to occur almost completely via biliary elimination; only small amounts may be excreted in feces as unabsorbed drug following oral administration. Most urinary excretion occurs within the first 6-24 hours after oral administration of the drug.

Following oral administration of a single 5-mg dose of glyburide in healthy individuals, approximately 30-50% of the dose is excreted in urine as metabolites within 24 hours; about 80% of the urinary excretion occurs as the 4-trans-hydroxy metabolite, 15% as the 3-cis-hydroxy metabolite, and 5% as an unidentified metabolite. Fecal excretion occurs more slowly, but a single oral dose of the drug is completely excreted in urine and feces within 3-5 days in healthy individuals.

The effects of renal impairment on the elimination of glyburide and its metabolites have not been fully evaluated. Limited data indicate that renal excretion of glyburide metabolites and plasma clearance of glyburide may be substantially decreased in patients with severe renal impairment. Glyburide appears to be only minimally removed by hemodialysis.

USES: Glyburide is used with a proper diet and exercise program to control high blood sugar in people with type 2 diabetes. It may also be used with other diabetes medications. Controlling high blood sugar helps prevent kidney damage, blindness, nerve problems, loss of limbs, and sexual function problems.

Proper control of diabetes may also lessen your risk of a heart attack or stroke. Glyburide belongs to the class of drugs known as sulfonylureas. It lowers blood sugar by causing the release of your body's natural insulin.

Generic name: glyburide
Pronunciation: (GLYE-bure-ide)

The following indications are listed for Glyburide:

• Type 2 Diabetes Mellitus

Also known as: Adult Onset Diabetes, Adult Onset Diabetes Mellitus, Adult Onset Dm, Diabetes Mellitus Type 2, Diabetes Mellitus Type Ii, Ketosis-Resistant Diabetes Mellitus, Ketosis-Resistant Dm, Maturity Onset Diabetes, Maturity Onset Diabetes Mellitus, Non-Insulin Dependent Diabetes Mellitus, Non-Insulin-Dependent Diabetes Mellitus, Type Ii Diabetes Mellitus.

No ICD codes are available for this drug.