Glucotrol (glipizide)

Glipizide 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 glipizide, initially appear to lower blood glucose concentration principally by binding to the sulfonylurea receptor in the pancreatic beta cell plasma membrane, leading to closure of the ATP-sensitive potassium channel and stimulating the release of insulin. Glipizide also appears to enhance peripheral insulin action at postreceptor (probably intracellular) site(s) during short-term therapy. Like other sulfonylureas, glipizide alone is ineffective in the absence of functioning beta cells.

The glipizide-induced increase in glucose- or meal-stimulated secretion of endogenous insulin appears to be sustained during prolonged administration and has persisted in most diabetic patients for up to at least 2 years. The prolonged effect of glipizide on secretion of endogenous insulin is unlike that of most other sulfonylureas, but its clinical importance in the long-term efficacy of the drug remains to be clearly determined; while this effect likely contributes to the improvement in glucose tolerance in many patients during prolonged glipizide therapy, it alone does not appear to be sufficient for a long-term, effective response to the drug and glucose tolerance can improve in some patients without an increase in insulin secretion. Fasting plasma insulin concentrations are usually not increased during prolonged glipizide therapy but have been reported to be slightly increased in some patients.

The drug generally does not appear to alter glucagon secretion. During prolonged administration of sulfonylureas, including glipizide, 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 glipizide enhances the peripheral action of insulin at postreceptor (probably intracellular) site(s) during long-term administration, and this appears to be a principal mechanism of action during prolonged therapy. An increase in insulin binding in erythrocytes obtained from diabetic patients receiving long-term therapy with the drug has also been reported. On a weight basis, glipizide is one of the most potent of the sulfonylurea antidiabetic agents; although an exact dosage relationship does not exist, a daily glipizide dose of 5 mg controls blood glucose concentration to approximately the same degree as daily doses of glyburide 2.5-5 mg.

Glipizide is rapidly and essentially completely absorbed from the GI tract. First-pass metabolism of glipizide appears to be minimal, and the absolute oral bioavailability of the drug is reported to be 80-100%. Food delays the absorption of glipizide but does not affect peak serum concentrations achieved or the extent of absorption of the drug.

Following oral administration of a single 5-mg dose of glipizide as conventional (immediate-release) tablets in fasting and nonfasting individuals, the drug appears in plasma within 15-30 minutes and average peak plasma concentrations are attained within 1-3 hours (range: 1-6 hours). Peak serum concentrations generally are delayed 20-40 minutes in the nonfasting state compared with the fasting state. A few reports indicate that biphasic peak serum concentrations may occur in some patients, suggesting that the drug may undergo enterohepatic circulation.

The AUC for glipizide increases in proportion to increasing doses. Following single oral doses in fasting healthy individuals, the hypoglycemic action of glipizide generally begins within 15-30 minutes and is maximal within 1-2 hours. In nonfasting diabetic patients, the hypoglycemic action of a single morning dose of the drug may persist for up to 24 hours.

Distribution of glipizide into human body tissues and fluids has not been fully characterized. In humans, small amounts of glipizide are apparently distributed into bile and very small amounts are distributed into erythrocytes and saliva. It is not known if glipizide is distributed into milk in humans.

Glipizide is approximately 92-99% bound to plasma proteins. Unlike the protein binding of some other sulfonylurea antidiabetic agents and like that of glyburide, the protein binding of glipizide appears to be principally nonionic; consequently, glipizide 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. Following oral administration in healthy individuals or diabetic patients with normal renal and hepatic function, the terminal elimination half-life of glipizide averages 3-4.7 hours (range: 2-7.3 hours).

The terminal elimination half-life of total glipizide metabolites reportedly ranges from 2-6 hours in patients with normal renal and hepatic function. Serum glipizide concentrations may be increased in patients with renal or hepatic insufficiency. The terminal elimination half-life of total glipizide metabolites may be prolonged to greater than 20 hours in patients with impaired renal function; however, since glipizide metabolites are considered essentially inactive, this is probably of little clinical importance, at least in patients with moderate renal impairment.

Glipizide is almost completely metabolized, mainly in the liver. The drug is metabolized principally at the cyclohexyl ring to 4-trans-hydroxyglipizide; the drug is also metabolized to the 3-cis-hydroxy derivative, N-(2-acetylaminoethylphenylsulfonyl)-N'-cyclohexyl urea (DCDA), and at least 2 unidentified metabolites. There is no information regarding the effects of hepatic impairment on the disposition of glipizide.

However, since glipizide is highly protein bound and hepatic biotransformation is the predominant route of elimination, the pharmacokinetics and/or pharmacodynamics of glipizide may be altered in patients with hepatic impairment. Glipizide and its metabolites are excreted principally in urine. The drug and its metabolites are also excreted in feces, apparently 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 glipizide in individuals with normal renal and hepatic function, approximately 60-90% of the dose is excreted in urine as unchanged drug and metabolites within 24-72 hours and about 5-20% is excreted in feces within 24-96 hours; less than 10% of a dose is excreted in urine as unchanged drug within 24 hours, about 20-60% as the 4-trans-hydroxy metabolite, 10-15% as the 3-cis-hydroxy metabolite, 1-2% as DCDA, and the remainder as unidentified metabolites. The effects have not been fully evaluated, but elimination of glipizide may be reduced in patients with impaired renal and/or hepatic function.

Limited data indicate that renal excretion and terminal elimination half-life of glipizide metabolites are substantially decreased and increased, respectively, in patients with severe renal impairment. Following single-dose administration in older diabetic patients, there were no differences in glipizide pharmacokinetics compared with that in younger healthy individuals.

USES: Glipizide 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. Glipizide 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: glipizide
Pronunciation: (GLIP-i-zide)

The following indications are listed for Glucotrol:

• 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.