Glipizide Glucotrol

Ball-and-Stick Model

Ball-and-Stick Model

Space-filling Model

9 = Carbon = Hydrogen ^ = Oxygen ^ = Nitrogen = Sulfur

Year of discovery: ca. late 1970s; Year of introduction: 1984 (Pfizer); Drug category: Potassium channel blocker in pancreas beta cells (ß-cells)/sulfonylurea class (sulfonylurea functional group is highlighted in red in the structures); Main uses: For treatment of type 2 diabetes; Related drugs: Tolazamide (Orinase), Tolbutamide (Tolinase), Glibenclamide (Glynase), Glimepiride (Amaryl).

The various medicines for type 2 diabetes take advantage of several different mechanisms of action (see metformin, sitagliptin phosphate and pioglitazone). The class of drugs known as sulfonylureas works by stimulating insulin secretion in pancreatic ¡3-cells. This beneficial activity of sulfonylureas was discovered in 1942 by Marcel Janbon and coworkers who observed that these compounds lower blood glucose levels in experimental animals.1

Glipizide, a second generation sulfonylurea which is currently an important treatment of type 2 diabetes, has been widely used since it entered the market in the 1980s under the trade name of Glucotrol. Glipizide and other sulfonylureas bind, to ATP-sensitive potassium ion (K+) channels traversing the membranes of p-cells and partially block these channels. Changes in the electric potential of the cell result and voltage-gated calcium ion (Ca2+) channels open, allowing Ca2+ ions into the cell. The higher levels of Ca2+ in pancreatic (3-cells stimulate insulin production and increase the secretion of insulin.

Ion channels are essential to mammalian life. They allow precise control of the levels of critical ions such as sodium (Na+), potassium (K+) and calcium (Ca2+) in cells. Each ion flows through ion channels embedded in the cell membrane that are selective for it. Potassium channels are ubiquitous in cells and control a variety of cell functions (e.g., the shape of action potential in neurons, the duration of action potential in heart muscle, and the secretion of hormones). Potassium channel malfunction adversely effects the production of the hormone insulin by the p-cells of the pancreas. Lowered insulin levels result in elevated blood glucose levels and eventually in type 2 diabetes.2

Recent research suggests that in addition to increasing insulin production (which falls off with prolonged use), sulfonylureas also sensitize p-cells to glucose, limit excess glucose production in the liver and decrease metabolism of insulin in the liver. It has also been reported that sulfonylureas increase the levels of the protein which transports glucose into cells.

Glipizide can be used as a monotherapy or, at lower doses, in combination with other diabetes medications such as biguanides and thiazolidinediones. Side effects of glipizide include weight gain (which also can occur with insulin administration and various other antidiabetic therapies) and hypoglycemia (dangerously low concentration of blood glucose). Thus, the dose must be carefully chosen.3 Profound or long-lasting hypoglycemia can produce permanent nerve damage and even death.

Glimepiride (Amaryl™, Sanofi Aventis), a third-generation sulfonylurea, was introduced in 1995. It is advantageous for those with impaired liver or kidney function.

Glimepiride (Amaryl™)

1. Drugs 2004, 64, 1339-1358; 2. Lancet 2005, 365, 13331346; 3. British Journal of Diabetes & Vascular Disease 2006, 6, 159-165; Refs. p. 82

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