Sulfonylureas

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The primary mechanism of action of the sulfonylureas is to stimulate insulin release from pancreatic B cells. Specific receptors on the surface of pancreatic B cells bind sulfonylureas in the rank order of their insulinotropic potency (glyburide with the greatest affinity and tolbutamide with the least affinity). It has been shown that activation of these receptors closes potassium channels, resulting in depolarization of the B cell. This depolarized state permits calcium to enter the cell and actively promote insulin release.

Sulfonylureas are not indicated for use in type 1 diabetes patients since these drugs require functioning pancreatic B cells to produce their effect on blood glucose. These drugs are used in patients with type 2 diabetes, in whom acute administration improves the early phase of insulin release that is refractory to acute glucose stimulation. Sulfonylureas are generally contraindicated in patients with hepatic or renal impairment. Idiosyncratic reactions are rare, with skin rashes or hematologic toxicity (leukopenia, thrombocytopenia) occurring in less than 0.1% of users.

(1) First-generation sulfonylureas (tolbutamide, tolazamide, acetohexamide, chlorpropamide)

Tolbutamide is supplied as 500-mg tablets. It is rapidly oxidized in the liver to inactive metabolites, and its approximate duration of effect is relatively short (6-10 hours). Tolbutamide is probably best administered in divided doses (eg, 500 mg before each meal and at bedtime); however, some patients require only one or two tablets daily with a maximum dose of 3000 mg/d. Because of its short duration of action, which is independent of renal function, tolbutamide is probably the safest sulfonylurea to use if liver function is normal. Prolonged hypoglycemia has been reported rarely with tolbutamide, mostly in patients receiving certain antibacterial sulfonamides (sulfisoxazole), phenylbutazone for arthralgias, or the oral azole antifungal drugs to treat candidiasis. These drugs apparently compete with tolbutamide for oxidative enzyme systems in the liver, resulting in maintenance of high levels of unmetabolized, active sulfonylurea in the circulation.

Tolazamide is supplied in tablets of 100, 250, and 500 mg. It has a longer duration of action than tolbutamide, lasting up to 20 hours, with maximal hypoglycemic effect occurring between the fourth and fourteenth hours. It is often effective, as are other longer-acting sulfonylureas also, when tolbutamide fails to correct prebreakfast hyperglycemia. Tolazamide is metabolized to several compounds that retain hypoglycemic effects. If more than 500 mg/d is required, the dose should be divided and given twice daily. Doses larger than 1000 mg daily do not improve the degree of glycemic control.

Acetohexamide and chlorpropamide are now rarely used. Chlorpropamide has a prolonged biologic effect, and severe hypoglycemia can occur especially in the elderly as their renal clearance declines with aging. Its other side effects include alcohol-induced flushing and hyponatremia due to its effect on vasopressin secretion and action.

(2) Second-generation sulfonylureas (glyburide, glipizide, gliclazide, glimepiride)

Glyburide, glipizide, gliclazide, and glimepiride are 100-200 times more potent than tolbutamide. These drugs should be used with caution in patients with cardiovascular disease or in elderly patients, in whom prolonged hypoglycemia would be especially dangerous.

Glyburide is available in 1.25-mg, 2.5-mg, and 5-mg tablets. The usual starting dose is 2.5 mg/d, and the average maintenance dose is 5-10 mg/d given as a single morning dose; maintenance doses higher than 20 mg/d are not recommended. Some reports suggest that 10 mg is a maximum daily therapeutic dose, with 15-20 mg having no additional benefit in poor responders and doses over 20 mg actually worsening hyperglycemia. Glyburide is metabolized in the liver into products with hypoglycemic activity, which probably explains why assays specific for the unmetabolized compound suggest a plasma half-life of only 1-2 hours, yet the biologic effects of glyburide are clearly persistent 24 hours after a single morning dose in diabetic patients. Glyburide is unique among sulfonylureas in that it not only binds to the pancreatic B cell membrane sulfonylurea receptor but also becomes sequestered within the B cell. This may also contribute to its prolonged biologic effect despite its relatively short circulating half-life. A "Press Tab" formulation of "micronized" glyburide-easy to divide in half with slight pressure if necessary-is available in tablet sizes of 1.5 mg, 3 mg, and 6 mg.

Glyburide has few adverse effects other than its potential for causing hypoglycemia, which at times can be prolonged. Flushing has rarely been reported after ethanol ingestion. It does not cause water retention, as chlorpropamide does, but rather slightly enhances free water clearance. Glyburide is absolutely contraindicated in the presence of hepatic impairment and should not be used in patients with renal insufficiency, in elderly patients, or in those who would be put at serious risk from an episode of hypoglycemia.

Glipizide is available in 5-mg and 10-mg tablets. For maximum effect in reducing postprandial hyperglycemia, this agent should be ingested 30 minutes before meals, since rapid absorption is delayed when the drug is taken with food. The recommended starting dose is 5 mg/d, with up to 15 mg/d given as a single daily dose before breakfast. When higher daily doses are required, they should be divided and given before meals. The maximum dose recommended by the manufacturer is 40 mg/d, although doses above 10-15 mg probably provide little additional benefit in poor responders and may even be less effective than smaller doses.

At least 90% of glipizide is metabolized in the liver to inactive products, and 10% is excreted unchanged in the urine. Glipizide therapy is therefore contraindicated in patients with hepatic or renal impairment, who would be at high risk for hypoglycemia; but because of its lower potency and shorter duration of action, it is preferable to glyburide in elderly patients. Glipizide has also been marketed as Glucotrol-XL in 5-mg and 10-mg tablets. It provides extended release during transit through the gastrointestinal tract with greater effectiveness in lowering prebreakfast hyperglycemia than the shorter-duration immediate-release standard glipizide tablets. However, this formulation appears to have sacrificed its lower propensity for severe hypoglycemia compared with longer-acting glyburide without showing any demonstrable therapeutic advantages over glyburide.

Gliclazide (not available in the United States) is another intermediate duration sulfonylurea with a duration of action of about 12 hours. It is available as 80 mg tablets. The recommended starting dose is 40-80 mg/d with a maximum dose of 320 mg. Doses of 160 mg and above are given as divided doses before breakfast and dinner. The drug is metabolized by the liver; the metabolites and conjugates have no hypoglycemic effect. An extended release preparation is available.

Glimepiride is given once daily as monotherapy or in combination with insulin to lower blood glucose in diabetes patients who cannot control their glucose level through diet and exercise. Glimepiride achieves blood glucose lowering with the lowest dose of any sulfonylurea compound, and this tends to increase its cost-effectiveness. A single daily dose of 1 mg/d has been shown to be effective, and the maximal recommended dose is 8 mg. It has a long duration of action with a pharmacodynamic half-life of 5 hours, allowing once-daily administration, which improves compliance. It is completely metabolized by the liver to relatively inactive metabolic products.