Mechanisms of action

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a-Glucosidase inhibitors are competitive, reversible inhibitors of pancreatic a-amylase and membrane-bound intestinal a-glucosidase hydrolase enzymes that line the brush border of the enterocytes in the proximal portion of the small intestine. These enzymes normally convert dietary polysaccharides into absorbable monosaccharide. Enzyme inhibition delays hydrolysis of polysaccharides, reducing the rate of absorption of monosaccharides, and thereby decreasing the peak of postprandial blood glucose and blunting the plasma insulin response. Clinical use a-Glucosidase inhibitors reduce postprandial glucose excursions and have little effect on FPG concentrations. To exert enzymatic inhibition in the small intestine effectively, acarbose and miglitol are administered immediately prior to or within 15min after the start of each meal.

When used as monotherapy, acarbose and miglitol lower mean postprandial glucose levels by 40-60 mgdL_ 1 and mean FPG levels by 10-20 mg dL_ 1. Mean HbA1C levels are reduced by 0.5-1.0%.66 Acarbose, as combination therapy with sulfonylureas, metformin, and insulin, further reduces HbA1C by 0.3-0.5% and mean postprandial glucose by 25-30mgdL_ 1. Miglitol, in combination with sulfonylureas, reduces mean HbA1C by 0.7% and mean postprandial glucose by 60-70 mgdL_ 1. In individuals with T1DM, acarbose therapy decreases the amplitude of postprandial glycemic excursions and HbA1C values. Side effects/contraindications a-Glucosidase inhibitors are associated with significant gastrointestinal side effects that affect over 50% of individuals. Increased colonic gas production due to fermentation of unabsorbed carbohydrate cause abdominal bloating, cramping, increased flatulence, or diarrhea. Individuals with acute or chronic diseases involving the gastrointestinal tract should not be prescribed a-glucosidase inhibitors. Renal impairment (serum creatinine >2.0 mgdL_ 1) and hepatic dysfunction are contraindications to a-glucosidase inhibitor therapy.

Hypoglycemia in acarbose- or miglitol-treated subjects must be treated with simple carbohydrates found in milk, juices, or glucose tablets. Disaccharides or polysaccharides (sucrose (table sugar), candy, and soft drinks) cannot be used because the a-glucosidase inhibitory effects delay their hydrolysis and absorption. Advantages

When used as monotherapy, acarbose and miglitol are not associated with hypoglycemia or significant weight changes. Blocking the absorption of complex carbohydrates decreases the caloric uptake of the small intestine, but the large intestine compensates to assure that adequate caloric goals are met. a-Glucosidase inhibitors do not significantly affect LDL or HDL cholesterol concentrations, but triglyceride levels decline. These agents may prove to be useful in the management of severe hypertriglyceridemia in both the diabetic and non-diabetic population. Disadvantages

Due to the enteral action of a-glucosidase inhibitors, pharmacological agents that alter the normal gastrointestinal flora may cause increased gastrointestinal side effects, decrease distal colonic absorption of glucose, and decrease overall caloric uptake. a-Glucosidase inhibitors may also affect pharmacologic agents absorbed in the proximal small intestine, such as digoxin and warfarin. Combined use of acarbose, alcohol, and acetaminophen can be fatal and should be avoided. Both acarbose and alcohol enhance the activity of the hepatic isoenzyme CYP2E1, which is responsible for acetaminophen metabolism to a toxic reactive metabolite. Buildup of this metabolite can put persons at risk for acute hepatic injury.

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