What are the pharmacokinetic properties and adverse effects of acarbose?

Pharmacokinetics and Side Effects of Acarbose

Pharmacokinetic Properties

Acarbose has minimal systemic absorption with less than 2% of an oral dose absorbed as active drug, which is therapeutically ideal since it acts locally within the gastrointestinal tract. 1

Absorption and Distribution

• Peak plasma concentrations of active acarbose occur at approximately 1 hour after oral administration 1
• Approximately 35% of total radioactivity from a labeled dose is absorbed, representing metabolites rather than parent drug 1
• The low systemic bioavailability (< 2%) is intentional, as acarbose exerts its therapeutic effect exclusively within the intestinal lumen 1, 2
• Acarbose does not cross enterocytes and remains in the gastrointestinal tract 2

Metabolism

• Acarbose is metabolized exclusively within the gastrointestinal tract by intestinal bacteria and digestive enzymes 1
• At least 13 metabolites have been identified, with the major ones being 4-methylpyrogallol derivatives (sulfate, methyl, and glucuronide conjugates) 1
• Approximately 34% of metabolites are absorbed and subsequently excreted in urine 1
• One metabolite formed by cleavage of a glucose molecule retains alpha-glucosidase inhibitory activity 1

Excretion and Half-Life

• The plasma elimination half-life is approximately 2 hours in healthy volunteers, preventing drug accumulation with three-times-daily dosing 1
• When given intravenously, 89% is recovered in urine within 48 hours 1
• An average of 51% of an oral dose is excreted in feces as unabsorbed drug within 96 hours 1

Special Populations

• Elderly patients: Mean steady-state AUC and maximum concentrations are approximately 1.5 times higher than in young volunteers, though not statistically significant 1
• Severe renal impairment (CrCl < 25 mL/min/1.73m²): Patients attain 5 times higher peak plasma concentrations and 6 times larger AUCs compared to those with normal renal function 1
• Race: Reductions in glycosylated hemoglobin were similar in Caucasians and African-Americans, with a trend toward better response in Latinos 1

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Mechanism of Action

Acarbose competitively and reversibly inhibits pancreatic alpha-amylase and membrane-bound intestinal alpha-glucosidase hydrolase enzymes, delaying carbohydrate digestion and reducing postprandial glucose excursions without stimulating insulin secretion. 1, 3

• Pancreatic alpha-amylase hydrolyzes complex starches to oligosaccharides in the small intestine lumen 1
• Intestinal alpha-glucosidases break down oligosaccharides, trisaccharides, and disaccharides into glucose and other monosaccharides at the brush border 1
• The inhibition results in delayed glucose absorption and lowering of postprandial hyperglycemia 1
• Acarbose has no inhibitory activity against lactase and does not induce lactose intolerance 1

Metabolic Effects

• Reduces postprandial hyperglycemia by delaying glucose absorption, resulting in a smaller and delayed rise in blood glucose following meals 3
• Decreases the hyperinsulinemic response that typically follows carbohydrate-rich meals 3
• Prevents reactive hypoglycemia by preventing the initial hyperglycemic spike, particularly beneficial in dumping syndrome and post-bariatric hypoglycemia 3, 4
• Reduces gastric inhibitory polypeptide (GIP) secretion and decreases glucagon-like peptide-1 (GLP-1) release, lowering postprandial insulin secretion 3

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Adverse Effects

Gastrointestinal Side Effects (Most Common)

The most frequent adverse effects are gastrointestinal symptoms—abdominal pain (19%), diarrhea (31%), and flatulence (74%)—which are a direct manifestation of acarbose's mechanism of action and typically diminish over time. 1

• In U.S. placebo-controlled trials with 1,255 patients on acarbose 50-300 mg three times daily, gastrointestinal symptoms occurred at substantially higher rates than placebo (abdominal pain 9%, diarrhea 12%, flatulence 29%) 1
• Clinical trials show that 25-45% of participants discontinued alpha-glucosidase inhibitor use specifically due to gastrointestinal side effects 5
• These symptoms result from increased delivery of undigested carbohydrate to the colon, causing gas production 5
• In one-year safety studies, abdominal pain and diarrhea tended to return to pretreatment levels over time, and flatulence frequency and intensity abated with continued use 1

Critical Management Strategy: Starting with a low dose (25 mg once daily) and gradually titrating upward over 1-2 weeks significantly reduces gastrointestinal adverse effects 5, 6

Hepatic Effects

• Elevated serum transaminase levels have been reported 1
• Rare postmarketing reports include fulminant hepatitis with fatal outcome, jaundice and/or hepatitis with associated liver damage 1
• Regular monitoring of liver function is warranted, particularly during the first year of therapy 1

Hematologic and Metabolic Effects

• Small reductions in hematocrit occurred more often with acarbose than placebo but were not associated with reductions in hemoglobin 1
• Low serum calcium and low plasma vitamin B6 levels were associated with acarbose therapy but are thought to be either spurious or of no clinical significance 1
• Rare thrombocytopenia has been reported 1

Serious but Rare Adverse Events

• Pneumatosis cystoides intestinalis: Rare postmarketing reports exist, presenting with diarrhea, mucus discharge, rectal bleeding, and constipation 1
• Complications may include pneumoperitoneum, volvulus, intestinal obstruction, intussusception, intestinal hemorrhage, and intestinal perforation 1
• If suspected, discontinue acarbose immediately and perform appropriate diagnostic imaging 1
• Other rare events include hypersensitive skin reactions (rash, erythema, exanthema, urticaria), edema, and ileus/subileus 1

Hypoglycemia Risk

• Acarbose does not cause hypoglycemia when used as monotherapy 5, 1
• When combined with sulfonylureas or insulin, the risk of hypoglycemia increases and requires dose adjustments of concomitant agents 5, 1
• Critical treatment consideration: If hypoglycemia occurs in patients taking acarbose, treatment must use glucose tablets or honey—not sucrose or complex carbohydrates—because acarbose blocks the breakdown of these substances 4, 5

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Drug Interactions

Acarbose has minimal systemic drug interactions due to its local gastrointestinal action and negligible systemic absorption. 1

• No effect on the pharmacokinetics or pharmacodynamics of nifedipine, propranolol, or ranitidine 1
• Does not interfere with the absorption or disposition of glyburide in diabetic patients 1
• May affect the bioavailability of metformin 6
• May be less effective when used with intestinal adsorbents and digestive enzyme preparations 6

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Clinical Efficacy

• Lowers HbA1c by approximately 0.5-1.0% as monotherapy 5, 7
• In Asian patient cohorts, acarbose 300 mg daily provides glucose-lowering efficacy comparable to metformin 1500 mg daily 5
• Reduces the incidence of newly diagnosed diabetes by 36.4% in patients with impaired glucose tolerance 8
• Provides additive glycemic control when combined with sulfonylureas, insulin, or metformin 1
• Does not cause weight gain; modest weight loss has been reported 5