ACETOHEXAMIDE
Clinical safety rating: caution
Comprehensive clinical and safety monograph for ACETOHEXAMIDE (ACETOHEXAMIDE).
Sulfonylurea that stimulates insulin release from pancreatic beta cells by binding to the sulfonylurea receptor (SUR1) on ATP-sensitive potassium channels (K_ATP), causing membrane depolarization, calcium influx, and exocytosis of insulin-containing granules. Also may increase peripheral insulin sensitivity.
| Metabolism | Primarily hepatic metabolism via reduction of the ketone group to hydroxyhexamide, which has weak hypoglycemic activity. Metabolites are excreted renally. |
| Excretion | Renal: 85-90% (60-70% as unchanged drug, remainder as hydroxylated metabolite); biliary/fecal: <10% |
| Half-life | Terminal elimination half-life: 6-12 hours (parent drug); ~5-6 hours (active metabolite hydroxyhexamide); clinical context: prolonged in renal impairment due to accumulation of active metabolite |
| Protein binding | 70-90% (bound primarily to albumin) |
| Volume of Distribution | 0.2-0.35 L/kg (relatively small, consistent with low tissue distribution) |
| Bioavailability | Oral: 80-90% (well absorbed, minimal first-pass metabolism) |
| Onset of Action | Oral: 1-2 hours (reduction in blood glucose begins) |
| Duration of Action | 12-24 hours (depending on dose and renal function); note: active metabolite contributes to prolonged effect |
Initial: 250 mg orally once daily; maintenance: 250-1500 mg orally once daily or in divided doses twice daily.
| Dosage form | TABLET |
| Renal impairment | GFR 50-80 mL/min: no adjustment; GFR 10-50 mL/min: reduce dose by 50%; GFR <10 mL/min: contraindicated. |
| Liver impairment | Child-Pugh Class A: no adjustment; Child-Pugh Class B: use with caution, reduce dose by 50%; Child-Pugh Class C: contraindicated. |
| Pediatric use | Not recommended for use in pediatric patients due to lack of safety and efficacy data. |
| Geriatric use | Start with lowest dose (250 mg orally once daily) due to increased risk of hypoglycemia; monitor renal function closely. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for ACETOHEXAMIDE (ACETOHEXAMIDE).
| Breastfeeding | Acetohexamide is excreted into breast milk in low concentrations. M/P ratio is not established. Risk of infant hypoglycemia and jaundice. Use during breastfeeding is not recommended; insulin is preferred. |
| Teratogenic Risk | First trimester: sulfonylureas cross placenta; limited human data show possible increased risk of congenital anomalies (low absolute risk). Second/third trimester: risk of neonatal hypoglycemia, macrosomia, and respiratory distress if used near term. Acetohexamide is contraindicated in pregnancy; insulin preferred. |
■ FDA Black Box Warning
No FDA boxed warning.
| Serious Effects |
["Hypersensitivity to sulfonylureas or sulfonamides","Type 1 diabetes mellitus","Diabetic ketoacidosis","Severe renal or hepatic impairment"]
| Precautions | ["Hypoglycemia risk, especially in elderly, debilitated, or malnourished patients, those with renal or hepatic impairment, or after prolonged fasting.","Increased cardiovascular mortality risk compared to diet or insulin (controversial, from University Group Diabetes Program study).","Hematologic reactions (agranulocytosis, aplastic anemia, leukopenia, thrombocytopenia).","Hepatic porphyria exacerbation."] |
| Food/Dietary | Avoid alcohol due to risk of prolonged hypoglycemia and potential disulfiram-like reaction. Maintain consistent carbohydrate intake; sudden increases or decreases in carbohydrate consumption (e.g., skipping meals, high-carb binges) can destabilize glycemic control. Grapefruit juice may interact; limit intake. Avoid excessive sugar intake to prevent hyperglycemia. High-fiber foods may delay absorption; take medication consistently relative to meals. |
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| Fetal Monitoring |
| Maternal: blood glucose, renal function, hepatic function, signs of hypoglycemia. Fetal/neonatal: ultrasound for growth abnormalities, neonatal blood glucose monitoring for 24-48 hours postpartum if maternal use continued late in pregnancy. |
| Fertility Effects | No direct evidence of impaired fertility in humans. Uncontrolled diabetes can adversely affect fertility and pregnancy outcomes. Use of acetohexamide in women of reproductive potential should be accompanied by effective contraception if not planning pregnancy. |
| Clinical Pearls | Acetohexamide is a first-generation sulfonylurea with active metabolites that have prolonged hypoglycemic effects, increasing risk of severe and prolonged hypoglycemia, especially in elderly or renally impaired patients. Its metabolism produces hydroxyhexamide and hydrohexamide, both active, leading to half-life extension with renal dysfunction. Avoid use in patients with G6PD deficiency due to risk of hemolytic anemia. Monitor liver function as hepatic impairment can prolong hypoglycemic effect. Discontinue at least 48–72 hours before elective surgery or procedures requiring prolonged fasting to reduce hypoglycemia risk. |
| Patient Advice | Take acetohexamide with breakfast or the first main meal to reduce gastrointestinal upset and to align with peak glucose levels. · Never skip meals after taking this medication; doing so can cause dangerously low blood sugar (hypoglycemia). · Recognize symptoms of hypoglycemia: shakiness, sweating, rapid heartbeat, confusion, and hunger; treat immediately with fast-acting sugar like glucose tablets, juice, or regular soda. · Avoid alcohol consumption; it can increase the risk of hypoglycemia and may cause a disulfiram-like reaction (nausea, flushing, headache). · Monitor your blood sugar as directed by your healthcare provider and maintain a consistent carbohydrate intake. · Report any signs of liver problems (yellowing skin/eyes, dark urine, abdominal pain) or unusual bruising/bleeding to your doctor immediately. · This medication may increase photosensitivity; use sunscreen and protective clothing when outdoors. · Do not drive or operate heavy machinery until you know how this medication affects your blood sugar levels. |