AcetoHEXAMIDE

Pronunciation

 (a set oh HEKS a mide)

Synonyms

 Dymelor [DSC]

Generic Available

 Yes

Use

 Adjunct to diet for the management of mild to moderately severe, stable, type 2 diabetes mellitus (noninsulin dependent, NIDDM)

Pregnancy Risk Factor

 D

Pregnancy Implications

 Abnormal blood glucose levels are associated with a higher incidence of congenital abnormalities. Insulin is the drug of choice for the control of diabetes mellitus during pregnancy.

Lactation

 Excretion in breast milk unknown/not recommended

Contraindications

 Hypersensitivity to sulfonylureas; diabetes complicated by ketoacidosis; therapy of type 1 diabetes mellitus (insulin dependent, IDDM); pregnancy

Warnings/Precautions

 Patients should be properly instructed in the early detection and treatment of hypoglycemia. Use caution in renal impairment. Chemical similarities are present among sulfonamides, sulfonylureas, carbonic anhydrase inhibitors, thiazides, and loop diuretics (except ethacrynic acid). Use in patients with sulfonylurea allergy is specifically contraindicated in product labeling, however, a risk of cross-reaction exists in patients with allergy to any of these compounds; avoid use when previous reaction has been severe.

Product labeling states oral hypoglycemic drugs may be associated with an increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. Data to support this association are limited, and several studies, including a large prospective trial (UKPDS) have not supported an association.

Adverse Reactions

>10%:

Central nervous system: Dizziness, headache

Gastrointestinal: Anorexia, constipation, diarrhea, epigastric fullness, heartburn

1% to 10%: Dermatologic: Photosensitivity, rash, urticaria

<1% (Limited to important or life-threatening): Agranulocytosis, aplastic anemia, bone marrow suppression, cholestatic jaundice, hemolytic anemia, hypoglycemia, porphyria, SIADH, thrombocytopenia

Drug Interactions

 Monitor patient closely; large number of drugs interact with sulfonylureas

Decreased effect: Decreases hypoglycemic effect when coadministered with cholestyramine, diazoxide, hydantoins, rifampin, thiazides, loop or thiazide diuretics, and phenylbutazone

Increased effect: Increases hypoglycemia when coadministered with salicylates or beta-adrenergic blockers; MAO inhibitors; oral anticoagulants, NSAIDs, sulfonamides, phenylbutazone, insulin, clofibrate, fluconazole, gemfibrozil, H2 antagonists, methyldopa, tricyclic antidepressants

Mechanism of Action

 Believed to cause hypoglycemia by stimulating insulin release from the pancreatic beta cells; reduces glucose output from the liver (decreases gluconeogenesis); insulin sensitivity is increased at peripheral target sites (alters receptor sensitivity/receptor density); potentiates effects of ADH; may produce mild diuresis and significant uricosuric activity

Pharmacodynamics/Kinetics

Onset of action: 1 hour

Peak effect, hypoglycemic: 8-10 hours

Duration: 12-24 hours; prolonged with renal impairment

Half-life elimination, serum: Parent drug: 0.8-2.4 hours; Metabolite: 5-6 hours

Dosage

 Oral: Adults (elderly patients may be more sensitive and should be started at a lower dosage initially):

Initial: 250 mg/day; increase in increments of 250-500 mg daily at intervals of 5-7 days up to 1.5 g/day. Patients on 1 g/day can be controlled with once daily administration. Patients receiving 1.5 g/day usually benefit from twice daily administration before the morning and evening meals. Doses >1.5 g daily are not recommended.

Dosing adjustment in renal impairment: Clcr<50 mL/minute: Not recommended due to increased potential for developing hypoglycemia

Dosing adjustment in hepatic impairment: Initiate therapy at lower than recommended doses; further dosage adjustment may be necessary because acetohexamide is extensively metabolized but no specific guidelines are available

Monitoring Parameters

 Blood (preferred) and urine glucose concentrations should be monitored when therapy is started; normally takes 7 days to determine therapeutic response

Dietary Considerations

 May be taken with food. Avoid ethanol.

Patient Education

 This medication is used to control diabetes; it is not a cure. Other components of treatment plan are important: follow prescribed diet, medication, and exercise regimen. Take exactly as directed; with breakfast or the first main meal of the day. Do not change dose or discontinue without consulting prescriber. Avoid alcohol while taking this medication; could cause severe reaction. Inform prescriber of all other prescription or OTC medications you are taking; do not introduce new medication without consulting prescriber. Do not take other medication within 2 hours of this medication unless so advised by prescriber. If you experience hypoglycemic reaction, contact prescriber immediately. Maintain regular dietary intake and exercise routine and always carry quick source of sugar with you. You may experience side effects during first weeks of therapy (headache, nausea); consult prescriber if these persist. Report severe or persistent side effects, extended vomiting or flu-like symptoms, skin rash, easy bruising or bleeding, or change in color of urine or stool. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Do not breast-feed.

Nursing Implications

Patients who are anorexic or NPO may need to have their dose held to avoid hypoglycemia

Blood (preferred) and urine glucose concentrations should be monitored when therapy is started; normally takes 7 days to determine therapeutic response

Anesthesia and Critical Care Concerns/Other Considerations

 The possibility of higher doses of sulfonylureas eliciting an increase in cardiovascular events, because of their effects on blocking potassium sensitive ATP channels, has been raised. However, there are presently only limited data to support this premise, particularly with newer generation agents.

Cardiovascular Considerations

 The possibility of higher doses of sulfonylureas eliciting an increase in cardiovascular events, because of their effects on blocking potassium sensitive ATP channels, has been raised. However, there are presently only limited data to support this premise, particularly with newer generation agents. An early study suggested poor cardiovascular outcomes in diabetic patients treated with tolbutamide. Retrospective studies evaluating cardiovascular outcomes following angioplasty and acute myocardial infarction in diabetic patients receiving newer sulfonylureas are inconsistent. Longer-term prospective trials of sulfonylurea therapy, such as the UKPDS, do not reveal any increased cardiovascular mortality.

Dental Health: Effects on Dental Treatment

 Key adverse event(s) related to dental treatment: Use salicylates with caution in patients taking acetohexamide due to potential increased hypoglycemia. NSAIDs such as ibuprofen, naproxen, and others may be safely used. Acetohexamide-dependent diabetics (noninsulin-dependent, type 1) should be appointed for dental treatment in mornings to minimize chance of stress-induced hypoglycemia.

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

 No information available to require special precautions

Mental Health: Effects on Mental Status

 Dizziness is common

Mental Health: Effects on Psychiatric Treatment

 Can rarely cause bone marrow suppression use cautiously with clozapine and carbamazepine; MAO inhibitors and TCAs may potentiate hypoglycemic effects

Dosage Forms

 Tablet: 250 mg, 500 mg

References

Alexander RW, "Prolonged Hypoglycemia Following Acetohexamide Administration,"Diabetes, 1966, 15(5):362-4.

"A Study of the Effects of Hypoglycemia Agents on Vascular Complications in Patients With Adult-onset Diabetes. VI. Supplementary Report on Nonfatal Events in Patients Treated With Tolbutamide. The University Group Diabetes Program,"Diabetes, 1976, 25(12):1129-53.

Cowen DL, Burtis B, and Youmans J, "Prolonged Coma After Acetohexamide Ingestion,"JAMA, 1967, 201(2):141-2.

"Effect of Intensive Blood-Glucose Control With Metformin on Complications in Overweight Patients With Type 2 Diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group,"Lancet, 1998, 352(9131):854-65.

Garratt KN, Brady PA, Hassinger NL, et al, "Sulfonylurea Drugs Increase Early Mortality in Patients With Diabetes Mellitus After Direct Angioplasty for Acute Myocardial Infarction,"J Am Coll Cardiol, 1999, 33(1):119-24.

"Intensive Blood-Glucose Control With Sulphonylureas or Insulin Compared With Conventional Treatment and Risk of Complications in Patients With Type 2 Diabetes (UKPDS 33) UK Prospective Diabetes Study (UKPDS) Group,"Lancet, 1998, 352(9131):837-53.

Klamann A, Sarfert P, Launhardt V, et al, "Myocardial Infarction in Diabetic vs Nondiabetic Subjects. Survival and Infarct Size Following Therapy With Sulfonylureas (Glibenclamide),"Eur Heart J, 2000, 21(3):220-9.

Meinert CL, Knatterud GL, Prout TE, et al, "A Study of the Effects of Hypoglycemic Agents on Vascular Complications in Patients With Adult-Onset Diabetes. II. Mortality Results,"Diabetes, 1970, 19:789-830.

O'Keefe JH, Blackstone EH, Sergeant P, et al, "The Optimal Mode of Coronary Revascularization for Diabetics. A Risk-Adjusted Long-Term Study Comparing Coronary Angioplasty and Coronary Bypass Surgery,"Eur Heart J, 1998, 19(11):1696-703.

"Standards of Medical Care for Patients With Diabetes Mellitus. American Diabetes Association,"Diabetes Care, 1994, 17(6):616-23.

International Brand Names

 Dimelin (JP); Dymelor (HK)

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