Acetohexamide

324.4

324.40

213-530-4

QGC8W08I6I

759128

DTXSID7020007

C47380

Crystals from 90% aq ethanol|WHITE CRYSTALLINE POWDER

A - Alimentary tract and metabolism

2935009090

101

2.7

white solid

1.3g/cm3

188-190 °C

1.581

DMSO: ~45 mg/mL

Oral-Rat LD50: 5000 mg/kg

Flammable; decomposes by heating to release toxic nitrogen oxides and sulfur oxide fumes

PRACTICALLY ODORLESS

PKA= 6.6

178.2 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

From dil ethanol, mp 175-177 °C

Water insoluble.

Amides and Imides

An amide. Organic amides/imides react with azo and diazo compounds to generate toxic gases. Flammable gases are formed by the reaction of organic amides/imides with strong reducing agents. Amides are very weak bases (weaker than water). Imides are less basic yet and in fact react with strong bases to form salts. That is, they can react as acids. Mixing amides with dehydrating agents such as P2O5 or SOCl2 generates the corresponding nitrile. The combustion of these compounds generates mixed oxides of nitrogen (NOx).

NONH for all modes of transport

2

36

YR7350000

Warehouse ventilated, low temperature and dry

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392).

DHEW/NCI; Bioassay of Acetohexamide for Possible Carcinogenicity (1980) Technical Rpt Series No.50 DHEW Pub No. (NIH) 78-850

Flash point data for this chemical are not available; however, it is probably combustible. (NTP, 1992)

Fires involving this chemical can be controlled with a dry chemical, carbon dioxide or Halon extinguisher. (NTP, 1992)

SMALL SPILLS AND LEAKAGE: If a spill of this chemical occurs, FIRST REMOVE ALL SOURCES OF IGNITION, then you should dampen the solid spill material with acetone and transfer the dampened material to a suitable container. Use absorbent paper dampened with acetone to pick up any remaining material. Seal your contaminated clothing and the absorbent paper in a vapor-tight plastic bag for eventual disposal. Solvent wash all contaminated surfaces with acetone followed by washing with a soap and water solution. Do not reenter the contaminated area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned. STORAGE PRECAUTIONS: You should store this material under ambient temperatures. (NTP, 1992)

RECOMMENDED RESPIRATOR: Where the neat test chemical is weighed and diluted, wear a NIOSH-approved half face respirator equipped with an organic vapor/acid gas cartridge (specific for organic vapors, HCl, acid gas and SO2) with a dust/mist filter. (NTP, 1992)

practically nontoxic

Oral, rat LD50: 5 gm/kg; Oral, mouse LD50: >2500 mg/kg. Symptoms of an acetohexamide overdose include hunger, nausea, anxiety, cold sweats, weakness, drowsiness, unconsciousness, and coma.

DRUGS THAT MAY INCR RISK OF HYPOGLYCEMIA FROM SULFONYLUREAS INCL OTHER HYPOGLYCEMIC AGENTS, SULFONAMIDES, PROPRANOLOL, SALICYLATES, PHENYLBUTAZONE, PROBENECID, DICUMAROL, CHLORAMPHENICOL, MONOAMINE OXIDASE INHIBITORS, & ALCOHOL. /SULFONYLUREAS/|IN DIABETIC PT WITHOUT HEPATIC OR RENAL IMPAIRMENT, PLASMA HALF-LIFE...WAS NOT CHANGED BY CONCURRENT TREATMENT WITH PHENYLBUTAZONE, BUT THERE WAS CONSIDERABLE PROLONGATION OF HALF-LIFE OF ITS METABOLITE, HYDROXYHEXAMIDE, WHICH IS ALSO AN EFFECTIVE HYPOGLYCEMIC AGENT.|DAILY INGESTION ACETOHEXAMIDE (100 MG/KG) & PHENFORMIN (50 MG/KG) 7 DAYS WITH IP DIPHENYLHYDANTOIN RESTORED THIAMINE CONTENT.|CONCOMITANT ADMIN OF SALICYLIC ACID (20 MG/KG) WITH ACETOHEXAMIDE (30 MG/KG) IV TO DOGS INCR RENAL CLEARANCE OF METABOLITE HYDROXYHEXAMIDE.|For more Interactions (Complete) data for ACETOHEXAMIDE (19 total), please visit the HSDB record page.

... Groups of 35 male and female Fischer 344 rats were fed diets containing 10,000 or 20,000 ppm, acetoheximide for 103 wk. Matched controls consisted of 15 untreated rats of each sex. All surviving rats were killed at 105 to 107 wk. Groups of 35 male and female mice were fed diets containing a time-weighted avg of 6,359 or 12,718 ppm acetoheximide for 103 wk. Matched controls consisted of 15 untreated mice of each sex. All surviving animals were killed between 105 and 108 wk. Under the conditions of this study, acetohexamide was not carcinogenic in either Fischer 344 rats or B6C3F1 mice.

90%

Used in the management of diabetes mellitus type 2 (adult-onset).

Hypoglycemic Agents|...USED IN TREATMENT OF MILD TO MODERATELY SEVERE DIABETES MELLITUS OF MATURITY-ONSET, NONKETOTIC TYPE IN PT IN WHOM DIET ALONE CANNOT CONTROL GLYCOSURIA.|...MAY BE USEFUL IN PT WHO ARE ALLERGIC TO INSULIN & ARE UNWILLING OR UNABLE TO UNDERGO DESENSITIZATION OR...TO INJECT INSULIN. ...ESP USEFUL IN ELDERLY DIABETIC WITH POOR VISION WHO LIVES ALONE & IS IN DANGER OF DEVELOPING HYPOGLYCEMIA FROM INCORRECT INSULIN DOSAGE. /ORAL HYPOGLYCEMIC AGENTS/|...IT IS ONLY ONE WITH URICOSURIC PROPERTIES, SOME CLINICIANS PREFER THIS AGENT FOR DIABETIC WITH GOUT.|For more Therapeutic Uses (Complete) data for ACETOHEXAMIDE (6 total), please visit the HSDB record page.

HEMATOLOGICAL (LEUKOPENIA, AGRANULOCYTOSIS, THROMBOCYTOPENIA, PANCYTOPENIA, & HEMOLYTIC ANEMIA), CUTANEOUS (RASHES, PHOTOSENSITIVITY), GI (NAUSEA, VOMITING, RARELY HEMORRHAGE), & HEPATIC (INCR SERUM ALKALINE PHOSPHATASE, CHOLESTATIC JAUNDICE) REACTIONS HAVE BEEN REPORTED.|INCIDENCE OF UNTOWARD EFFECTS IS LOW & REACTIONS ARE REVERSIBLE WHEN...DISCONTINUED.|IT IS INEFFECTIVE IN JUVENILE-ONSET, UNSTABLE, OR BRITTLE DIABETES & IS CONTRAINDICATED IN DIABETES COMPLICATED BY ACIDOSIS, KETOSIS, SEVERE INFECTIONS, COMA, SEVERE TRAUMA, OR MAJOR SURGERY.|Caution in elderly and patients with renal disease. Significant uricosuric effects. /from table/|For more Drug Warnings (Complete) data for ACETOHEXAMIDE (17 total), please visit the HSDB record page.

Acetohexamide is an intermediate-acting, first-generation oral sulfonylurea. It lowers blood sugar by stimulating the pancreatic beta cells to secrete insulin and by helping the body use insulin efficiently. Due to its primary action on the pancreatic beta cells, the drug is only effective when there are functional pancreatic beta cells that can produce insulin granules. Acetohexamide has one-third the potency of chlorpropamide, and twice the potency of tolbutamide; however, similar hypoglycemic efficacy occurs with equipotent dosage of sulfonylureas.

Substances which lower blood glucose levels. (See all compounds classified as Hypoglycemic Agents.)

Rapidly absorbed from the GI tract.|ACETOHEXAMIDE IS RAPIDLY ABSORBED, & MAX HYPOGLYCEMIC ACTIVITY IS OBSERVED ABOUT 3 HR AFTER INGESTION. TOTAL DURATION OF ACTION IS 12-24 HR. MUCH OF ACTIVITY IS ASCRIBABLE TO METABOLITE, HYDROXYHEXAMIDE, WHICH HAS PLASMA T/2 OF ABOUT 6 HR...ACETOHEXAMIDE, HAS PLASMA T/2 OF 1.3 HR.|IN PERSONS WITH NORMAL RENAL & HEPATIC FUNCTION, MORE THAN 80% IS EXCRETED, LARGELY AS METABOLITES, IN 24 HR.|TIME OF PEAK CONCN AFTER ORAL DOSE: 3 HR /FROM TABLE/|...5 DAYS AFTER ORAL DOSE...TO RATS. 86% WAS EXCRETED IN 24-HR URINE & 9% IN 48-HR FECES. RESULTS INDICATED RAPID ABSORPTION & EXCRETION...|For more Absorption, Distribution and Excretion (Complete) data for ACETOHEXAMIDE (8 total), please visit the HSDB record page.

Extensively metabolized in the liver to the active metabolite hydroxyhexamide, which exhibits greater hypoglycemic potency than acetohexamide. Hydroxyhexamide is believed to be responsible for prolonged hypoglycemic effects.|HYDROXYHEXAMIDE...MAJOR METABOLITE OF ACETOHEXAMIDE...IN HUMANS, HAS L-CONFIGURATION. ...CONTRIBUTES SIGNIFICANTLY TO HYPOGLYCEMIC RESPONSE THAT FOLLOWS ADMIN...|PRINCIPAL ROUTE OF METABOLIC DEGRADATION IN MAN...REDUCTION OF P-ACETYL GROUP TO /1-[(P-ALPHA-HYDROXYETHYLBENZENE)SULFONYL]-3-CYCLOHEXYLUREA WHICH/ EXHIBITS HYPOGLYCEMIA IN MAN & OTHER ANIMALS. &...MAY PROLONG HYPOGLYCEMIC ACTIVITY OF ACETOHEXAMIDE /ORAL/|Sulfonylureas are rapidly absorbed from the gastrointestinal tract, transported in the blood in highly protein-bound complexes, and subjected to extensive hepatic metabolism (except for chlorpropamide). Wide variation exists among the sulfonylureas in hepatic metabolism and remnal clearance, factors that tend to alter the steady-state serum levels. Metabolites may be active, so there may be a variation between the plasma half-life of the parent drug and the degree of hypoglycemia encountered. /Sulfonylurea/|Active metabolite greater than parent drug. Metabolite excreted, in part, by kidney. /from table/

Elimination half-life of the parent compound is 1.3 hours and the elimination half-life of the active metabolite is approximately 5-6 hours.|Half-life...3.5-11 /hours/ /from table/

Sulfonylureas such as acetohexamide bind to an ATP-dependent K⁺ channel on the cell membrane of pancreatic beta cells. This inhibits a tonic, hyperpolarizing outflux of potassium, which causes the electric potential over the membrane to become more positive. This depolarization opens voltage-gated Ca²⁺ channels. The rise in intracellular calcium leads to increased fusion of insulin granulae with the cell membrane, and therefore increased secretion of (pro)insulin.|SULFONYLUREAS STIMULATE ISLET TISSUE TO SECRETE INSULIN. ... ADMIN OF SULFONYLUREAS INCR CONCN OF INSULIN IN PANCREATIC REIN... /SULFONYLUREAS/|Sulfonylureas are now...thought to act by a number of different mechanisms. 1. ...produce a depolarization of the pancreatic islet beta cell membrane potassium ion permeability. This results in a release of preformed insulin into the circulation and occurs mostly in non-insulin dependent diabetics. 2. ...reduce basal glucose output from the liver... 3. increase insulin receptor binding... 4. ...increasing intracellular levels of AMP... 5. increase insulin secretion by suppressing the release of glucagon and somatostatin from alpha and delta pancreatic cells. /Sulfonylureas/|Sulfonylureas lower blood glucose in NIDDM by directly stimulating the acute release of insulin from functioning beta cells of pancreatic islet tissue by an unknown process that involves a sulfonylurea receptor on the beta cell. Sulfonylureas inhibit the ATP potassium channels on the beta cell membrane and potassium efflux, which results in depolarization and calcium influx, calcium-calmodulin binding, kinase activation, and release of insulin containing granules by exocytosis, an effect similar to that of glucose. Insulin is a hormone that lowers blood glucose and controls the storage and metabolism of carbohydrates, proteins, and fats. Therefore, sulfonylureas are effective only in patients whose pancreata are capable of producing insulin. /Sulfonylurea antidiabetic agents/

SYMPTOMS: Symptoms of exposure to this compound include nausea, vomiting, epigastric pain, dizziness, weakness, paresthesia and sensitivity reactions with fever, eosinophilia, skin rashes, cholestatic jaundice and blood disorders including aplastic anemia, leukopenia, agranulocytosis and thrombocytopenia. Other symptoms include pancytopenia, hemolytic anemia, photosensitivity, hemorrhage (rarely), increases serum alkaline phosphatase and hypoglycemia reactions including coma and death (rarely). It can cause an intolerance to alcohol with flushing, palpitations and nausea. It can also cause headache, diarrhea and alteration in liver function tests. Stillbirth may occur. ACUTE/CHRONIC HAZARDS: When heated to decomposition this compound emits very toxic fumes of sulfur oxides and nitrogen oxides. (NTP, 1992)

EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. If symptoms (such as redness or irritation) develop, immediately transport the victim to a hospital. SKIN: IMMEDIATELY flood affected skin with water while removing and isolating all contaminated clothing. Gently wash all affected skin areas thoroughly with soap and water. If symptoms such as redness or irritation develop, IMMEDIATELY call a physician and be prepared to transport the victim to a hospital for treatment. INHALATION: IMMEDIATELY leave the contaminated area; take deep breaths of fresh air. If symptoms (such as wheezing, coughing, shortness of breath, or burning in the mouth, throat, or chest) develop, call a physician and be prepared to transport the victim to a hospital. Provide proper respiratory protection to rescuers entering an unknown atmosphere. Whenever possible, Self-Contained Breathing Apparatus (SCBA) should be used; if not available, use a level of protection greater than or equal to that advised under Protective Clothing. INGESTION: DO NOT INDUCE VOMITING. If the victim is conscious and not convulsing, give 1 or 2 glasses of water to dilute the chemical and IMMEDIATELY call a hospital or poison control center. Be prepared to transport the victim to a hospital if advised by a physician. If the victim is convulsing or unconscious, do not give anything by mouth, ensure that the victim's airway is open and lay the victim on his/her side with the head lower than the body. DO NOT INDUCE VOMITING. IMMEDIATELY transport the victim to a hospital. (NTP, 1992)

HYPOGLYCEMIC REACTIONS, INCL COMA, MAY OCCUR. WHILE THEY ARE USUALLY NOT SEVERE, SEVERAL FATALITIES HAVE BEEN REPORTED.|Coma or altered mental status is generally the most important presenting sign in the majority (90%) of patients who have ingested excessive doses of the sulfonylureas ... /Sulfonylurea/

Acetohexamide

...IS AVAILABLE IN 250- & 500-MG TABLETS.|...doses for Acetohexamide are 250 and 1500 mg.

Benzenesulfonamide, 4-acetyl-N-[(cyclohexylamino)carbonyl]-: INACTIVE

FLUORIMETRIC DETERMINATION OF ACETOHEXAMIDE IN PLASMA AND TABLETS.|METHOD FOR DETERMINATION OF ACETOHEXAMIDE IN PLASMA BY ELECTRON-CAPTURE GC.|HPLC DETERMINATION OF ACETOHEXAMIDE AND METABOLITE HYDROXYHEXAMIDE IN PLASMA.|A GLC METHOD FOR THE DETERMINATION OF ACETOHEXAMIDE (DYMELOR) & HYDROXYHEXAMIDE METABOLITE IN HUMAN PLASMA & URINE IS PRESENTED.

Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients|Pharmaceuticals