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Toxicity, Oral Hypoglycemic Agents
Updated: Apr 14, 2009
Introduction
Background
Oral hypoglycemic agents commonly are referred to as sulfonylureas, a class of compounds. Sulfonylurea compounds are among the most widely prescribed medications in the world. The drugs are frequently used to treat patients with type II diabetes.1 Wide availability of these medications increases potential for either intentional or unintentional overdose in pediatric and adult populations.2
First-generation sulfonylurea compounds became widely available in 1955. They are acetohexamide, chlorpropamide, tolazamide, and tolbutamide. First-generation agents have longer half-lives (eg, 49 hours for chlorpropamide). Second-generation sulfonylureas were introduced in 1984. Known as glipizide, glyburide, and glimepiride, second-generation sulfonylureas are more potent and have shorter half-lives than the first-generation sulfonylureas.
Other agents besides sulfonylureas are used to treat type II diabetes, including biguanides, alpha-glucosidase inhibitors, and troglitazone. Metformin (Glucophage in the United States) is one such agent.3 Even in excessive dosage, these agents do not decrease serum glucose below euglycemia; consequently, they are referred to appropriately as antihyperglycemic agents rather than hypoglycemic agents.
The Joslin Diabetes Center released a clinical guideline for the pharmacological management of type II diabetes in 2007.4
Pathophysiology
Sulfonylureas are sulfonamide derivatives but do not have any antibacterial activity. The exact mechanism of sulfonylureas' hypoglycemic effect remains to be elucidated. These drugs are mainly effective in patients with functional pancreatic beta cells. Sulfonylureas bind to receptors that are associated with potassium channels sensitive to adenosine triphosphate in beta-cell membrane. The binding inhibits efflux of potassium ions from the cells, resulting in depolarization, influx of calcium ions, and release of preformed insulin. Sulfonylureas may also cause the decrease of serum glucagon and potentiate the action of insulin at the extrapancreatic tissues.
Frequency
United States
The American Association of Poison Control Centers' (AAPCC) National Data Collection System compiles an annual report of human poison exposure cases. The number of exposures to oral hypoglycemic agents increased steadily from 1989-1997.5,6,7,8,9,10,11,12,13,14 Most exposures are in the pediatric population and are due to unintentional ingestion.
The American Association of Poison Control Centers' National Data Collection System from 1989-1997
Open table in new window
Table
Year | Exposures | <6 Years | 6-19 Years | Unintentional Exposures | Overall Mortality* | Pediatric Mortality |
1989 | 1467 | 808 | † 130 | 1139 | 1 | 0 |
1990 | 1601 | 910 | † 120 | 1265 | 1 | 1 |
1991 | 2013 | 1143 | † 158 | 1577 | 3 | 0 |
1992 | 2341 | 1310 | † 143 | 1824 | 2 | 0 |
1993 | 2272 | 1207 | 180 | 1794 | 1 | 0 |
1994 | 2482 | 1246 | 192 | 1945 | 8 | 1 |
1995 | 2815 | 1381 | 230 | 2214 | 3 | 0 |
1996 | 3333 | 1468 | 276 | 2594 | 4 | 0 |
1997 | 3846 | 1619 | 370 | 3033 | 4 | 1 |
Total | 22170 | 11092 | 1799 | 17385 | 27 | 3 |
Year | Exposures | <6 Years | 6-19 Years | Unintentional Exposures | Overall Mortality* | Pediatric Mortality |
1989 | 1467 | 808 | † 130 | 1139 | 1 | 0 |
1990 | 1601 | 910 | † 120 | 1265 | 1 | 1 |
1991 | 2013 | 1143 | † 158 | 1577 | 3 | 0 |
1992 | 2341 | 1310 | † 143 | 1824 | 2 | 0 |
1993 | 2272 | 1207 | 180 | 1794 | 1 | 0 |
1994 | 2482 | 1246 | 192 | 1945 | 8 | 1 |
1995 | 2815 | 1381 | 230 | 2214 | 3 | 0 |
1996 | 3333 | 1468 | 276 | 2594 | 4 | 0 |
1997 | 3846 | 1619 | 370 | 3033 | 4 | 1 |
Total | 22170 | 11092 | 1799 | 17385 | 27 | 3 |
† Denotes patients aged 6-17 years
Race
No racial predilection has been reported in oral hypoglycemic agent exposure.
Sex
No sex predilection is noted in oral hypoglycemic agent exposure.
Age
Toxicity can occur in all ages. Most hypoglycemic overdoses occur in persons aged 6-19 years.
Clinical
History
A single tablet of sulfonylurea has been reported to produce hypoglycemia in a child.
Normal hypoglycemic counterregulation.
Glipizide has been reported to produce hypoglycemia within 5 minutes of ingestion in an adult. A child can become hypoglycemic after ingestion of 1 glipizide 5-mg tablet. Patients usually become symptomatic within 2 hours of ingestion. Symptoms of hypoglycemia may be delayed if food is taken with the oral hypoglycemic agents. Symptoms may include the following:
- Lethargy
- Confusion
- Irritability
- Unresponsiveness
- Dizziness
- Headache
- Blurred vision
- Psychotic behavior
- Emesis
- Delirium
- Feeding difficulties
Physical
Patient presentation depends on the severity and duration of hypoglycemia. In the nondiabetic individual, signs and symptoms of hypoglycemia may not occur until serum glucose is less than 40 mg/dL. Signs may include the following:
- Altered mental status
- Generalized weakness
- Diaphoresis
- Tachycardia
- Tachypnea
- Transient neurologic deficit
- Pallor
- Seizure
- Cyanosis
- Coma
- Hypothermia
- Athetotic movement
Causes
Sulfonylurea compounds are widely available, contributing to unintentional exposures to oral hypoglycemic agents in the pediatric population.
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Further Reading
Keywords
oral hypoglycemic agents, sulfonylurea, glyburide, glipizide, glimepiride, tolbutamide, chlorpropamide, tolazamide, diabetes mellitus, type 2 diabetes, type II diabetes, poisoning, exposure, overdose, treatment, diaphoresis, tachycardia, tachypnea, seizure
