Oral hypoglycemic agents—sulfonylureas—which are used to treat patients with type 2 diabetes,[1] are among the most widely prescribed medications in the world. Wide availability of these medications increases the 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 long half-lives (eg, 49 hours for chlorpropamide). Second-generation sulfonylureas were introduced in 1984 and include 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 2 diabetes, including biguanides, alpha-glucosidase inhibitors, and thiazolidinediones. Metformin (Glucophage in the United States), a biguanide, is one such agent.[3] Even in overdose, these agents do not decrease serum glucose below euglycemia; consequently, they are appropriately referred to as antihyperglycemic agents rather than hypoglycemic agents. Although overdose of antihyperglycemic agents can have dangerous adverse effects (for example, lactic acidosis from metformin[4] ), this article focuses on acute overdose of sulfonylureas.
Hypoglycemia from sulfonylureas can result from small doses, can be delayed in onset, and can be persistent. Prolonged observation and intensive care to restore and maintain euglycemia may be required.[5] (See Treatment and Medication.)
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.
Normal hypoglycemic counterregulation is illustrated in the image below.
View Image | Normal hypoglycemic counterregulation. |
United States
The American Association of Poison Control Centers' (AAPCC) National Data Collection System compiles an annual report of human poison exposure cases. Overall, the number of exposures to oral sulfonylureas fell between 2006 and 2013 but increased in 2014.[6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16] Most exposures are in the pediatric population and are due to unintentional ingestion.
Table. Sulfonylurea exposures reported to the American Association of Poison Control Centers' National Data Collection System from 2006-2015
View Table | See Table |
No racial or sex predilection has been reported in oral hypoglycemic agent exposure. Toxicity can occur in all ages, but most hypoglycemic overdoses occur in persons 6-19 years old.
A single tablet of sulfonylurea (eg, a glipizide 5-mg tablet) may produce hypoglycemia in a child. Glipizide has been reported to produce hypoglycemia within 5 minutes of ingestion in an adult. 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:
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 drops below 40 mg/dL. Signs may include the following:
Most hospitals do not have the capability to analyze for levels of sulfonylureas and/or their metabolites. Even if it is possible to obtain these levels, no data indicate they should be used in the clinical setting. Tests for oral hypoglycemic agent exposure may include the following:
Head computed tomographic scanning without, and then with, intravenous contrast is recommended in patients with any of the following:
Electrocardiography (ECG) is recommended in patients with a suspected history of tricyclic antidepressant toxicity or in those with severe electrolyte abnormalities.
The main goal in oral hypoglycemic agent exposure is supportive care, which includes airway, breathing, and circulation.
Intravenous administration of glucose rapidly resolves the effects of hypoglycemia. Its onset is quicker than oral administration of sugar, and it is safer in patients with a depressed mental status who should not take anything by mouth for fear of aspiration. Glucagon is helpful and can be administered intravenously, intramuscularly, or subcutaneously. Glucagon is particularly useful in the intramuscular mode when intravenous access cannot be obtained immediately.
Generally, all symptomatic patients who present with hypoglycemia need admission to the hospital in a monitored setting. Patients who remain asymptomatic and who do not develop hypoglycemia in the first 8-12 hours may be discharged safely home. However, the data from one study suggest that because accidental ingestion of sulfonylurea results in delayed and often prolonged hypoglycemia, admission for at least 16 hours is recommended, with frequent glucose monitoring.[17]
At minimum, patients need intravenous access. If the patient is lethargic, then oxygen, continuous cardiac monitoring, and pulse oximeter are indicated. Until the patient totally regains normal mental status, do not administer anything by mouth.
Administer intravenous glucose to all patients with hypoglycemic symptoms. Depending on the amount of the drug and its half-life, patients may require intravenous glucose administration for anywhere from several hours to several days. If patients do not respond to continuous glucose administration with supplemental boluses, then octreotide or diazoxide can be administered.
Ipecac is not recommended because of the possibility of aspiration in patients with a depressed mental status.
Administer activated charcoal as soon as possible, preferably within 1 hour of ingestion. However, most unintentional pediatric exposure involves the ingestion of only one or two tablets of sulfonylureas, and no data indicate that gastric lavage or administration of activated charcoal has any benefit in these cases.
Multiple doses of activated charcoal have been suggested in patients with glipizide overdose because this hypoglycemic agent has an enterohepatic circulation.
Hemodialysis is not indicated because most sulfonylureas have high protein binding.
Consultations may include the following:
Clinical Context: Used to promptly elevate serum glucose. Monosaccharide absorbed from intestine and then distributed, stored, and used by tissues. Parenterally injected dextrose is used in patients who are unable to sustain adequate oral intake. Direct oral absorption results in a rapid increase in blood glucose concentrations. Effective in small doses. No evidence suggests that it may cause toxicity. Concentrated dextrose infusions provide higher amounts of glucose and increased energy intake in a small volume of fluid.
Clinical Context: Extracted from beef and pork pancreas. Chemically unrelated to insulin, glucagon is a single-chain polypeptide with 29 amino acid residues and a molecular weight of 3,483. In patients with insulinoma, IV administration of glucagon produces an initial increase in blood glucose; however, because of glucagon's insulin-releasing effect, it may cause the insulinoma to release its insulin and subsequently cause hypoglycemia. Glucagon increases blood glucose concentration and is used to treat hypoglycemia. It is effective in small doses, and no evidence of toxicity has been reported with its use. Glucagon acts only on liver glycogen, converting it to glucose. Parenteral administration of glucagon produces relaxation of the smooth muscle of the stomach, duodenum, small bowel, and colon. The half-life of glucagon in plasma is approximately 3-6 min, similar to that of insulin.
Prompt gluconeogenesis is achieved with glucagon. Emergent blood glucose elevation requires intravenous dextrose. First-line agent for oral hypoglycemic toxicity is dextrose.
Pancreatic alpha cells of the islets of Langerhans produce glucagon, a polypeptide hormone. Exerts opposite effects of insulin on blood glucose. Glucagon elevates blood glucose levels by inhibiting glycogen synthesis and enhancing formation of glucose from noncarbohydrate sources, such as proteins and fats (gluconeogenesis). Increases hydrolysis of glycogen to glucose (glycogenolysis) in liver in addition to accelerating hepatic glycogenolysis and lipolysis in adipose tissue. Glucagon increases force of contraction in the heart and has a relaxant effect on the GI tract.
Clinical Context: Increases blood glucose by inhibiting pancreatic insulin release and possibly through an extrapancreatic effect. Hyperglycemic effect begins within an hour and usually lasts a maximum of 8 h with normal renal function.
Clinical Context: Acts primarily on somatostatin receptor subtypes II and V. A somatostatin analogue, which activates G-protein K channel. Hyperpolarization of the beta cell results in inhibition of Ca influx and insulin release. Octreotide is also used for acromegaly, carcinoid tumors, and Vipomas.
Insulin secretion may be altered by various mechanisms. Diazoxide inhibits pancreatic secretion of insulin, stimulates glucose release from the liver, and stimulates catecholamine release, which elevates blood glucose levels. It causes a false-negative insulin response to glucagon.
Octreotide is a peptide with pharmacologic action similar to somatostatin, which inhibits insulin secretion.
A child in whom ingestion of any first-generation sulfonylurea (eg, chlorpropamide, acetohexamide, tolbutamide, tolazamide) is suspected should be admitted to the pediatric ward for at least 24 hours of observation, regardless of initial symptoms.
A child in whom ingestion of a second-generation sulfonylurea (eg, glyburide, glipizide, glimepiride) is suspected may be discharged safely home if the patient remains asymptomatic and euglycemic for 8-12 hours. If the patient is lethargic, comatose, or has refractory seizures, admit the patient to the intensive care unit.
Possible complications include the following:
Prognosis depends mainly on the early recognition of sulfonylurea exposures, the amount ingested, and the half-life of the drug. Most patients with oral hypoglycemic poisoning recover without any complications.
Parents should keep medication inaccessible to children. For patient education resources, see the Poisoning - First Aid and Emergency Center, as well as Poisoning, Activated Charcoal, and Poison Proofing Your Home.
Year Exposures <6 Years ≥6 Years Unintentional Exposures Overall Mortality* Pediatric Mortality 2006 1951 974 903 1647 1 0 2007 1975 991 890 1666 0 0 2008 1850 987 808 1571 0 0 2009 1769 922 769 1515 1 0 2010 1712 898 745 1453 0 0 2011 1687 804 807 1404 1† - 2012 1753 850 798 1449 1† - 2013 1590 778 762 1340 0 0 2014 1584 778 769 1316 2 0 2015 1659 807 852 1413 2 0 *Overall mortality includes adult and pediatric cases † Patient age not noted