Sulfonylureas are oral hypoglycemic agents extensively used in the treatment of type 2 diabetes,[1] The wide availability of these medications increases the potential for intentional or unintentional overdose in pediatric and adult populations.
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 oral agents besides sulfonylureas are used to treat type 2 diabetes, including biguanides, alpha-glucosidase inhibitors, thiazolidinediones, selective sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) agonists, and dipeptidyl peptidase IV (DPP-4) inhibitors.[2] Metformin, a biguanide, is one such agent. Even in overdose, for the most part those agents do not decrease serum glucose below euglycemia; consequently, they are appropriately referred to as antihyperglycemic agents rather than hypoglycemic agents. Overdose of antihyperglycemic agents can have other dangerous adverse effects (for example, lactic acidosis from metformin,[3] decreased kidney function from an SGLT2 inhibitor[4] ). However, 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. The risk of hypoglycemia varies by drug and patient populations. For example, glyburide has greater hypoglycemic effects than glipizide and glimepiride, particularly in patients with kidney dysfunction and in the elderly.[5]
Prolonged observation and intensive care to restore and maintain euglycemia may be required.[6] (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.
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 from 2012 to 2022.[7, 8, 9, 10, 11, 12, 13, 14, 15, 16] Approximately half of 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 2012-2022
View Table
See Table
Race, Sex, and Age
No racial or sex predilection has been reported in sulfonylurea exposure. Toxicity can occur in all ages, but most hypoglycemic overdoses occur in persons 6-19 years old.
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. In severe cases, possible complications include coma, recurrent seizures, permanent neurologic deficits, intellectual disability, and death.
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.
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:
Fingerstick and/or serum glucose test to detect hypoglycemia (If hypoglycemia does not occur within the first 2-4 hours after suspected ingestion/overdose, then other laboratory tests are unnecessary.)
Baseline complete blood cell (CBC) count (in symptomatic patients)
Baseline electrolytes, especially potassium (in symptomatic patients)
Serum aspirin and acetaminophen concentrations, and urine toxicological screening, if intentional ingestion/suicide attempt is suspected
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 sulfonylurea 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.
Emergency Department Care
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 oximetry 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.
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.
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.
Contact a regional poison control center for assistance.
Consult a psychiatrist for all suicidal cases. Notify the Department of Social Services of suicide attempts as well as cases of possible neglect and inappropriate child supervision.
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.
David Tran, MD, Attending Physician, Department of Emergency Medicine, North Shore-LIJ Plainview Hospital
Disclosure: Nothing to disclose.
Specialty Editors
Mary L Windle, PharmD, Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Nothing to disclose.
Jeffrey R Tucker, MD, Assistant Professor, Department of Pediatrics, Division of Emergency Medicine, University of Connecticut School of Medicine, Connecticut Children's Medical Center
Disclosure: Received salary from Merck for employment.
Chief Editor
Stephen L Thornton, MD, Associate Clinical Professor, Department of Emergency Medicine (Medical Toxicology), University of Kansas Hospital; Medical Director, University of Kansas Hospital Poison Control Center; Staff Medical Toxicologist, Children’s Mercy Hospital
Disclosure: Nothing to disclose.
Additional Contributors
Michael E Mullins, MD, Assistant Professor, Division of Emergency Medicine, Washington University in St Louis School of Medicine; Attending Physician, Emergency Department, Barnes-Jewish Hospital
Disclosure: Received stock ownership from Johnson & Johnson for none; Received stock ownership from Savient Pharmaceuticals for none.
Timothy E Corden, MD, Associate Professor of Pediatrics, Co-Director, Policy Core, Injury Research Center, Medical College of Wisconsin; Associate Director, PICU, Children's Hospital of Wisconsin
Disclosure: Nothing to disclose.
Acknowledgements
The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author Michael Lucchesi, MD, to the original writing and development of this article.
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