Continuing Education Activity

Glucagon, a polypeptide hormone, is an essential medication in the anti-hypoglycemic class and is crucial in managing various medical conditions. This drug is approved by the US Food and Drug Administration (FDA) for treating acute hypoglycemia and as a diagnostic aid during gastrointestinal imaging. Glucagon is effective in treating refractory anaphylaxis that does not respond to epinephrine, thereby highlighting its versatility in critical situations. The medication exerts its effects through glucagon receptors, increasing cAMP levels to stimulate glycogenolysis and gluconeogenesis, raising blood glucose levels. Glucagon has several off-label uses, including treating beta-blocker overdoses, serving as adjunctive therapy for calcium channel blocker overdoses, and managing esophageal food impaction. Glucagon serves as a valuable intervention for esophageal obstructions caused by food bolus impaction, which assists healthcare professionals in resolving such blockages.

Glucagon can be administered via intravenous, intramuscular, subcutaneous, or intranasal routes. Common adverse effects include nausea, hypertension, and rare hypersensitivity reactions. This activity reviews the indications, mechanism of action, administration, and contraindications of glucagon, highlighting its pharmacological properties, potential adverse effects, off-label uses, optimal dosing strategies, and essential monitoring requirements. This activity provides healthcare providers with the knowledge and skills necessary to effectively treat patients receiving glucagon in various clinical scenarios. In addition, this activity also emphasizes the importance of interdisciplinary collaboration among healthcare providers to monitor glucose levels, manage hypoglycemia, and optimize dosing in overdose cases.

Objectives:

• Identify the clinical indications for glucagon use, including its role in treating severe hypoglycemia, beta-blocker and calcium channel blocker overdoses, and esophageal food impactions.

• Implement glucagon administration protocols based on established guidelines for acute hypoglycemia, overdose management, and gastrointestinal imaging.

• Apply knowledge of glucagon's pharmacodynamics and off-label uses to guide therapeutic decisions in emergency settings.

• Collaborate with interprofessional healthcare providers, including pharmacists, endocrinologists, and nurses, to optimize glucagon dosing, particularly in patients with complex conditions.

Indications

FDA-Approved Indications

Glucagon is a polypeptide hormone approved by the US Food and Drug Administration (FDA) and is primarily used to treat severe hypoglycemia, which is a life-threatening condition. This medication can be administered via various routes, including oral carbohydrates, intravenous (IV) glucose, or glucagon. Glucagon is particularly advantageous for diabetic patients due to its ease of use and safe administration, as it does not require patent IV access.[1]

Patients with decreased levels of consciousness cannot safely consume oral carbohydrates to raise their blood sugar levels due to the risk of aspiration, and obtaining IV access can be difficult in the diabetic population, delaying prompt administration of IV glucose. IV glucose increases the risk of severe tissue necrosis in the event of medication extravasation. Glucagon provides a reliable alternative for raising glucose levels and alleviating severe hypoglycemia, allowing time for more definitive correction when IV access is unavailable or has failed.[1]

Glucagon is FDA-approved as a diagnostic aid for gastrointestinal imaging. This medication works by inducing hypotonia in the bowel and upper gastrointestinal tract, allowing for more precise visualization during studies and procedures. This same mechanism also helps facilitate the passage of esophageal food boluses. The primary indication for glucagon is to reduce peristalsis during abdominal vascular procedures, such as the treatment of esophageal varices and other gastrointestinal bleeds. Glucagon is also used in procedures such as biopsies, abscess drainage, gastrointestinal stenting, and gastrostomy tube placement. In the 1970s, radiologists transitioned from using anticholinergic agents to glucagon for these indications due to its safer adverse effect profile.[2][3]

Off-Label Uses

Glucagon has several off-label indications, including the treatment of beta-blocker and calcium channel blocker overdoses, as well as the medical management of esophageal food impaction. For beta-blocker and calcium channel blocker overdoses, high-dose glucagon infusion may be used in conjunction with beta-agonists such as epinephrine. Due to the logistical challenges of obtaining large amounts of glucagon for infusion, it is recommended to optimize high-dose insulin euglycemic therapy and catecholamine therapy before considering glucagon infusion, unless glucagon is readily available in sufficient quantities. In calcium channel blocker overdose, glucagon serves as a second-line therapy, following calcium, epinephrine, high-dose insulin, and dextrose.[4][5]

Glucagon's indications have expanded since its discovery. Ongoing research is exploring its potential in treating asthmatic bronchospasm as part of a bi-hormonal artificial pancreas, as well as its use in managing insulin and arrhythmias secondary to cardiac anaphylaxis.[6][7][8]

Mechanism of Action

Glucagon binds G-protein–coupled surface receptors found throughout the body in varying concentrations, specifically targeting glucagon receptors in the liver, gastrointestinal tract, heart, pancreas, fat, adrenal glands, and kidneys. This binding activates adenylate cyclase, which increases cyclic adenosine monophosphate (cAMP) levels. Elevated cAMP stimulates glycogenolysis and gluconeogenesis, leading to the release of glucose, primarily from liver glycogen stores. Additionally, glucagon's extrahepatic effects, including relaxation of gastrointestinal smooth muscle and positive inotropic effects, are mediated through adenylate cyclase.[9] Please see StatPearls' companion resource, "Physiology, Glucagon," for more information.

Pharmacokinetics

Absorption: When administered subcutaneously (SC), glucagon reaches peak plasma concentration (3533 pg/mL) within 10 to 13 minutes. After intramuscular (IM) administration of 1 mg, it reaches peak plasma concentration (3391 pg/mL) in about 10 minutes.

Metabolism: Glucagon is metabolized in the liver, kidneys, and plasma.

Elimination: The mean half-life of glucagon is approximately 42 minutes following SC administration and 26 minutes following IM administration.

Pharmacodynamics

Intravenous: When administered via the IV route at a dose of 0.25 to 0.5 mg, glucagon reaches maximum glucose concentration within 5 to 20 minutes. This medication also induces gastrointestinal smooth muscle relaxation with an onset of 45 seconds and a duration of 9 to 17 minutes.

Intramuscular: When injected via the IM route at a dose of 1 mg, glucagon reaches maximum glucose concentration within 30 minutes. This medication induces gastrointestinal smooth muscle relaxation with an onset of 8 to 10 minutes and a duration of 12 to 27 minutes. When administered via the IM route at a dose of 2 mg, glucagon reaches maximum glucose concentration within 30 minutes. This medication induces gastrointestinal smooth muscle relaxation with an onset of 4 to 7 minutes and a duration of 21 to 32 minutes.

Administration

Available Dosage Forms

Glucagon can be administered via the IV (as a bolus or infusion), IM, SC, and intranasal routes. Glucagon is also available as a dehydrated powder, known as the "Glucagon Emergency Kit," which is reconstituted with the supplied sterile water. Additionally, glucagon is available as a purpose-formulated intranasal spray. Similar to epinephrine auto-injectors, a pre-filled glucagon injector has been approved for injection into the patient's thigh.

Healthcare providers frequently encounter the emergency kit formulation, which requires reconstitution before injecting the medication. However, the intranasal spray may become more prevalent in hypoglycemia kits for layperson use. The intranasal powder requires no preparation and is administered by spraying into one nostril of the patient while the other nostril is held closed.[10][11]

Strength

Glucagon is available in 1 mg injectable vials and various formulations, as listed below.

• SC injection solution: 1 mg/0.2 mL.
• SC auto-injector solution: 0.5 mg/0.1 mL and 1 mg/0.2 mL.
• SC solution in pre-filled syringe: 0.5 mg/0.1 mL and 1 mg/0.2 mL.
• Reconstituted solution for injection: 1 mg/mL.
• Nasal powder: 3 mg per dose in both single-dose and 2-dose packs.

Unpunctured vials remain suitable for use until the expiration date indicated on the label. After reconstitution, the glucagon solution should be used immediately, and any unused portion should be discarded.

Adult Dosage

Hypoglycemia: A glucagon dose of 1 mg should be administered via the IM, SC, or IV routes. The dosage may be repeated in 15 minutes if necessary. Alternatively, a 3 mg dose of glucagon can be administered intranasally into a single nostril; if no adequate response is observed, the dose can be repeated. Unconscious patients should be positioned in a lateral recumbent position to prevent choking. When treating hypoglycemia, oral carbohydrates should be administered as soon as possible if the patient is conscious and responds to glucagon.[12][13]

Radiologic examinations

• As a diagnostic aid for colon relaxation: A glucagon dose of 2 mg should be administered via the IM route 10 minutes before the procedure.
• As a diagnostic aid for the stomach, duodenum, duodenal bulb, or small bowel: A glucagon dose ranging from 0.25 to 2 mg should be administered via the IV route over 1 minute or 1 to 2 mg via the IM route, as indicated.

Special Patient Populations

Hepatic impairment: The manufacturer's label does not provide specific information regarding the use of glucagon in patients with hepatic or renal impairment, including those on peritoneal or hemodialysis.

Renal impairment: The manufacturer's label does not provide specific information regarding the use of glucagon in patients with renal impairment, including those on peritoneal or hemodialysis.

Pregnancy considerations: Glucagon can be administered to treat hypoglycemia in pregnant patients with diabetes.[14]

Breastfeeding considerations: Information on the use of glucagon in breastfeeding women does not exist. Due to its high molecular weight, glucagon is secreted in small amounts in breast milk and is likely broken down by the infant's gastrointestinal tract. Given the safety profile of glucagon when administered directly to infants via injection, no special precautions are necessary.[15]

Pediatric patients: The safety and effectiveness of glucagon injections have been established for treating severe hypoglycemia in pediatric patients with diabetes. However, limited data exist on using glucagon as a diagnostic aid during radiologic examinations to temporarily inhibit gastrointestinal tract movement in pediatric patients.

Older patients: Specific dosing restrictions are unavailable for patients aged 65 or older.

Adverse Effects

Nausea is the most commonly reported adverse effect of glucagon administration, with an incidence reaching up to 35% in some studies. Hypertension may occur for up to 2 hours following administration, particularly in gastrointestinal cases, due to glucagon's inotropic effects. Additionally, severe anaphylactic reactions, including hypotension, rash, and vomiting, have been reported due to its protein structure. Although hypersensitivity reactions are rare, most have occurred during endoscopic procedures with IV administration. The likelihood of adverse reactions increases with higher doses and the IV route of administration.[13][16]

Less common adverse reactions include rebound hypoglycemia in patients with insulinoma and exacerbation of hyperglycemia in those with pancreatic glucagon-secreting tumors. Additionally, the positive inotropic effects of glucagon can trigger severe hypertension in patients with pheochromocytoma. In such cases, glucagon should be avoided, with oral or IV glucose preferred for emergency management, and the clonidine suppression test recommended for diagnosing pheochromocytoma.[17]

Contraindications

The only absolute contraindication to glucagon administration is a known hypersensitivity to the medication, which most commonly occurs in patients undergoing gastrointestinal imaging procedures.[18] Relative contraindications include use in neonates or children who may lack adequate glycogen stores, as well as in patients with known insulinoma, pheochromocytoma, or glucagon-secreting tumors.[19][20] 

Patients with known lactose allergies should avoid formulations containing lactose, such as certain dry powder inhalers.[21]

Monitoring

Following glucagon administration, monitoring should include blood pressure, heart rate, electrocardiogram (ECG), serial blood glucose checks, and observation for signs of hypersensitivity reactions. Monitoring is advised for up to 2 hours after administration due to the medication's duration of action. Patients and caregivers should also be educated on recognizing severe hypoglycemia, with a detailed explanation of its signs and symptoms, as well as the risks of untreated hypoglycemia.

Toxicity

Administering excessive doses of exogenous glucagon can lead to predictable adverse reactions requiring intervention, though such occurrences are rarely documented in the literature. While insulin antagonizes glucagon, it is generally not recommended for treating glucagon toxicity. The transient hyperglycemia associated with glucagon administration is rarely life-threatening, but iatrogenic rebound hypoglycemia poses a significant risk.

Management of Overdose

Treatment should prioritize mitigating the hypertensive response to glucagon using alpha-blocking agents and vasodilators.[22]

Enhancing Healthcare Team Outcomes

Glucagon is essential for treating various conditions, with hypoglycemic shock being the most common indication. Effective management of these conditions requires an interprofessional healthcare team led by specialty clinicians and advanced practice practitioners, supported by pharmacists for guidance, nurses or paramedics for administration, and the nursing staff and laboratory technicians for monitoring. Collaboration and coordination among the interdisciplinary healthcare team are essential to ensure the timely identification of at-risk patients who may benefit from glucagon administration, especially when first-line therapies have failed or are unavailable. Without timely intervention, morbidity and mortality from hypoglycemic shock, as well as beta-blocker and calcium channel blocker overdoses, can be significant.[1] 

Glucagon administration enhances gastrointestinal imaging by improving image clarity and increasing safety, as it has largely replaced anticholinergics in this context.[18][23] Pharmacists are crucial in determining the appropriate use and dosage of glucagon, particularly in high-stress situations where its administration may be necessary. Their consultation has been shown to increase the availability of glucagon for patients on insulin therapy.[24] 

Coordinated care by an interdisciplinary healthcare team should include:

• Clinicians who can order blood glucose levels, with nurses and technicians responsible for obtaining the necessary samples.
• Nurses and clinicians who monitor patients for signs of hypoglycemia, including tachycardia, diaphoresis, tremors, altered mentation, or coma.
• The patient should ingest carbohydrates and protein to prevent rebound hypoglycemia once they are able to protect their airway.
  • Note: tachycardia may be absent in cases of beta-blocker and calcium channel blocker overdoses.
• A pharmacist should be consulted regarding glucagon infusions in the setting of an overdose.[5] 
• A toxicologist should be consulted for all glucagon therapy in the setting of an overdose and engaged if a glucagon overdose is suspected.

Patients requiring prompt intervention due to hypoglycemia, overdose, or imaging can be encountered throughout the hospital system and by the general public. Once the acute intervention has stabilized the patient, preventing relapse is crucial, as glucagon's duration of action is typically shorter than the underlying cause of the emergency.

Patients with diabetes experiencing hypoglycemic shock will likely require hospitalization and should also have prompt follow-up with their endocrinologist or managing physician shortly after discharge. In cases of suspected intentional overdose, the involvement of a caseworker and psychiatrist is recommended. A coordinated, interdisciplinary approach to patient care is essential for improving patient safety, access to care, and the safe administration of glucagon.