Continuing Education Activity

Glucagon, a member of the anti-hypoglycemic class of medications, is crucial in managing diverse medical scenarios. This medication is employed to address acute hypoglycemia, offering an option for treating overdoses of beta-blockers and calcium channel blockers. Its efficacy includes refractory anaphylaxis cases not responsive to epinephrine, showcasing its versatility in critical situations. Moreover, glucagon serves as a valuable intervention in cases of esophageal obstruction caused by food bolus impaction, aiding healthcare professionals in facilitating the passage of such obstructions.

This activity explores the indications and contraindications of glucagon, shedding light on its pharmacological attributes, potential adverse events, off-label applications, optimal dosing strategies, and the crucial monitoring required. The course encompass relevant interactions, equipping interprofessional healthcare team members with the necessary insights for managing patients requiring glucagon in various clinical contexts.

Objectives:

• Identify the indications for glucagon administration in various clinical scenarios, including severe hypoglycemia, beta-blocker overdose, calcium channel blocker overdose, and esophageal food impaction.

• Screen patients to determine their eligibility for glucagon therapy based on their medical history, allergies, and potential contraindications.

• Assess the patient's response to glucagon therapy and monitor for adverse effects or complications.

• Determine methods with pharmacists and other healthcare professionals to optimize the use of glucagon and address any drug-drug interactions or medication-related concerns.

Indications

FDA-Approved Indications

Glucagon is a polypeptide hormone commonly used in the treatment of severe hypoglycemia. Glucagon is FDA-approved for the treatment of severe hypoglycemia. Severe hypoglycemia is a life-threatening event treated with oral carbohydrate intake, IV glucose, or glucagon by various routes. Glucagon has attractive traits in the diabetic population due to its simplicity of use and safe administration, not requiring patent IV access.[1]

Patients with decreased levels of consciousness cannot safely consume the oral carbohydrates needed to raise their blood sugar without risk of aspiration, and obtaining IV access can be problematic in the diabetic population, preventing prompt administration of IV glucose. IV glucose increases the risk of severe tissue necrosis in IV medication extravasation. Glucagon is a reliable method of raising the patient's glucose and relieving severe hypoglycemia long enough for more definitive correction of the patient's glucose levels by mouth, mainly when IV access is unavailable to the provider or has failed.[1]

Glucagon is FDA-approved as a diagnostic aid during imaging of the GI tract. Glucagon's role in gastrointestinal imaging is to induce bowel and upper gastrointestinal tract hypotonia, which permits more precise visualization for studies and procedures; this is the same mechanism by which it helps esophageal food boluses pass. The primary indicated use is to decrease peristalsis during abdominal vascular procedures such as treating esophageal varices and other GI bleeds. Glucagon is also utilized in biopsies, abscess drainage, GI stenting, and gastrostomy tube placement. Previously, radiologists used anticholinergic agents for the same indication but switched to glucagon in the 1970s due to a safer side effect profile.[2][3]

Off-Label Uses

Glucagon has several off-label indications, including beta-blocker overdose therapy, calcium channel blocker overdose adjunctive therapy, and medical treatment of esophageal food impaction. Beta-blocker overdose and calcium channel blocker overdose can be treated with high-dose glucagon infusion in addition to beta-agonists such as epinephrine. Because of the logistical difficulties associated with obtaining large amounts of glucagon needed for infusion, the recommendation is that high-dose insulin euglycaemic therapy (HIET) and catecholamine therapy be optimized before adding glucagon infusion, unless readily available in adequate quantities. Calcium channel blocker overdose can also receive treatment with glucagon; glucagon is a second-line therapy behind calcium, epinephrine, high-dose insulin, and dextrose.[4][5]

Glucagon's indications have continued to develop since its discovery. Research is ongoing to treat asthmatic bronchospasm as a constituent in the bi-hormonal artificial pancreas, as well as more traditional insulin and arrhythmias secondary to cardiac anaphylaxis.[6][7][8]

Mechanism of Action

Glucagon binds G-coupled surface receptors found throughout the body in varying concentrations, binding to the glucagon receptors in the liver, GI tract, heart, pancreas, fat, adrenal glands, and kidneys to activate adenylate cyclase, which raises cAMP levels. cAMP stimulates glycogenolysis and glucogenesis, resulting in the release of glucose, primarily from liver glycogen stores. The extrahepatic effects of glucagon are also mediated by adenylate cyclase, including relaxation of GI smooth muscle and positive inotropic effects.[9][10]

Pharmacokinetics

Absorption: Glucagon, when administered subcutaneously, reaches peak plasma concentration (3533 pg/mL) in 10 to 13 minutes. When glucagon 1 mg is administered intramuscularly, it reaches peak plasma concentration (3391 pg/mL) in 10 minutes.

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

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

Pharmacodynamics

Intravenous: Glucagon, administered IV (0.25 mg to 0.5 mg), reaches maximum glucose concentration in 5 to 20 minutes. Glucagon produces GI smooth muscle relaxation, with an onset of 45 seconds and a duration of smooth muscle relaxation from 9 to 17 minutes.

Intramuscular: Glucagon, when injected IM (1 mg), reaches maximum glucose concentration in 30 minutes. Glucagon produces GI smooth muscle relaxation, with an onset of 8 to 10 minutes and a duration of smooth muscle relaxation from 12 to 27 minutes. Glucagon, when injected with IM (2 mg), reaches maximum glucose concentration in 30 minutes and produces GI smooth muscle relaxation onset in 4 to 7 minutes and duration of smooth muscle relaxation from 21 to 32 minutes.

Administration

Dosage Forms

Glucagon can be administered intravenously as a bolus or infusion, intramuscularly, subcutaneously, and intranasally. Glucagon is available as a dehydrated powder termed a "Glucagon Emergency Kit," which is reconstituted with supplied sterile water or as a purpose-formulated intranasal spray. Like epinephrine auto-injectors, a pre-filled glucagon injector has received approval to inject glucagon into the patient's thigh.

Healthcare providers often encounter the emergency kit formulation necessitating reconstitution before injecting the medication. Still, the intranasal spray may be encountered with increasing frequency in hypoglycemia kits for layperson use. The intranasal powder requires no preparation, and administration is via a spray into the patient's nose while holding the other nostril closed.[11][12]

It is available on the market in injections of 1 mg glucagon, subcutaneous injection solution 1 mg/0.2 mL; subcutaneous auto-injector solution 0.5 mg/0.1 mL, 1 mg/0.2 mL; subcutaneous solution in pre-filled syringe 0.5 mg/0.1 mL, 1 mg/0.2 mL; reconstituted solution for injection 1 mg/mL and nasal powder 3 mg/dose in a single dose and 2-dose pack. The unpunctured vials are suitable until the expiration date on the label, and after reconstitution, use the glucagon solution immediately and discard any unused portion.

Adult Dose

Hypoglycemia:  Administer 1 mg glucagon intramuscularly, subcutaneously, or intravenously; repeat in 15 minutes if required or administer 3 mg (1 dose) intranasally into a single nostril; if no adequate response, can repeat the dose. Unconscious patients should be placed in a lateral recumbent position to prevent choking. When treating hypoglycemia, administer oral carbohydrates as soon as possible if the patient is conscious and responds to glucagon.[13][14]

Radiologic Examinations as a Diagnostic Aid for Relaxation of the Colon: Administer 2 mg IM 10 minutes before the procedure.

Radiologic Examinations as a Diagnostic Aid for the Stomach, Duodenum, Duodenal Bulb, or Small Bowl: Administer a dose ranging between 0.25 mg to 2 mg IV over 1 minute or 1 mg to 2 mg IM as indicated.

Special Patient Populations

Hepatic impairment: No information is provided on the manufacturer's label regarding hepatic or renal impaired patients, including those on peritoneal or hemodialysis.

Renal impairment: No information is provided on the manufacturer's label regarding hepatic or renal impaired patients, including those on peritoneal or hemodialysis.

Pregnancy considerations: Glucagon can be administered to treat hypoglycemia in pregnant patients with diabetes.[15]

Breastfeeding implications: There is no information about using glucagon in breastfeeding women. Because of its high molecular weight, glucagon is secreted in low amounts in breast milk and can be destroyed by an infant's gastrointestinal tract. Glucagon has a good safety profile when administered directly to infants by injection, so no special precautions are needed.[16]

Pediatric patients: The safety and effectiveness of glucagon injections are established in pediatric patients with diabetes experiencing severe hypoglycemia. However, there is a lack of data on glucagon's use as a diagnostic aid during radiologic examinations to inhibit the gastrointestinal tract's movement in pediatric patients temporarily.

Older patients: No dosing restrictions are available for patients older than 65.

Adverse Effects

Nausea is the most frequently encountered adverse effect of glucagon administration, with an incidence as high as 35% in some studies. Hypertension has been described up to 2 hours following administration for GI cases due to the inotropic effects of glucagon. Additionally, severe anaphylactic reactions, including hypotension, rash, and vomiting, have been observed due to the protein structure. Hypersensitivity reactions are rare; most have occurred in the endoscopic setting with IV administration. Adverse reactions from glucagon administration become more likely with the IV route and when given higher doses.[14][17]

Less common adverse reactions include rebound hypoglycemia in the setting of insulinoma and worsening hyperglycemia in the setting of pancreatic glucagon-secreting tumors. Additionally, the positive inotropic effects of glucagon can precipitate severe hypertension when administered to patients with pheochromocytoma. They should be avoided in favor of oral or IV glucose for emergency use and the clonidine suppression test for pheochromocytoma diagnosis.[18]

Contraindications

The only absolute contraindication to glucagon administration is known hypersensitivity to the medication. Most hypersensitivity reactions occur in GI imaging patients.[19] Relative contraindications include use in neonates or children, which may not have sufficient glycogen stores, and patients with known insulinoma, pheochromocytoma, or glucagon-secreting tumors.[20][21] 

Patients with known lactose allergy (some dry powder inhalers contain lactose) should not use the formulation containing lactose.[22]

Monitoring

Monitoring following glucagon injection should include blood pressure, heart rate, ECG, serial blood glucose checks, and signs of a hypersensitivity reaction. Monitoring is recommended for up to 2 hours after administration due to the medication's duration of action. Also, inform the patient and the care given on recognizing severe hypoglycemia with a detailed explanation of its signs and symptoms and the risk associated if left untreated.

Toxicity

Administering doses of exogenous glucagon over the amount required can predictably result in adverse reactions requiring intervention. However, this is rare in the literature. Insulin antagonizes glucagon, but toxicity should not be treated with insulin in most circumstances. The transient hyperglycemia associated with glucagon administration is rarely life-threatening, and iatrogenic rebound hypoglycemia has a substantial risk of harm. 

Management of Overdose

Treatment should focus on mitigating the hypertensive response to glucagon with alpha-blocking agents and vasodilators.[23]

Enhancing Healthcare Team Outcomes

Glucagon may be necessary for treating various conditions, as discussed above, with hypoglycemic shock being the most common indication. The emergent nature of many of these indications necessitates the involvement of an interdisciplinary team led by various specialty clinicians, advised by a pharmacist, administered by nurses or paramedics, and monitored by nurses and lab technicians. Without intervention, morbidity and mortality from hypoglycemic shock and beta-blocker and calcium channel blocker overdoses are substantial.[1] 

Gastrointestinal imaging benefits from glucagon administration by improving image clarity and has been made safer by transitioning from anticholinergics to glucagon.[19][24] 

The interprofessional healthcare team can enhance outcomes by coordinating care when physicians, advanced practice practitioners, nurses, laboratory technicians, and pharmacists work together to identify at-risk patients who may benefit from glucagon administration, often after failed first-line therapies or when first-line treatment is not immediately available. Pharmacists should be available to guide whether to utilize glucagon and at what dosage, particularly given the high-stress environment in which this medication may be necessary. Pharmacist consultation has demonstrably increased the availability of glucagon to patients taking insulin.[25] 

Coordinated care of an interdisciplinary team would include:

• Clinicians ordering and nurses and technicians obtaining blood glucose levels
• Nurses and clinicians monitor the patient for signs of hypoglycemia, including tachycardia, diaphoresis, tremors, altered mentation, or coma.
• Ensuring the patient has ingested carbs and protein capable of preventing rebound hypoglycemia once capable of protecting their airway.
  • Note: tachycardia may be absent in beta-blocker and calcium channel blocker overdoses.
• Consulting a pharmacist regarding glucagon infusions in the setting of overdose.[5] 
• Consulting a toxicologist for all glucagon therapy in the setting of overdose, additionally, engaging a toxicologist if an overdose of glucagon is suspected.

Patients requiring prompt intervention with glucagon resulting from 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 a relapse of the condition is crucial, as glucagon's duration of action is likely shorter than the underlying cause of the emergency.

Patients with diabetes experiencing hypoglycemic shock will likely require hospitalization but should also have a prompt follow-up with their endocrinologist or managing physician shortly after discharge. A caseworker and psychiatrist should be brought in for suspected intentional overdoses. A coordinated interdisciplinary approach to patient care is generally necessary to improve patient safety and access and is essential in the safe treatment of patients with glucagon.