Glucagon

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.