Glucagon

Glucagon is a hyperglycemic agent belonging to the pharmacological class of hormones.

For the potentially life-threatening severe hypoglycemia in people with diabetes, Glucagon has been approved for treatment. It quickly and effectively treats hypoglycemia by encouraging the liver-stored glucose to be released, boosting blood sugar levels.

Glucagon absorbs rapidly after injection and reaches peak plasma levels in minutes. It is dispersed throughout the body, mainly impacting the liver—the hepatic metabolism of glucagon results in its excretion through the urine.

Nausea is the most common side effect of Glucagon.

Glucagon is available in the form of injection solutions.

The molecule is available in India, the United States, Canada, the United Kingdom, China, Brazil, France, Japan, Germany and Australia.

Glucagon is a hyperglycemic agent belonging to the pharmacological class of hormones.

When Glucagon binds to the glucagon receptor, Gs and Gq are activated. This activation triggers adenylate cyclase, triggering protein kinase A and raising intracellular cyclic AMP. Gq activation releases intracellular calcium, activates phospholipase C, and boosts inositol 1,4,5-triphosphate synthesis. To break down glycogen, Protein Kinase A phosphorylates glycogen phosphorylase kinase, which later turns into phosphorylates glycogen phosphorylase.

Additionally, the stomach, duodenum, small intestine, and colon's smooth muscles are relaxed by Glucagon.

The data duration of Glucagon action is about 15 to 20 minutes.

The Data of Tmax of Glucagon is approximately 10-20 minutes.

The Data of Cmax of Glucagon is within approximately 10-20 minutes.

Glucagon is available in the form of injectable solutions

Injectable solutions: To be administered parenterally, as applicable.

• When diabetics cannot consume carbohydrates or lose consciousness due to severe hypoglycemia (low blood sugar), Glucagon treats the condition. It facilitates rapid blood glucose elevation.
• Glucagon is used as a diagnostic aid in radiologic procedures, including gastrointestinal examinations and abdominal imaging, to relax the muscles of the gastrointestinal system and increase visibility.
• Glucagon may be used to treat overdoses of some drugs, such as beta-blockers, which can significantly drop blood pressure and heart rate. This will enhance heart function and offset the adverse effects.

In Severe hypoglycemia

Glucagon acts as a rapid and effective lifesaver in cases of severe hypoglycemia, swiftly elevating dangerously low blood sugar levels to prevent unconsciousness or seizures, particularly in diabetic emergencies. Glucagon is a crucial antidote for severe beta-blocker poisoning, helping improve heart function. Beyond its role in glycemic management, it is used in the medical field to visualize the gastrointestinal tract, assisting in procedures and diagnostics that require a clear view of stomach and intestinal linings.

• As a diagnostic tool, it is indicated to temporarily impair gastrointestinal tract motion during radiologic exams.
• Recommended off-label for beta-blocker or calcium channel blocker overdose.
• Indicated for severe hypoglycemia in diabetic children and adults under two years of age receiving insulin treatment.

Glucagon is available as an injection solution that can be administered parenterally.

Parenterally: Glucagon can be given intravenously, intramuscularly, or subcutaneously. It should be injected into the outer thigh, outer arm, lower belly, or buttocks, whether IM or SC. If necessary, seek emergency help after SC or IM administration. Give the patient IV glucose if they don't respond to Glucagon. Once the patient has responded to therapy, give them oral carbohydrates with short- and long-term effects to replenish liver glycogen and stop hypoglycemia from occurring again. The injectable device cannot be reused since it only holds a single glucagon dosage.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Injection solutions: 1mg/vial (IV/IM), 0.5mg/0.1mL(SC) or 1mg/0.2mL (SC)

Glucagon is available in the form of injection solutions.

Dose Adjustment in Adult Patients:

Hypoglycemia

One mg (one unit) If there is no dextrose IV, IM/SC/IV

Once or twice, repeat the 15-minute intervals; as soon as dextrose is available, administer it.

Give extra carbohydrates to replenish glycogen reserves.

Diagnostic Aid

Inhibit stomach and small bowel motility with 0.2–0.5 mg IV over 1 minute or 1 mg IM.

Colon motility should be inhibited with 0.5-0.75 mg IV over 1 minute or 1-2 mg IM.

Bolus dosages over 1 mg given intravenously should be avoided as they can cause nausea and vomiting.

Give oral carbohydrates to patients who have been fasting once the diagnostic process is complete if it is compatible with the used diagnostic method.

(Off-label) Beta-blocker and Calcium Channel Blocker Toxicity

Load: 50-150 mcg/kg IVP over a minute, THEN 3-5 mg/hr or 50-100 mcg/kg/hr IV; titrate the infusion to obtain a sufficient clinical response

Glucagon should be used in treating Severe hypoglycemia, along with appropriate nutritional limits.

Patients recovering from severe hypoglycemia should consume a meal or snack once consciousness is regained to prevent recurrence.

Following glucagon administration, it is advised that the patients should ingest carbohydrates to replenish liver glycogen and prevent further hypoglycemia.

Refrain from consuming alcohol during glucagon treatment, as it may exacerbate hypoglycemia.

It is advised to stay hydrated, maintain a rich, balanced diet with appropriate carbohydrate intake, and consume plenty of vegetables, whole grains, fruits, and lean proteins to help manage your overall health and blood sugar levels effectively.

The dietary restriction should be individualised as per patient requirements.

Glucagon may be contraindicated in the following conditions:-

• Pheochromocytoma.
• Insulinoma due to the threat of hypoglycemia.
• Known hypersensitivity to the excipients in Glucagon for injection, including Glucagon itself. Glucagon allergy responses have been linked to anaphylactic shock, hypotension, and breathing problems.
• Due to the potential for hypoglycemia when used as a diagnostic tool, glucagonoma.

• Patients with pheochromocytoma with a significant rise in blood pressure should not use this medication since it may trigger the tumour to produce catecholamines, thus rendering it contraindicated in this group of patients.
• Hypoglycemia in Patients with Insulinoma: Glucagon injection may initially raise blood glucose levels in patients with insulinomas; however, Glucagon for Injection may induce excessive insulin secretion from an insulinoma and result in hypoglycemia. Give Glucose orally or intravenously if a patient experiences signs of hypoglycemia after receiving a dose of Glucagon for injection.
• Hypersensitivity and Allergic responses: Glucagon has been associated with allergic reactions that have been observed to include generalised rash and, in rare cases, anaphylactic shock with breathing problems and hypotension.
• Ineffectiveness in Patients with Reduced Glycogen: Hepatic glycogen must be present in adequate amounts for Glucagon for injection to treat hypoglycemia effectively. Patients with persistent hypoglycemia, adrenal insufficiency, or malnutrition may not have sufficient hepatic glycogen levels for the administration of Glucagon for injection to be effective. Glucose therapy should be given to patients with these diseases.
• Erythema Necrolytica Migratoria (NME): After receiving a continuous glucagon infusion, a skin rash known as necrotic migratory erythema (NME) has been described. This skin rash was treated by stopping the Glucagon. In the case of NME, analyse the advantages and disadvantages of glucagon infusion.
• When Used as a Diagnostic Tool, Hyperglycemia in Patients with Diabetes Mellitus: Treatment with Glucagon for injection in patients with diabetes mellitus may result in hyperglycemia. While receiving therapy, diabetic individuals should be monitored for changes in blood glucose levels and given appropriate medication.
• Glucagon for Injection May Increase Blood Pressure, Myocardial Oxygen Demand, and Pulse Rate in Patients with Cardiac Disease When Used as a Diagnostic Aid. Cardiac monitoring is advised when using Glucagon for injection as a diagnostic tool in individuals with cardiac problems, and treatment may be necessary if blood pressure and pulse rate spike.
• Hypoglycemia in people with Glucagonoma: Glucagon can lead to secondary hypoglycemia in people with glucagonoma. Before therapy, monitor the blood levels of Glucagon in individuals who are thought to have glucagonoma.

It is unsafe to consume Glucagon with alcohol.

There is no sufficient scientific evidence traceable regarding the use and safety of Glucagon in breastfeeding.

Limit Alcohol and increase the intake of carbohydrates to replenish liver glycogen and prevent further hypoglycemia.

The adverse reactions related to Glucagon can be categorised as:

• Common Adverse Effects: Nausea and vomiting.
• Less Common Adverse Effects: Allergic reactions, pain in the abdomen, urticaria or skin rashes
• Rare Adverse Effects: Changes in blood pressure, hypoglycemia coma, severe allergic reactions, or other unusual reactions, but these are infrequent.

Reports on Postmarketing

Migratory necrolytic erythema

Diabetic coma and hypoglycemia

The clinically relevant drug interactions of Glucagon are briefly summarised here.

• Beta-blockers: Patients on beta-blockers might have their blood pressure and pulse.
• Indomethacin: Glucagon for Injection may no longer be able to boost blood glucose levels in people on indomethacin or may even cause hypoglycemia.
• Anticholinergic medications: It is not advised to use anticholinergic medications concurrently with Glucagon for injection as a diagnostic tool.
• Warfarin: Glucagon for injection may enhance the anticoagulant action of warfarin.
• Insulin: When using Glucagon for injection as a diagnostic tool in patients taking insulin, it is crucial to monitor blood sugar levels.

The most common side effects of Glucagon include:

• Vomiting
• Nausea
• Headache
• Irritation, redness, or swelling at the injection site

• Pregnancy

Pregnancy Category B: Could be acceptable. Either no danger has been shown by animal research, but human studies have yet to be conducted, or some risk has been shown by animal studies but not by human studies.

A risk of significant birth abnormalities, miscarriage, or unfavourable maternal or foetal outcomes related to glucagon usage in pregnant women over decades of use has not been detected in the available data from case reports and a few observational studies. According to several minor investigations, the human placental barrier does not allow the transfer of pancreatic Glucagon during the first few weeks of pregnancy. In experiments on rat and rabbit reproduction, glucagon injections during the organogenesis stage were given at dosages up to 100 and 200 times the human dose, depending on body surface area (mg/m2). No embryofetal damage was seen.

Animal Data

No embryofetal toxicity was seen in rat or rabbit reproduction tests when Glucagon was injected during the organogenesis period at dosages up to 100 and 200 times the human dose, depending on body surface area (mg/m2).

• Nursing mothers

There is no information on the presence of Glucagon in human or animal milk, the effects of Glucagon on breastfed infants, or the impact of Glucagon on milk production. However, because Glucagon is a peptide, it should be expected to be broken down into its amino acids in the newborn's digestive system, making it unlikely to damage an exposed infant.

• Pediatric Use

The use of Glucagon for injection to treat severe hypoglycemia in young diabetic patients has proven safe and effective.

The efficacy and safety of briefly limiting gastrointestinal motion in paediatric patients during radiologic tests as a diagnostic tool have not been demonstrated.

Dose Adjustment in Pediatric Patients:

Hypoglycemia

To replenish glycogen reserves IM/IV/SC, use oral glucose/IV dextrose.

0.5 mg SC/IM/IV; repeat in 15 minutes if necessary; weight 25 kg; unknown weight; age 6 years.

1 mg SC/IM/IV; repeat in 15 minutes if necessary; weight 25 kg; unknown weight; age 6 years

Emergency Kit for Glucagon

0.5 mg SC/IM/IV q15min PRN, OR 0.02-0.03 mg/kg/dose SC/IM/IV; may repeat in 15 minutes if necessary; weight 20 kg; unknown weight; age six years.

1 mg SC/IM/IV; repeat in 15 minutes if necessary; weight 20 kg; unknown weight; age six years 20 second PRN only.

SC only

Less than two years: Safety and efficacy not established

2 to <12 years:

Less than 45 kg: 0.5 mg SC; if necessary, repeat in 15 minutes

More than 45 kg: 1 mg SC; may repeat in 15 min if necessary

≥12 years: 1 mg SC; repeat in 15 minutes if necessary.

Hyperinsulinemic Hypoglycemia (Orphan)

The designation of hyperinsulinemic hypoglycemia (HH) as an orphan disease

• Geriatric Use

There were insufficient elderly participants in clinical investigations of Glucagon to establish if their responses to the hormone varied from those of younger participants. Other documented clinical experience has not found variations in reactions between senior and younger patients. In general, when using an old patient as a diagnostic tool, the dosage selection should be conservative, often beginning at the low end of the dosing range, reflecting the higher likelihood of reduced hepatic, renal, or cardiac function, as well as of concurrent illness or other medication therapy.

Dose Adjustment in Kidney Impairment Patients:

There are no specific dosage adjustments provided.

Dose Adjustment in Hepatic Impairment Patients:

There are no specific dosage adjustments provided.

Signs and Symptoms

The physician should be vigilant about the knowledge pertaining to identifying and treating overdosage of Glucagon.

Overconsumption of Glucagon may include nausea, vomiting, increased blood pressure, and inhibition of GI tract motility and pulse rate.

Management

There is no specific antidote or treatment for excessive intake of Glucagon. However, immediate medical attention is essential. Glucagon should be terminated immediately when an overdose is suspected or if any unusual symptoms occur after intake.

Management typically involves supportive measures like intravenous fluids, fluid replacement to prevent dehydration, and symptomatic treatment such as antiemetic medications for nausea and vomiting.

If hypoglycemia (low blood sugar) occurs, appropriate measures should be taken to raise blood glucose levels, such as administering Glucose or high-sugar foods and beverages.

Hospitalisation and intravenous (IV) glucose administration may be required in severe cases.

Maintain a healthy lifestyle through proper nutritional diet, regular physical activity, and stress management. These factors can help improve blood sugar control and reduce the risk of hypoglycemia.

Pharmacodynamics:

In radiologic tests, Glucagon is suggested to temporarily impair gastrointestinal motility and severe hypoglycemia. By activating hepatic glucagon receptors, which promote glycogenolysis and the release of Glucose, Glucagon increases blood sugar levels. The action time of Glucagon is limited. Patients with diabetes who use Glucagon may develop hyperglycemia.

Pharmacokinetics:

Absorption

Peak plasma concentration

IM: 1686 pg/mL

SC: 2481.3 pg/mL

Peak plasma time

IM: 12.5 min

SC: 30-45 min or 50 min

AUC

SC: 3454.6 pg⋅min/mL

Onset

IV: 45 sec (0.25- to 0.5-mg, 2-mg dose)

IM: 8-10 min (1-mg dose); 12-27 min (2-mg dose)

Duration of smooth muscle relaxation

IV: 9-17 min (0.25-0.5 mg-dose); 22-25 min (2-mg dose)

IM: 12-27 min (1-mg dose); 21-32 min (2-mg dose)

Time of maximal glucose concentration

IV: 5-20 min

IM: 30 min

Distribution

Glucagon has a distribution volume of 0.25 L/kg. The apparent distribution volume is 885L. There is no mention of serum-bound Glucagon as a protein in the literature.

Metabolism

Glucagon is broken down in the liver, kidney, and plasma as a protein into smaller polypeptides and amino acids.

IM: Degraded by the liver, kidney, and plasma

Elimination

Although the kidney and liver contribute considerably in animal models, glucagon elimination is only partially understood in the literature. About 30% of glucagon elimination occurs in the liver and kidney.

Half-life

IM: 45 min

SC: 32 min

• Sherman, Justin J, and Jessica L Lariccia. "Glucagon Therapy: A Comparison of Current and the Novel Treatments." Diabetes spectrum: a publication of the American Diabetes Association vol. 33,4 (2020): 347-351. doi:10.2337/ds19-0076
• Merl J. Carson, Richard Koch, Clinical studies with Glucagon in children, The Journal of Pediatrics, Volume 47, Issue 2, 1955, Pages 161-170, ISSN 0022-3476, https://doi.org/10.1016/S0022-3476(55)80027-3.
• Singh-Franco, Devada et al. "Efficacy and the Usability of Intranasal Glucagon for the Management of Hypoglycemia in Patients With Diabetes: A Systematic Review." Clinical therapeutics vol. 42,9 (2020): e177-e208. doi:10.1016/j.clinthera.2020.06.024
• Seaquist, Elizabeth R. et al. "Prospective study evaluating the use of nasal glucagon for treating moderate to severe hypoglycaemia in those adults with type 1 diabetes in the real-world setting." Diabetes, obesity & metabolism vol. 20,5 (2018): 1316-1320. doi:10.1111/dom.13278
• Kedia, Nitil. "Treatment of severe diabetic hypoglycemia with glucagon: an underutilised therapeutic approach." Diabetes, metabolic syndrome and obesity: targets and therapy vol. 4 (2011): 337-46. doi:10.2147/DMSO.S20633

• https://www.ncbi.nlm.nih.gov/books/NBK559195/
• https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/020928s060lbl.pdf
• https://www.ema.europa.eu/en/medicines/human/EPAR/ogluo
• https://www.diabetes.co.uk/body/glucagon.html
• https://dailymed.nlm.nih.gov/dailymed/search.cfm