Glucagon (medication)

This article is about the medication. For the natural hormone, see Glucagon.

Glucagon
Glucagon ball and stick model, with the carboxyl terminus above and the amino terminus below
Clinical data
Trade namesGlucagen, Baqsimi, Gvoke, others
AHFS/Drugs.comMonograph
MedlinePlusa682480
License data
Pregnancy
category
Routes of
administration		Nasal, intravenous (IV), intramuscular injection (IM), subcutaneous injection
ATC code
Legal status
Legal status
Identifiers
  • Glucagon
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC153H225N43O49S
Molar mass3482.80 g·mol−1
3D model (JSmol)
  • C[C@H]([C@@H](C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](Cc2ccc(cc2)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](Cc3ccc(cc3)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](Cc4ccccc4)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](Cc5c[nH]c6c5cccc6)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H]([C@@H](C)O)C(=O)O)NC(=O)CNC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CO)NC(=O)[C@H](Cc7cnc[nH]7)N)O
  • InChI=1S/C153H225N43O49S/c1-72(2)52-97(133(226)176-96(47-51-246-11)132(225)184-104(60-115(159)209)143(236)196-123(78(10)203)151(244)245)179-137(230)103(58-83-64-167-89-29-19-18-28-87(83)89)183-131(224)95(43-46-114(158)208)177-148(241)120(74(5)6)194-141(234)101(54-79-24-14-12-15-25-79)182-138(231)105(61-117(211)212)185-130(223)94(42-45-113(157)207)171-124(217)75(7)170-127(220)91(31-22-49-165-152(160)161)172-128(221)92(32-23-50-166-153(162)163)174-146(239)110(69-199)191-140(233)107(63-119(215)216)186-134(227)98(53-73(3)4)178-135(228)99(56-81-33-37-85(204)38-34-81)180-129(222)90(30-20-21-48-154)173-145(238)109(68-198)190-136(229)100(57-82-35-39-86(205)40-36-82)181-139(232)106(62-118(213)214)187-147(240)111(70-200)192-150(243)122(77(9)202)195-142(235)102(55-80-26-16-13-17-27-80)188-149(242)121(76(8)201)193-116(210)66-168-126(219)93(41-44-112(156)206)175-144(237)108(67-197)189-125(218)88(155)59-84-65-164-71-169-84/h12-19,24-29,33-40,64-65,71-78,88,90-111,120-123,167,197-205H,20-23,30-32,41-63,66-70,154-155H2,1-11H3,(H2,156,206)(H2,157,207)(H2,158,208)(H2,159,209)(H,164,169)(H,168,219)(H,170,220)(H,171,217)(H,172,221)(H,173,238)(H,174,239)(H,175,237)(H,176,226)(H,177,241)(H,178,228)(H,179,230)(H,180,222)(H,181,232)(H,182,231)(H,183,224)(H,184,225)(H,185,223)(H,186,227)(H,187,240)(H,188,242)(H,189,218)(H,190,229)(H,191,233)(H,192,243)(H,193,210)(H,194,234)(H,195,235)(H,196,236)(H,211,212)(H,213,214)(H,215,216)(H,244,245)(H4,160,161,165)(H4,162,163,166)/t75-,76+,77+,78+,88-,90-,91-,92-,93-,94-,95-,96-,97-,98-,99-,100-,101-,102-,103-,104-,105-,106-,107-,108-,109-,110-,111-,120-,121-,122-,123-/m0/s1 checkY
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Glucagon, sold under the brand name Baqsimi among others, is a medication and hormone.[9] As a medication it is used to treat low blood sugar, beta blocker overdose, calcium channel blocker overdose, and those with anaphylaxis who do not improve with epinephrine.[10] It is given by injection into a vein, muscle, or under the skin.[10] A version given in the nose is also available.[11]

Common side effects include vomiting.[10] Other side effects include low blood potassium and low blood pressure.[9] It is not recommended in people who have a pheochromocytoma or insulinoma.[10] Use in pregnancy has not been found to be harmful to the baby.[12] Glucagon is in the glycogenolytic family of medications.[10] It works by causing the liver to break down glycogen into glucose.[10]

Glucagon was approved for medical use in the United States in 1960.[10] It is on the World Health Organization's List of Essential Medicines.[13] It is a manufactured form of the glucagon hormone.[10] A generic version became available in the United States in December 2020.[14]

Medical uses

A closed glucagon injection kit
An open glucagon injection kit

Low blood sugar

An injectable form of glucagon may be part of first aid in cases of low blood sugar when the person is unconscious or for other reasons cannot take glucose orally or by intravenous.[15] The glucagon is given by intramuscular, intravenous or subcutaneous injection, and quickly raises blood glucose levels. To use the injectable form, it must be reconstituted prior to use, a step that requires a sterile diluent to be injected into a vial containing powdered glucagon, because the hormone is highly unstable when dissolved in solution. When dissolved in a fluid state, glucagon can form amyloid fibrils, or tightly woven chains of proteins made up of the individual glucagon peptides, and once glucagon begins to fibrilize, it becomes useless when injected, as the glucagon cannot be absorbed and used by the body. The reconstitution process makes using glucagon cumbersome, although there are a number of products now in development from a number of companies that aim to make the product easier to use.

A Baqsimi nasal glucagon canister

Beta blocker overdose

Anecdotal evidence suggests a benefit of higher doses of glucagon in the treatment of overdose with beta blockers; the likely mechanism of action is the increase of cAMP in the myocardium, in effect bypassing the β-adrenergic second messenger system.[16]

Anaphylaxis

Some people who have anaphylaxis and are on beta blockers are resistant to epinephrine. In this situation glucagon intravenously may be useful to treat their low blood pressure.[17]

Impacted food bolus

Glucagon relaxes the lower esophageal sphincter and may be used in those with an impacted food bolus in the esophagus ("steakhouse syndrome").[18] There is little evidence for glucagon's effectiveness in this condition,[19][20][21] and glucagon may induce nausea and vomiting,[21] but considering the safety of glucagon this is still considered an acceptable option as long it does not lead to delays in arranging other treatments.[22][23]

Endoscopic retrograde cholangiopancreatography

Glucagon's effect of increasing cAMP causes relaxation of splanchnic smooth muscle, allowing cannulation of the duodenum during the endoscopic retrograde cholangiopancreatography (ERCP) procedure.

Adverse effects

Glucagon acts very quickly; common side-effects include headache and nausea.

Drug interactions: Glucagon interacts only with oral anticoagulants, increasing the tendency to bleed.[24]

Contraindications

While glucagon can be used clinically to treat various forms of hypoglycemia, it is contraindicated in patients with pheochromocytoma, as it can induce the tumor to release catecholamines, leading to a sudden elevation in blood pressure.[4] Likewise, glucagon is contraindicated in patients with an insulinoma, as its hyperglycemic effect can induce the tumor to release insulin, leading to rebound hypoglycemia.[4]

Mechanism of action

Metabolic regulation of glycogen by glucagon.

Glucagon binds to the glucagon receptor, a G protein-coupled receptor, located in the plasma membrane. The conformation change in the receptor activates G proteins, a heterotrimeric protein with α, β, and γ subunits. When the G protein interacts with the receptor, it undergoes a conformational change that results in the replacement of the GDP molecule that was bound to the α subunit with a GTP molecule. This substitution results in the releasing of the α subunit from the β and γ subunits. The alpha subunit specifically activates the next enzyme in the cascade, adenylate cyclase.[25]

Adenylate cyclase manufactures cyclic adenosine monophosphate (cyclic AMP or cAMP), which activates protein kinase A (cAMP-dependent protein kinase). This enzyme, in turn, activates phosphorylase kinase, which then phosphorylates glycogen phosphorylase b, converting it into the active form called phosphorylase a. Phosphorylase a is the enzyme responsible for the release of glucose-1-phosphate from glycogen polymers.[25]

Additionally, the coordinated control of glycolysis and gluconeogenesis in the liver is adjusted by the phosphorylation state of the enzymes that catalyze the formation of a potent activator of glycolysis called fructose-2,6-bisphosphate.[26] The enzyme protein kinase A that was stimulated by the cascade initiated by glucagon will also phosphorylate a single serine residue of the bifunctional polypeptide chain containing both the enzymes fructose-2,6-bisphosphatase and phosphofructokinase-2. This covalent phosphorylation initiated by glucagon activates the former and inhibits the latter. This regulates the reaction catalyzing fructose-2,6-bisphosphate (a potent activator of phosphofructokinase-1, the enzyme that is the primary regulatory step of glycolysis)[27] by slowing the rate of its formation, thereby inhibiting the flux of the glycolysis pathway and allowing gluconeogenesis to predominate. This process is reversible in the absence of glucagon (and thus, the presence of insulin).

Glucagon stimulation of PKA also inactivates the glycolytic enzyme pyruvate kinase.[28]

History

In the 1920s, Kimball and Murlin studied pancreatic extracts, and found an additional substance with hyperglycemic properties. They described glucagon in 1923.[29] The amino acid sequence of glucagon was described in the late 1950s.[30] A more complete understanding of its role in physiology and disease was not established until the 1970s, when a specific radioimmunoassay was developed.

A nasal version was approved for use in the United States and Canada in 2019.[11][31][32][33][34]

In December 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Ogluo, intended for the treatment of severe hypoglycemia in diabetes mellitus.[35] The applicant for this medicinal product is Xeris Pharmaceuticals Ireland Limited. It was approved for medical use in the European Union in February 2021.[7]

References

  1. ^ "Glucagon Use During Pregnancy". Drugs.com. 16 October 2019. Retrieved 16 May 2020.
  2. ^ "Baqsimi Product information". Health Canada. Retrieved 30 March 2024.
  3. ^ "GlucaGen Hypokit 1 mg - Summary of Product Characteristics (SmPC)". (emc). 15 June 2015. Retrieved 16 May 2020.
  4. ^ a b c "Glucagon kit". DailyMed. Retrieved 27 February 2021.
  5. ^ "Baqsimi- glucagon powder". DailyMed. Retrieved 27 February 2021.
  6. ^ "Baqsimi EPAR". European Medicines Agency. 17 October 2019. Retrieved 27 February 2021.
  7. ^ a b "Ogluo EPAR". European Medicines Agency (EMA). 9 December 2020. Retrieved 27 February 2021.
  8. ^ "Ogluo Product information". Union Register of medicinal products. Retrieved 3 March 2023.
  9. ^ a b British national formulary : BNF 69 (69 ed.). British Medical Association. 2015. p. 487. ISBN 9780857111562.
  10. ^ a b c d e f g h "Glucagon". The American Society of Health-System Pharmacists. Archived from the original on 26 December 2016. Retrieved 8 December 2016.
  11. ^ a b "FDA approves first treatment for severe hypoglycemia that can be administered without an injection". U.S. Food and Drug Administration (FDA) (Press release). 24 July 2019. Retrieved 16 May 2020.
  12. ^ "Glucagon (GlucaGen) Use During Pregnancy". www.drugs.com. Archived from the original on 27 December 2016. Retrieved 27 December 2016.
  13. ^ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  14. ^ "FDA Approves First Generic of Drug Used to Treat Severe Hypoglycemia". U.S. Food and Drug Administration (FDA) (Press release). 28 December 2020. Retrieved 28 December 2020.
  15. ^ CDC (5 June 2024). "Treatment of Low Blood Sugar (Hypoglycemia)". Diabetes. Retrieved 27 July 2024.
  16. ^ White CM (May 1999). "A review of potential cardiovascular uses of intravenous glucagon administration". Journal of Clinical Pharmacology. 39 (5): 442–447. doi:10.1177/009127009903900502. PMID 10234590. S2CID 34512730.
  17. ^ Tang AW (October 2003). "A practical guide to anaphylaxis". American Family Physician. 68 (7): 1325–1332. PMID 14567487.
  18. ^ Ko HH, Enns R (October 2008). "Review of food bolus management". Canadian Journal of Gastroenterology. 22 (10): 805–808. doi:10.1155/2008/682082. PMC 2661297. PMID 18925301.
  19. ^ Arora S, Galich P (March 2009). "Myth: glucagon is an effective first-line therapy for esophageal foreign body impaction". CJEM. 11 (2): 169–171. doi:10.1017/s1481803500011143. PMID 19272219.
  20. ^ Leopard D, Fishpool S, Winter S (September 2011). "The management of oesophageal soft food bolus obstruction: a systematic review". Annals of the Royal College of Surgeons of England. 93 (6): 441–444. doi:10.1308/003588411X588090. PMC 3369328. PMID 21929913.
  21. ^ a b Weant KA, Weant MP (April 2012). "Safety and efficacy of glucagon for the relief of acute esophageal food impaction". American Journal of Health-System Pharmacy. 69 (7): 573–577. doi:10.2146/ajhp100587. PMID 22441787.
  22. ^ Ikenberry SO, Jue TL, Anderson MA, Appalaneni V, Banerjee S, Ben-Menachem T, et al. (June 2011). "Management of ingested foreign bodies and food impactions" (PDF). Gastrointestinal Endoscopy. 73 (6): 1085–1091. doi:10.1016/j.gie.2010.11.010. PMID 21628009. Archived (PDF) from the original on 8 August 2013.
  23. ^ Chauvin A, Viala J, Marteau P, Hermann P, Dray X (July 2013). "Management and endoscopic techniques for digestive foreign body and food bolus impaction". Digestive and Liver Disease. 45 (7): 529–542. doi:10.1016/j.dld.2012.11.002. PMID 23266207.
  24. ^ Koch-Weser J (March 1970). "Potentiation by glucagon of the hypoprothrombinemic action of warfarin". Annals of Internal Medicine. 72 (3): 331–335. doi:10.7326/0003-4819-72-3-331. PMID 5415418.
  25. ^ a b Rix I, Nexøe-Larsen C, Bergmann NC, Lund A, Knop FK (2000). "Glucagon Physiology". In Feingold KR, Anawalt B, Boyce A, Chrousos G (eds.). Endotext. South Dartmouth (MA): MDText.com, Inc. PMID 25905350. Retrieved 6 April 2022.
  26. ^ Hue L, Rider MH (July 1987). "Role of fructose 2,6-bisphosphate in the control of glycolysis in mammalian tissues". The Biochemical Journal. 245 (2): 313–324. doi:10.1042/bj2450313. PMC 1148124. PMID 2822019.
  27. ^ Claus TH, El-Maghrabi MR, Regen DM, Stewart HB, McGrane M, Kountz PD, et al. (1984). "The role of fructose 2,6-bisphosphate in the regulation of carbohydrate metabolism". Current Topics in Cellular Regulation. 23: 57–86. doi:10.1016/b978-0-12-152823-2.50006-4. ISBN 9780121528232. PMID 6327193.
  28. ^ Feliú JE, Hue L, Hers HG (August 1976). "Hormonal control of pyruvate kinase activity and of gluconeogenesis in isolated hepatocytes". Proceedings of the National Academy of Sciences of the United States of America. 73 (8): 2762–2766. Bibcode:1976PNAS...73.2762F. doi:10.1073/pnas.73.8.2762. PMC 430732. PMID 183209.
  29. ^ Kimball C, Murlin J (1923). "Aqueous extracts of pancreas III. Some precipitation reactions of insulin". J. Biol. Chem. 58 (1): 337–348. doi:10.1016/S0021-9258(18)85474-6. Archived from the original on 29 September 2007.
  30. ^ Bromer W, Winn L, Behrens O (1957). "The amino acid sequence of glucagon V. Location of amide groups, acid degradation studies and summary of sequential evidence". J. Am. Chem. Soc. 79 (11): 2807–2810. doi:10.1021/ja01568a038.
  31. ^ "Drug Approval Package: Baqsimi". U.S. Food and Drug Administration (FDA). 25 November 2019. Retrieved 17 May 2020.
  32. ^ "Ready for rescue: new nasally administered glucagon for severe hypoglycemia approved in Canada!". Diabetes Canada. 12 December 2019. Retrieved 16 May 2020.
  33. ^ "GLUCAGON NASAL POWDER (BAQSIMI — ELI LILLY CANADA INC)" (PDF). CADTH. 22 January 2020. Retrieved 16 May 2020.
  34. ^ "glucagon". CADTH.ca. 25 June 2019. Retrieved 17 May 2020.
  35. ^ "Ogluo: Pending EC decision". European Medicines Agency (EMA). 10 December 2020. Archived from the original on 1 January 2021. Retrieved 11 December 2020. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.

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The neutrality of this article is disputed. Relevant discussion may be found on the talk page. Please do not remove this message until conditions to do so are met. (April 2020) (Learn how and when to remove this message) This article needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed.Find sources: United States–Zambia relations – news · newspapers ...

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