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Glucagon is a polypeptide counterregulatory hormone with a molecular weight of 3500 daltons, secreted by the α-cells of the pancreas. Glucagon was discovered in 1923, just 2 years after the discovery of insulin.9 Previously animal derived, and possibly contaminated with insulin, the current Food and Drug Administration (FDA)-approved form has been synthesized by recombinant DNA technology since 1998.29 Its traditional role was to reverse life-threatening hypoglycemia in diabetic patients who were unable to ingest dextrose in the outpatient setting. In medical toxicology, however, glucagon is used in the management of β-adrenergic antagonist and calcium channel blocker toxicity.

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The volume of distribution of glucagon is 0.25 L/kg.19 The plasma, liver, and kidney extensively metabolize glucagon with an elimination half-life of 8 to 18 minutes.19 In human volunteers following a single intravenous (IV) bolus, the cardiac effects of glucagon begin within 1 to 3 minutes, are maximal within 5 to 7 minutes, and persist for 10 to 15 minutes.50 The time to maximal glucose concentration is 5 to 20 minutes, with a duration of action of 60 to 90 minutes.20 Smooth muscle relaxation begins within 1 minute and lasts 10 to 20 minutes.20 The onset of action following intramuscular and subcutaneous administration occurs in about 10 minutes, with a peak at about 30 minutes.19

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Tachyphylaxis or desensitization of receptors may occur with repetitive dosing. Experimental heart preparations exposed to glucagon for varying lengths of time demonstrated a decrease in the amount of cyclic adenosine monophosphate (cAMP) generated.28,74 Possible explanations for tachyphylaxis include uncoupling from the glucagon receptor and/or increased phosphodiesterase (PDE) hydrolysis of cAMP.28,70,74,77 Other experiments demonstrated a transient effect of glucagon on contractility and hyperglycemia, also suggesting tachyphylaxis.24,30

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Glucagon receptors are demonstrated in animal and human hearts and brains as well as the pancreas, and binding is closely correlated with activation of cardiac adenylate cyclase.26,37,68 A large number of glucagon binding sites are demonstrated, and as little as 10% occupancy produces near maximal stimulation of adenylate cyclase. The binding of glucagon to its receptor results in coupling with two isoforms of the Gs protein, catalyzing the exchange of guanosine triphosphate (GTP) for guanosine diphosphate (GDP) on the α subunit of the Gs protein.25,56,73 One isoform is coupled to β agonists, while both isoforms are coupled to glucagon.73 The GTP-Gs units stimulate adenylate cyclase to convert adenosine triphosphate (ATP) to cAMP.36,44 In frog, mouse, and guinea pig hearts, glucagon also inhibits the cyclic guanosine monophosphate (cGMP)-inhibited, milrinone-sensitive phosphodiesterase, PDE-3.4,47 Selective inhibition of PDE-4 potentiated the cAMP response to glucagon in adult rat ventricular myocytes.55 Glucagon, along with β2 agonists, histamine, and serotonin (but not β1 agonists), also activates Gi, which inhibits cAMP formation in human atrial heart tissue.31

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Stimulation of glucagon receptors ...

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