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Chemistry/Preparation
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Glucagon is a polypeptide counterregulatory hormone with a molecular weight of 3500 Da, secreted by the α cells of the pancreas. Previously animal derived, and possibly contaminated with insulin, the form approved by the US Food and Drug Administration (FDA) has been synthesized by recombinant DNA technology since 1998; therefore, it no longer contains any insulin.25
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In both animals and humans, glucagon receptors can be found in the heart, brain, and pancreas.22,33,64 Binding of glucagon to cardiac receptors is closely correlated with activation of cardiac adenylate cyclase (AC).52 A large number of glucagon binding sites are demonstrated, and as little as 10% occupancy produces near maximal stimulation of adenylate cyclase. Binding of glucagon to its receptor results in coupling with two isoforms of the Gs protein and catalyzes the exchange of guanosine triphosphate (GTP) for guanosine diphosphate on the α subunit of the Gs protein.21,51,69 One isoform is coupled to β agonists, while both isoforms are coupled to glucagon.69 The GTP-Gs units stimulate adenylate cyclase to convert adenosine triphosphate (ATP) to cAMP.32,40 In animal hearts, glucagon inhibits the phosphodiesterase PDE-3.5,43 Selective inhibition of PDE-4 potentiated the cAMP response to glucagon in adult rat ventricular myocytes.50 Glucagon, along with β2 agonists, histamine, and serotonin (but not β1 agonists), also activates Gi, which inhibits cAMP formation in human atrial heart tissue.27
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Evidence now suggests an additional mechanism of action for glucagon, independent of cAMP, and dependent on arachidonic acid.57 Cardiac tissue metabolizes glucagon, liberating mini-glucagon, an apparently active smaller terminal fragment.57,66 Mini-glucagon stimulates phospholipase A2, releasing arachidonic acid. Arachidonic acid acts to increase cardiac contractility through an effect on calcium. The effect of arachidonic acid—and therefore of mini-glucagon—is synergistic with the effect of glucagon and cAMP.58
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Stimulation of glucagon receptors in the liver and adipose tissue increases cAMP synthesis, resulting in glycogenolysis, gluconeogenesis, and ketogenesis.32 Other properties of glucagon include relaxation of smooth muscle in the lower esophageal sphincter, stomach, small and large intestines, common bile duct, and ureters.18,21,30
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Cardiovascular Effects
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Investigations of the mechanism of action of glucagon on the heart have been performed on cardiac tissue obtained from patients during surgical procedures and in a variety of in vivo and ex vivo animal studies. The results are often species specific and are affected by the presence or absence of congestive heart failure. The inotropic action of glucagon is likely related to an increase in cardiac cAMP concentrations.12,32,40 Both the positive inotropic3,15,38,45 and chronotropic3,12,15,30,38,40,45,67 actions of glucagon are very similar to those of the β-adrenergic agonists, except that they are not blocked by β-adrenergic antagonists.69 Although in some canine experiments glucagon caused ventricular tachycardia, glucagon is not dysrhythmogenic in patients with severe chronic congestive heart failure, myocardial infarction–related acute congestive heart failure, or in postoperative patients with myocardial depression.26,34,39,42 The effects of glucagon diminish markedly as the severity and chronicity of congestive heart failure increases.45
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Cardiovascular effects were extensively studied in 21 patients with heart failure who were given varied doses and durations of glucagon therapy.46 Eleven patients who received 3 to 5 mg via intravenous (IV) bolus had increases in the force of contraction, as measured by maximum dP/dT (upstroke pattern on apex cardiogram), heart rate, cardiac index, blood pressure, and stroke work. There was no change in systemic vascular resistance, left ventricular end-diastolic pressure, or stroke index. Additionally, glucose concentrations increased by 50% and the potassium concentrations fell. A study of nine patients demonstrated a 30% increase in coronary blood flow following a 50 µg/kg IV dose.42 Patients who received 1 mg via IV bolus also had an increase in cardiac index, but systemic vascular resistance fell, probably secondary to splanchnic and hepatic vascular smooth muscle relaxation.46 Patients who received an infusion of 2 to 3 mg/min for 10 to 15 minutes responded similarly to those who received the 3 to 5 mg IV boluses, but patients receiving boluses experienced significant dose limiting nausea and vomiting.46
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Pharmacokinetics and Pharmacodynamics
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The volume of distribution of glucagon is 0.25 L/kg.16 The plasma, liver, and kidney extensively metabolize glucagon with an elimination half-life of 8 to 18 minutes.16 In human volunteers following a single 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.45 The time to maximal glucose concentration is 5 to 20 minutes, with a duration of action of 60 to 90 minutes.16 Smooth muscle relaxation begins within 1 minute and lasts 10 to 20 minutes.16 The onset of action following intramuscular and subcutaneous administration occurs in about 10 minutes, with a peak at about 30 minutes.16
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Activation of AC in adipose, myocardial, and hepatic tissue and myocardial contractility requires pharmacologic levels of glucagon, exceeding 0.1 nM.52 At physiologic concentrations of glucagon below 0.1 nM, it appears to duplicate the cardiac metabolic effects of insulin by activating a phosphatidylinositol-3 kinase (PI3K)-dependent signal without stimulating AC.52 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 generated cAMP.24,70 Possible explanations for tachyphylaxis include uncoupling from the glucagon receptor, increased PDE hydrolysis of cAMP, or both.24,66,70,73 Other experiments demonstrated a transient effect of glucagon on contractility and hyperglycemia, also suggesting tachyphylaxis.20,26