Antidote Glucagon
Antidote Glucagon
Antidote Glucagon
INTRODUCTION
The traditional role of glucagon was to reverse life-threatening hypoglycemia in patients with
diabetes unable to receive dextrose in the outpatient setting. However, in medical toxicology,
glucagon is used “off label” early in the management of β-adrenergic antagonist and calcium channel
blocker toxicity to increase heart rate, contractility, and blood pressure by increasing myocardial
cyclic adenosine monophosphate (cAMP) via a non–β-adrenergic receptor mechanism of action.
The use of glucagon is based primarily on animal studies and as well as human case series and
case reports. The effects of glucagon are often transient.
HISTORY
Glucagon was discovered in 1923, just 2 years after the discovery of insulin.10 The positive inotropic
and chronotropic effects have been known since the 1960s.12,15
PHARMACOLOGY
Chemistry/Preparation
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
Mechanism of Action
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-Gsunits 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.50Glucagon,
along with β2 agonists, histamine, and serotonin (but not β1agonists), also activates Gi, which inhibits
cAMP formation in human atrial heart tissue.27
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
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
Cardiovascular Effects
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
Volunteer Studies
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.42Patients 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
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
Glucagon successfully reversed the bradycardia, low-output heart failure, and hypotension that
developed in a premature newborn, presumably as a result of an inappropriately large prenatal dose
of labetalol given to the mother. This neonate, delivered at 32 weeks’ gestation and weighing 1.8 kg,
received 0.3 mg/kg glucagon IV initially and five additional doses of 0.3 to 0.6 mg/kg over the next 5
hours, with improvement in heart rate, blood pressure, and perfusion. Epinephrineand diuretics were
also used.59
Combined Effects with Phosphodiesterase Inhibitors and Calcium
Strategies for enhancing the effects of glucagon have involved combining it with the PDE-3 inhibitor
amrinone (inamrinone), its derivative milrinone, and most recently rolipram, a selective PDE-4
inhibitor. In a canine model of propranolol toxicity, both amrinone (inamrinone) and milrinone, alone
were comparable with glucagon,36,56but the combination of amrinone and glucagon resulted in a
decrease in mean arterial pressure.35 Tachycardia occurred when milrinone was used with -
glucagon.55 In an ex vivo model using strips of rat ventricular heart, rolipram enhanced the inotropic
effect of glucagon and limited glucagon tachyphylaxis.24 However, because the evidence for the
effectiveness of HIE was demonstrated in animal models and human case reports, combining
glucagon with a phosphodiesterase inhibitor is no longer recommended.
The relationship between calcium and the chronotropic effects of glucagon was demonstrated in
rats.8 Maximal chronotropic effects of glucagon are dependent on a normal circulating ionized
calcium. Both hypocalcemia and hypercalcemia blunt the maximal chronotropic response.7,8
In patients with insulinoma, after an initial hyperglycemic response glucagon may actually worsen
hypoglycemia, as the result of a feedback increase in insulin.
ADVERSE EFFECTS AND SAFETY ISSUES
Side effects associated with glucagon include dose-dependent nausea, vomiting,39 hyperglycemia,
hypoglycemia, and hypokalemia; relaxation of the smooth muscle of the stomach, duodenum, small
bowel, and colon; and, rarely, urticaria, respiratory distress, and hypotension.16,39Hypotension is
reported up to 2 hours after administration in patients receiving glucagon as premedication for upper
gastrointestinal endoscopy procedures.16 The hyperglycemia is followed by an immediate rise in
insulin, which causes an intracellular shift in potassium, resulting in hypokalemia.20,39,45 It is unclear
whether stimulation of the Na+-K+-ATPase in skeletal muscle also contributes to the hypokalemia as
occurs with β-adrenergic agonists.29,48 Glucagon may increase the anticoagulant effect of warfarin.16
Glucagon can also increase the release of catecholamines in a patient with a pheochromocytoma,
resulting in a hypertensive crisis,20 which can be treated with phentolamine.16 Continuous prolonged
treatment with glucagon might lead to a dilated cardiomyopathy, as was reported in a patient with a
glucagonoma.6
SUMMARY
Glucagon can produce positive inotropic and chronotropic effects despite β-adrenergic
antagonism and calcium channel blockade.
The effects of glucagon may not persist and other therapies, such as insulin and dextrose,
should also be considered (Chaps. 61 and 62).
The relatively benign character of an IV bolus of glucagon in the patient with a serious
overdose of a β-adrenergic antagonist or calcium channel blocker should lead the clinician to
use glucagon early in patient management.
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