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A18: Antidotes in Depth

Mary Ann Howland

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

Pharmacokinetics and Pharmacodynamics


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

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

ROLE IN THE MANAGEMENT OF OVERDOSES WITH β-


ADRENERGIC ANTAGONISTS
Overdoses with β-adrenergic antagonists are particularly dangerous and are manifested by
hypotension, bradycardia, prolonged atrioventricular conduction times, depressed cardiac output,
and cardiac failure. Other noncardiovascular effects include alterations in consciousness, seizures,
and, rarely, hypoglycemia.1,14,19,65 Management is often complicated, and many therapies,
including atropine, isoproterenol, epinephrine, norepinephrine, dopamine, dobutamine, and various
combinations, are used with variable success.13,14 Recently high dose insulin with dextrose (Antidotes
in Depth: A17), and in the event of a cardiac arrest, IV fat emulsion (Antidotes in Depth: A20), have
been added to the armamentarium. Animal studies document the ability of glucagon to increase
contractility, restore the sinus node function after sinus node arrest, increase atrioventricular
conduction, and rarely improve survival.2,36,45,55 In canine studies, high-dose insulin euglycemia (HIE)
therapy has a more sustained effect on hemodynamic parameters and an improved survival rate
compared with glucagon.26 Glucagon has successfully reversed bradydysrhythmias and hypotension
in patients unresponsive to the aforementioned traditional xenobiotics, and should be administered
early in the management of patients with severe overdoses.54,63 By increasing myocardial cAMP
concentrations independent of the β receptor,36,44 glucagon is able to increase inotropy3,15,38,45 and
chronotropy.3,15,38,45,67

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

ROLE IN CALCIUM CHANNEL BLOCKER OVERDOSE


Calcium channel blocker overdoses produce a constellation of clinical findings similar to those
recognized with β-adrenergic antagonist overdoses, including hypotension, bradycardia, conduction
block, and myocardial depression. Animal studies2,23,53,60,61,71,72 demonstrate the ability of glucagon to
improve heart rate, atrioventricular conduction, and reverse the myocardial depression produced
by nifedipine, diltiazem, and verapamil. However, there was no survival benefit attributed to
glucagon in these studies, while a canine model of verapamil overdose comparing glucagon to HIE
only revealed a survival benefit for HIE.2,28Human case reports demonstrate improved
hemodynamics.11,41,44,62

ROLE IN REVERSAL OF HYPOGLYCEMIA


Glucagon was once proposed as part of the initial treatment for all comatose patients because it
stimulates glycogenolysis in the liver.49The theoretical rationale for this approach is only partially
sound in that glucagon requires time to act and may be ineffective in a patient with already depleted
glycogen stores. Patients with type 2 diabetes are more likely to respond than are patients with type
1 diabetes. The IV administration of 0.5 to 1.0 g/kg of 50% dextrose in adults rapidly reverses
hypoglycemia and does not rely on glycogen stores for its effect. Therefore, IV dextrose is preferred
over glucagon as the initial substrate to be given to all patients with an altered mental status
presumed to be related to hypoglycemia (Antidotes in Depth: A12). Glucagon may retain some role
as a temporizing measure, until medical help can be obtained, in settings such as in the home where
IV dextrose is not an option, or when IV access is not rapidly available.

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

PREGNANCY AND LACTATION


Glucagon is FDA pregnancy category B. It is presumed that benefit exceeds risk. There are no
reports of glucagon use during lactation. However, the size and peptide nature of glucagon suggest
that the exposure to a lactating infant would be limited.

DOSAGE AND ADMINSTRATION


An initial IV bolus of 50 µg/kg, infused over 1 to 2 minutes, is recommended (3–5 mg in a 70-kg
person).14 If clinically acceptable, then a longer duration of infusion may be used to minimize
vomiting. Higher doses may be necessary if the initial bolus is ineffective, and up to 10 mg can be
used in an adult.22 Using too small a dose can potentially decrease systemic vascular resistance.46 In
some cases, the bolus dose should be followed by a continuous infusion of 2 to 5 mg/h (≤ 10 mg/h)
in 5% dextrose in water, which can be tapered as the patient improves.1,21,22,47,54,65 This dosing regimen
has never been studied and is based on case reports. Experimental heart preparations clearly
demonstrate tachyphylaxis with continuous administration. Whether this occurs in humans is
unclear, but might argue for repeated bolus infusions over 1 to 5 minutes rather than continuous
infusion.24,70 In addition, the smooth muscle relaxation associated with a continuous infusion would be
assumed to impede attempts at gastrointestinal decontamination with multiple-dose activated
charcoal or whole-bowel irrigation.

FORMULATION AND ACQUISITION


Glucagon [rDNA origin] for injection is available as a sterile, lyophilized white powder in a vial, alone,
or accompanied by Sterile Water for Reconstitution, also in a vial. It is also supplied in the form of a
kit for treatment of hypoglycemia with one vial containing 1 mg (1 unit) of glucagon [rDNA origin] for
injection with a disposable prefilled syringe containing Sterile Water for Reconstitution, as well as a
“10-pack” with 10 vials, each containing 1 mg (1 unit) GlucaGen (glucagon [rDNA origin] for
injection). The glucagon powder should be reconstituted with 1 mL of sterile water for injection, after
which the vial should be shaken gently until the powder completely dissolves. The final solution
should be clear, without visible particles.16 The reconstituted glucagon should be used immediately
after reconstitution, and any unused part discarded. Concentrations greater than 1 mg/mL should not
be used. An adequate supply of glucagon in the emergency department is at least 20 1-mg vials,
with assurance of another 30 mg in the pharmacy.9,37

SUMMARY
 Glucagon can produce positive inotropic and chronotropic effects despite β-adrenergic
antagonism and calcium channel blockade.

 Glucagon is often beneficial in the treatment of patients with severe overdoses of β-


adrenergic antagonists and calcium channel blockers.

 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.

 Nausea and vomiting should be anticipated and managed.

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