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.

References

1.

Agura E, Wexler L, Witzburg R: Massive propranolol overdose. Am J Méd. 1986;80:755–757.

CrossRef

2.

Bailey B: Glucagon in beta blocker and calcium channel blocker overdoses: a systematic

review. Clin Tox. 2003;41:595–602.

CrossRef

3.

Benvenisty A, Spotnitz H, Rose EA et al.: Antagonism of chronic canine beta-adrenergic blockage

with dopamine, isoproterenol, dobutamine, and glucagon. Surg Forum. 1979;30:187–188. [PubMed:

538590]

4.

Brancato DJ: Recognizing potential toxicity of phenol. Vet Hum Toxicol. 1982;24:29–30. [PubMed:

7036514]

5.

Brechlert V, Pavoine C, Hanf R et al.: Inhibition by glucagon of the cGMP-inhibited low Km cAMP

phosphodiesterase in the heart is medicated by a pertussis toxin-sensitive G-protein. J Biolog

Chem.1992;267:15496–15501.

6.

Chang-Chretien K, Chew JT, Judge DP: Reversible dilated cardiomyopathy associated with

glucagonoma. Heart. 2004;90:e44.

CrossRef [PubMed: 15201270]

7.

Chernow B, Reed L, Geelhoed G et al.: Glucagon endocrine effects and calcium involvement in

cardiovascular actions in dogs. Circ Shock. 1986;19:393–407. [PubMed: 2427245]

8.

Chernow B, Zaloga G, Malcolm D et al.: Glucagon’s chronotropic action is calcium dependent. J

Pharm Exp Ther. 1987;241:833–837.

9.

Dart RC, Goldfrank LR, Chyka PA: Combined evidence-based literature analysis and consensus

guidelines for stocking of emergency antidotes in the United States. Ann Emerg Med.2000;36:126–

132.

CrossRef [PubMed: 10918103]

10.

Davis S, Granner D: Insulin, oral hypoglycemic agents and the pharmacology of the pancreas. In:

Hardman JG, Limbird LE, eds.Goodman and Gilman’s The Pharmacological Basis of

Therapeutics.10th ed. New York: McGraw-Hill;2001:1707–1708.

11.

Doyon S, Roberts JR: The use of glucagon in a case of calcium channel blocker overdose. Ann

Emerg Med. 1993;22:1229–1233.

CrossRef [PubMed: 8517580]

12.

Farah A: Glucagon and the circulation. Pharm Rev. 1983;35:181–217.

13.

Frishman W: Beta-adrenoceptor antagonists: new drugs and new indications. N Engl J

Med. 1980;305:500–506.

14.

Frishman W, Jacob H, Eisenberg E, Ribner H: Clinical pharmacology of the new beta-adrenergic

blocking drugs. Part 8. Self-poisoning with beta-adrenoceptor blocking agents: recognition and

management. Am Heart J. 1979;98:798–811.

CrossRef [PubMed: 40429]

15.

Glick G, Parmley W, Wechsler AS, Sonnenblick EH: Glucagon.Circ Res. 1968;22:798–799.

CrossRef

16.

GlucaGen and GlucaGen, Hypokit [package insert]. Princeton, NJ: Novo Nordisk A/S;2013.

17.

Golightly L, Smolinske S, Bennett M et al.: Pharmaceutical excipients. Med Toxicol. 1988;3:128–

165.

CrossRef

18.

Hall-Boyer K, Zaloga G, Chernow B: Glucagon: hormone or therapeutic agent. Crit Care

Med. 1984;12:584–589.

CrossRef [PubMed: 6375966]

19.

Heath A: β-Adrenoreceptor blocker toxicity: clinical features and therapy. Am J Emerg

Med. 1984;2:518–526.

CrossRef [PubMed: 6152169]

20.

Hendy GN, Tomlinson S, O’Riordan J: Impaired responsiveness to the effects of glucagon on

plasma adenosine 3′: 5′-cyclic monophosphate in normal man. Eur J Clin Invest. 1977;7:155–160.

CrossRef [PubMed: 196859]

21.

Homcy CJ: The beta adrenergic signaling pathway in the heart.Hosp Pract. 1991;26:43–50.

22.

Illingworth RN: Glucagon for beta-blocker poisoning. Practitioner.1979;223:683–685. [PubMed:

43509]

23.

Jolly S, Kipnis J, Lucchesi B.Cardiovascular depression byverapamil: reversal by glucagon and

interactions with propranolol.Pharmacology. 1987;35:249–255.

CrossRef [PubMed: 3423100]

24.

Juan-Fita M, Vargas M, Kaumann A: Rolipram reduces the inotropic tachyphylaxis of glucagon in

rat ventricular myocardium.Naunyn Schmiedebergs Arch Pharmacol. 2004;370:324–329.

CrossRef [PubMed: 15452686]

25.

Kerns W II: Management of beta-adrenergic blocker and calcium channel antagonist

toxicity. Emerg Med Clin North Am. 2007;25:309–331.

CrossRef [PubMed: 17482022]

26.

Kerns W II, Schroeder D, Williams C et al.: Insulin improves survival in a canine model of acute β-

blocker toxicity. Ann Emerg Med. 1997;29:748–757.

CrossRef [PubMed: 9174520]

27.

Kilts JD, Gerhardt MA, Richardson MD et al.: β2-Adrenergic and several other G protein-coupled

receptors in human atrial membranes activate both Gs and Gi. Circ Res. 2000;87:635–637.

CrossRef [PubMed: 11029395]

28.

Kline J, Tomaszewski C, Schroeder JD et al.: Insulin a superior antidote for cardiovascular toxicity

induced by verapamil in the anesthetized canine. J Pharm Exp Ther. 1993;267:744–750.

29.

Kraus-Friedmann N, Hummel L, Radominska-Pyrek A et al.: Glucagon stimulation of hepatic Na+,

K+-ATPase. Mol Cell Biochem.1982;44:173–180.

CrossRef [PubMed: 6287203]

30.

Powers AC, D’Alessio D. Chapter 43. Endocrine pancreas and pharmacotherapy of diabetes

mellitus and hypoglycemia. In: Brunton LL, Chabner BA, Knollmann BC, eds.Goodman & Gilman’s

The Pharmacological Basis ofTherapeutics. 12e. New York, NY: McGraw-Hill; 2011.

31.

Lawrence AM: Glucagon provocative test for pheochromocytoma.Ann Intern Med. 1967;66:1091–

1096.

CrossRef [PubMed: 6027944]

32.

Levey G, Epstein S: Activation of adenyl cyclase by glucagon in cat and human heart. Circ

Res. 1969;24:151–156.

CrossRef [PubMed: 4303624]

33.

Levey GS, Fletcher MA, Klein I et al.: Characterization of I-glucagon binding in a solubilized

preparation of cat myocardial adenylate cyclase. Further evidence for a dissociable receptor site.J

Biol Chem. 1974;249:2665–2673. [PubMed: 4828313]

34.

Lipski JI, Kaminsky D, Donoso E, Friedberg CK: Electrophysiological effects of glucagon on the

normal canine heart.Am J Physiol. 1972;222:1107–1112. [PubMed: 4336711]

35.

Love JN, Leasure JA, Mundt DJ: A comparison of combined amrinone and glucagon therapy to

glucagon alone for cardiovascular depression associated with propranolol toxicity in a canine

model.Am J Emerg Med. 1993;11:360–363.

CrossRef [PubMed: 8216517]

36.

Love JN, Leasure JA, Mundt DJ, Janz TG: A comparison of amrinone and glucagon therapy for

cardiovascular depression associated with propranolol toxicity in a canine model. J Toxicol Clin

Toxicol. 1992;30:399–412.

CrossRef [PubMed: 1512813]

37.

Love JN, Tandy TK: β-Adrenoreceptor antagonist toxicity: a survey of glucagon availability. Ann

Emerg Med. 1993;22:151–152.

CrossRef

38.

Lucchesi B: Cardiac actions of glucagon. Circ Res. 1968;22:777–787.

CrossRef [PubMed: 4385510]

39.

Lvoff R, Wilcken D: Glucagon in heart failure and in cardiogenic shock—experience in 50

patients. Circulation. 1972;45:534–542.

CrossRef [PubMed: 4401050]

40.

MacLeod K, Rodgers R, McNeil J: Characterization of glucagon-induced changes in rate,

contractility, and cyclic AMP levels in isolated cardiac preparations of the rat and guinea pig. J

Pharmacol Exp Ther. 1981;217:798–804. [PubMed: 6262497]

41.

Mahr NC, Valdes A, Lamas G: Use of glucagon for acute intravenous diltiazem toxicity. Am J

Cardiol. 1997;79:1570–1571.

CrossRef [PubMed: 9185662]

42.

Manchester JH, Parmley WW, Matloff JM et al.: Effects of glucagon on myocardial oxygen

consumption and coronary blood flow in man and in dog. Circulation. 1970;41:579–588.

CrossRef [PubMed: 5437404]

43.

Méry PF, Brechler V, Pavoine C et al.: Glucagon stimulates the cardiac Ca2+ current by activation

of adenyl cyclase and inhibition of phosphodiesterase. Nature. 1990;345:158–161.

CrossRef [PubMed: 2159595]

44.

Papadopoulos J, O’Neil M: Utilization of a glucagon infusion in the management of a

massive nifedipine overdose. J Emerg Med.2000;18:453–455.

CrossRef [PubMed: 10802424]

45.

Parmley WW: The role of glucagon in cardiac therapy. N Engl J Med. 1971;285:801–802.

CrossRef [PubMed: 5567270]

46.

Parmley W, Glick G, Sonnenblick E.Cardiovascular effects of glucagon in man. N Engl J

Med. 1968;279:12–17.

CrossRef [PubMed: 4872564]

47.

Peterson C, Leeder S, Sterner S: Glucagon therapy for beta-blocker overdose. Drug Intell Clin

Pharm. 1984;18:394–398. [PubMed: 6144498]

48.

Pettit GW, Vick RL, Kastello MD: The contribution of renal and extrarenal mechanisms to

hypokalemia induced by glucagon. Eur J Pharmacol. 1977;41:437–441.

CrossRef [PubMed: 844485]

49.

Rappolt R, Inaba D, Gay G: NAGD regime (Naloxone [Narcan], activated charcoal, glucagon,

doxapram [Dopram]) for the coma of drug related overdoses. Clin Toxicol. 1980;16:395–396.

CrossRef [PubMed: 7398231]

50.

Rochais F, Abi-Gerges A, Horner K et al.: A specific pattern of phosphodiesterases controls the

cAMP signals generated by different Gs-coupled receptors in adult rat ventricular myocytes. Circ

Res. 2006;98:1081–1088.

CrossRef [PubMed: 16556871]

51.

Rodell M: The role of hormone receptors and GTP-regulatory proteins in membrane

transduction. Nature. 1980;284:17–22.

CrossRef [PubMed: 6101906]

52.

Rodgers RL: Glucagon and cyclic AMP: time to turn the page?Curr Diabetes Rev. 2012;8:362–81.

CrossRef [PubMed: 22587514]

53.

Sabatier J, Pouyet T, Shelvey G, Cavero I: Antagonistic effects ofepinephrine, glucagon and

methylatropine but not calcium chloride against atrioventricular conduction of disturbances produced

by high doses of diltiazem, in conscious dogs. Fundam Clin Pharmacol.1991;5:93–106.

CrossRef [PubMed: 2071087]

54.

Salzberg M, Gallagher EJ: Propranolol overdose. Ann Emerg Med.1980;9:26–27.

CrossRef [PubMed: 7356190]

55.

Sato S, Tsuhi MH, Okubo N et al.: Combined use of glucagon and milrinone may not be

preferable for severe propranolol poisoning in the canine model. J Toxicol Clin

Toxicol. 1995;33:337–342.

CrossRef [PubMed: 7629900]

56.

Sato S, Tsuhi MH, Okubo N et al.: Milrinone versus glucagons: comparative effects in canine

propranolol poisoning. J Toxicol Clin Toxicol. 1994;32:277–289.

CrossRef [PubMed: 8007035]

57.

Sauvadet A, Rohn T, Pecker F, Pavione C: Arachidonic acid drives mini-glucagon action in

cardiac cells. J Biol Chem. 1997;272:12437–12445.

CrossRef [PubMed: 9139691]

58.

Sauvadet A, Rohn T, Pecker F, Pavione C: Synergistic actions of glucagons and miniglucagon on

Ca2 mobilization in cardiac cells. Cir Res. 1996;78:102–109.

CrossRef

59.

Stevens T, Guillet R: Use of glucagon to treat neonatal low-output congestive heart failure after

maternal labetalol therapy. J Pediatr.1995;127:151–153.

CrossRef [PubMed: 7608802]

60.

Stone CK, May WA, Carroll R: Treatment of verapamil overdose with glucagon. Ann Emerg

Med. 1995;25:369–374.

CrossRef [PubMed: 7864479]

61.

Stone CK, Thomas SH, Koury SI, Low RB: Glucagon andphenylephrine combination vs glucagon

alone in experimentalverapamil overdose. Acad Emerg Med. 1996;3:120–125.

CrossRef [PubMed: 8808371]

62.

Walter FG, Frye G, Mullen JT et al.: Amelioration of nifedipinepoisoning associated with glucagon

therapy. Ann Emerg Med.1993;22:1234–1237.

CrossRef [PubMed: 8517581]

63.

Ward DE, Jones B: Glucagon and beta-blocker toxicity. Br Med J.1976;2:151.

CrossRef [PubMed: 1276839]

64.

Wei Y, Mojsov S: Tissue-specific expression of the human receptor for glucagon-like peptide-I:

brain, heart and pancreatic forms have the same deduced amino acid sequences. FEBS

Lett.1995;358:219–224.

CrossRef [PubMed: 7843404]

65.

Weinstein R: Recognition and management of poisoning with beta-blocking agents. Ann Emerg

Med. 1984;13:1123–1131.

CrossRef [PubMed: 6150667]

66.

White CM: A review of potential cardiovascular uses of intravenous glucagon administration. J Clin

Pharmacol. 1999;39:442–447. [PubMed: 10234590]

67.

Whitehouse F, James T: Chronotropic action of glucagon on the sinus node. Proc Soc Exp Biol

Med. 1966;122:823–826.

CrossRef [PubMed: 4380626]

68.

Wolf LR, Spadafora MP, Otten EJ: Use of amrinone and glucagon in a case of calcium channel

blocker overdose. Ann Emerg Med.1993;22:1225–1228.

CrossRef [PubMed: 8517579]

69.

Yagami T: Differential coupling of glucagon and beta adrenergic receptors with the small and large

forms of the stimulatory G protein.Mol Pharmacol. 1995;48:849–854. [PubMed: 7476915]

70.

Yao L, Macleod KM, McNeill JH: Glucagon-induced desensitization: correlation between cyclic

AMP levels and contractile force. Eur J Pharmacol. 1982;9:147–150.

71.

Zaloga G, Malcolm D, Holaday J et al.: Glucagon reverses the hypotension and bradycardia

of verapamil overdose in rats. Crit Care Med. 1985;13:273.

CrossRef

72.

Zaritsky A, Morowitz M, Chernow B: Glucagon antagonism of calcium blocker-induced myocardial

dysfunction. Crit Care Med.1988;16:246–251.

CrossRef [PubMed: 3277781]

73.

Zeiders JL, Seidler FJ, Iaccarino G et al.: Ontogeny of cardiac beta-adrenoceptor desensitization

mechanisms: agonist treatment enhances receptor/G-protein transduction rather than eliciting

uncoupling. J Mol Cell Cardiol. 1999;31:413–423