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Beta-Blocker Toxicity

  • Author: Adhi Sharma, MD; Chief Editor: Asim Tarabar, MD  more...
 
Updated: May 02, 2016
 

Background

Beta-adrenergic antagonist (ie, beta-blocker) toxicity can produce clinical manifestations including bradycardia, hypotension, arrhythmias, hypothermia, hypoglycemia, and seizures (see the images below). The presentation may range from asymptomatic to shock.

Bradycardia is evident on a rhythm strip from a 48 Bradycardia is evident on a rhythm strip from a 48-year-old man who presented to the emergency department after a generalized tonic-clonic seizure. The patient was also hypotensive (82/55 mm Hg). The family reported that he was taking a medication, which proved to be propranolol, for a rapid heart rate. Propranolol is the most common beta-blocker involved in severe beta-blocker poisoning. It is nonselective and has membrane-stabilizing effects that are responsible for CNS depression, seizures, and prolongation of the QRS complex.
Sotalol is associated with the rhythm shown below Sotalol is associated with the rhythm shown below in both therapeutic doses and toxic ingestions. Sotalol has been used as a class III antiarrhythmic agent to control dangerous ventricular tachydysrhythmias in some individuals. It causes polymorphic ventricular tachycardia (torsade de pointes) in approximately 4% of patients. Rarely, prolongation of the QT interval has been reported with propranolol.

Beta-blockers have been in use for nearly 50 years. In addition to their traditional role in treating hypertension and other cardiovascular disorders, beta-blockers are also used for additional purposes such as migraine headaches, hyperthyroidism, glaucoma, anxiety, and various other disorders. As a result of their expanded use, the incidence of overdose with these agents has also increased.

Beta-blocker toxicity in children usually results from exposure to an adult's unattended medications. Beta-blocker toxicity in adults usually results from a suicide attempt or an accidental overdose of a routine medication.

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Pathophysiology

Understanding the direct and indirect effects of beta-receptor blockade is crucial to rapid identification and appropriate treatment of beta-blocker toxicity. Beta-blockers act as competitive inhibitors of catecholamines, exerting their effects at both central and peripheral receptors. Blockade of beta-receptors results in decreased production of intracellular cyclic adenosine monophosphate (cAMP) with a resultant blunting of multiple metabolic and cardiovascular effects of circulating catecholamines.

Beta1-receptor blockade reduces heart rate, blood pressure, myocardial contractility, and myocardial oxygen consumption. Beta2-receptor blockade inhibits relaxation of smooth muscle in blood vessels, bronchi, the gastrointestinal system, and the genitourinary tract. In addition, beta-adrenergic receptor antagonism inhibits both glycogenolysis and gluconeogenesis, which may result in hypoglycemia.

Other than the direct effects of the beta-adrenoreceptor blockade, toxicity may result from other mechanisms, including sodium and calcium channel blockade, centrally mediated cardiac depression, and alteration of cardiac myocyte energy metabolism.[1]

Numerous beta-blockers are available; these agents comprise a heterogeneous drug family with varying toxicologically relevant characteristics. An understanding of these different characteristics is helpful for understanding the clinical presentations with particular agents and for guiding therapy.

Nonselective activity

Propranolol was the first beta-blocker to enter widespread use; much of the clinical and overdose experience that exists with beta-blockers was provided by case reports and clinical studies of this drug. Propranolol is a nonselective beta-blocker, demonstrating equal affinity for both beta1- and beta2-receptors. Other nonselective beta-blockers include nadolol, timolol, and pindolol. Nonselective beta-blockers exert a wider variety of extracardiac manifestations.

Intrinsic sympathomimetic activity

Some beta-blockers, such as pindolol and acebutolol, also have beta-agonist properties. Although their agonist property is weaker than that of catecholamines, they are capable of stimulating beta-receptors, especially when catecholamine levels are low. Of note, acebutolol has been reported to be particularly lethal in overdose.

Membrane-stabilizing activity

Beta-blockers, such as propranolol, labetalol, and pindolol, can have membrane-stabilizing activity (MSA; eg, the quinidine-like effects of the class IA antidysrhythmic effects). MSA blocks myocyte sodium channels. This property, usually not evident at therapeutic doses, may significantly contribute to toxicity by prolonging QRS duration and impairing cardiac conduction. Seizures are more commonly observed in drugs with MSA. Beta-blockers with MSA are associated with the largest proportion of fatalities.

Lipid solubility

Lipid solubility is higher in agents such as propranolol and carvedilol, but lower in agents such as atenolol and nadolol. It may influence the degree of central nervous system (CNS) effects and utility of hemodialysis or hemoperfusion.[2]

High lipid solubility leads to a larger volume of distribution and better CNS penetration. Lipophilic beta-blockers are primarily metabolized by the liver. Propranolol is among these, and its active metabolite (4-OH propranolol) prolongs its biological activity. Conversely, hydrophilic beta-blockers have a small volume of distribution and are eliminated essentially unchanged by the kidneys; this property allows hydrophilic beta-blockers to be removed by hemodialysis.

QT-interval prolongation

The electrophysiologic effects of sotalol deserve special consideration. Unlike other beta-blockers, sotalol has antidysrhythmic properties consistent with the type III antidysrhythmic agents. Class III agents prolong the action potential duration and the effective refractory period of AV and atrioventricular myocytes, which can lengthen the QT-interval duration and result in polymorphic ventricular tachycardia (ie, torsade de pointes). Ventricular dysrhythmias associated with sotalol toxicity can occur up to 48 hours postingestion.

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Epidemiology

Propranolol is the most toxic beta-blocker and the most frequently used in suicide attempts worldwide. The 2014 Annual Report of the American Association of Poison Control Centers' (AAPCC) National Poison Data System reported 10,459 single exposures to beta-blockers, including propranolol. Of the reported exposures, 2952 were in children younger than 6 years, and 6285 were in adults 21 years of age and older. Approximately 83% of exposures were unintentional.[3]

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Prognosis

Prognosis is largely dependent on the initial response to therapy (6-12 h postingestion) as drug levels are likely to have peaked at this time. In addition, beta-blockers that are lipid soluble and have marked antidysrhythmic (ie, quinidine-like) effects are more lethal (eg, propranolol, sotalol, oxprenolol).

Underlying cardiac or pulmonary disease places the patient at increased risk for poor outcome.

The outcome is significantly worse when these agents are co-ingested with psychotropic or cardioactive drugs. This is true even if the amount of beta-blocker ingested is relatively small. The co-ingestants that most markedly worsen prognosis include calcium channel blockers, cyclic antidepressants, and neuroleptics. These co-ingestions are the most important factor associated with the development of cardiovascular morbidity and mortality.

After co-ingestions, the next most significant factor associated with major morbidity and mortality is exposure to a beta-blocker with membrane-stabilizing activity.

In 2014, the AAPCC reported the following numbers of outcomes with beta-blocker exposure[3] :

  • None - 4015
  • Minor - 537
  • Moderate - 914
  • Major - 89
  • Fatalities - 14
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Contributor Information and Disclosures
Author

Adhi Sharma, MD Medical Toxicology Consultant, New York City Poison Control Center

Adhi Sharma, MD is a member of the following medical societies: American Academy of Clinical Toxicology, American College of Emergency Physicians, American College of Medical Toxicology

Disclosure: Nothing to disclose.

Coauthor(s)

Lemeneh Tefera, MD, FAAEM Attending Physician, Department of Emergency Medicine, Beth Israel Medical Center

Lemeneh Tefera, MD, FAAEM is a member of the following medical societies: American Academy of Emergency Medicine

Disclosure: Nothing to disclose.

Aman Aminzay, MD Attending Physician, Department of Emergency Medicine, Beth Israel Medical Center, Albert Einstein College of Medicine

Aman Aminzay, MD is a member of the following medical societies: American College of Emergency Physicians

Disclosure: Nothing to disclose.

Chief Editor

Asim Tarabar, MD Assistant Professor, Director, Medical Toxicology, Department of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital

Disclosure: Nothing to disclose.

Acknowledgements

John G Benitez, MD, MPH, FACMT, FAACT, FACPM, FAAEM, Associate Professor, Department of Medicine, Medical Toxicology, Vanderbilt University Medical Center; Managing Director, Tennessee Poison Center

John G Benitez, MD, MPH, FACMT, FAACT, FACPM, FAAEM, is a member of the following medical societies: American Academy of Clinical Toxicology, American Academy of Emergency Medicine, American College of Medical Toxicology, American College of Preventive Medicine, Society for Academic Emergency Medicine, Undersea and Hyperbaric Medical Society, and Wilderness Medical Society

Disclosure: Nothing to disclose.

David C Lee, MD Research Director, Department of Emergency Medicine, Associate Professor, North Shore University Hospital and New York University Medical School

David C Lee, MD is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, American College of Medical Toxicology, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

John T VanDeVoort, PharmD Regional Director of Pharmacy, Sacred Heart & St. Joseph's Hospitals

John T VanDeVoort, PharmD is a member of the following medical societies: American Society of Health-System Pharmacists

Disclosure: Nothing to disclose.

Acknowledgments

The authors and editors of Medscape Reference gratefully acknowledge the medical review of this article by Lada Kokan, MD.

References
  1. Brubacher JR. Beta-Adrenergic Antagonists. In: Hoffman RS, Howland MA, Lewin NA, Nelson LS, Goldfrank LR, eds. Goldfrank’s Toxicologic Emergencies. 10th ed. New York, NY: McGraw-Hill Education; 2015.

  2. Lopes P, Kataky R. Chiral interactions of the drug propranolol and a1-acid-glycoprotein at a micro liquid-liquid interface. Anal Chem. 2012 Mar 6. 84(5):2299-304. [Medline].

  3. Mowry JB, Spyker DA, Brooks DE, McMillan N, Schauben JL. 2014 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 32nd Annual Report. Clin Toxicol (Phila). 2015. 53 (10):962-1147. [Medline]. [Full Text].

  4. Hoot NR, Benitez JG, Palm KH. Hemodynamically unstable: accidental atenolol toxicity?. J Emerg Med. 2013 Sep. 45(3):355-7. [Medline].

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  7. Escajeda JT, Katz KD, Rittenberger JC. Successful treatment of metoprolol-induced cardiac arrest with high-dose insulin, lipid emulsion, and ECMO. Am J Emerg Med. 2015 Aug. 33 (8):1111.e1-4. [Medline].

  8. Position statement and practice guidelines on the use of multi-dose activated charcoal in the treatment of acute poisoning. American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists. J Toxicol Clin Toxicol. 1999. 37(6):731-51.

  9. Engebretsen KM, Kaczmarek KM, Morgan J, Holger JS. High-dose insulin therapy in beta-blocker and calcium channel-blocker poisoning. Clin Toxicol (Phila). 2011 Apr. 49(4):277-83. [Medline].

  10. Sebe A, Dişel NR, Açıkalın Akpınar A, Karakoç E. Role of intravenous lipid emulsions in the management of calcium channel blocker and β-blocker overdose: 3 years experience of a university hospital. Postgrad Med. 2015 Mar. 127 (2):119-24. [Medline].

  11. Bania TC, Chu J, Perez E, Su M, Hahn IH. Hemodynamic effects of intravenous fat emulsion in an animal model of severe verapamil toxicity resuscitated with atropine, calcium, and saline. Acad Emerg Med. 2007 Feb. 14(2):105-11. [Medline].

  12. Hayes BD, Gosselin S, Calello DP, Nacca N, Rollins CJ, Abourbih D, et al. Systematic review of clinical adverse events reported after acute intravenous lipid emulsion administration. Clin Toxicol (Phila). 2016 Jun. 54 (5):365-404. [Medline].

 
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Bradycardia is evident on a rhythm strip from a 48-year-old man who presented to the emergency department after a generalized tonic-clonic seizure. The patient was also hypotensive (82/55 mm Hg). The family reported that he was taking a medication, which proved to be propranolol, for a rapid heart rate. Propranolol is the most common beta-blocker involved in severe beta-blocker poisoning. It is nonselective and has membrane-stabilizing effects that are responsible for CNS depression, seizures, and prolongation of the QRS complex.
Sotalol is associated with the rhythm shown below in both therapeutic doses and toxic ingestions. Sotalol has been used as a class III antiarrhythmic agent to control dangerous ventricular tachydysrhythmias in some individuals. It causes polymorphic ventricular tachycardia (torsade de pointes) in approximately 4% of patients. Rarely, prolongation of the QT interval has been reported with propranolol.
 
 
 
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