Introduction
Background
Beta-adrenergic antagonists (ie, 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.
A 48-year-old man presents to the ED after a generalized tonic-clonic seizure. He is noted to be hypotensive (82/55) and bradycardiac (see rhythm strip). The family reports that he is taking a medication 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.
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-blockers reduce 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.
Pharmacology
Numerous brands of beta-blockers are available; they comprise a heterogeneous drug family with toxicologic characteristics that vary between classes. An understanding of the different characteristics of each class is helpful for understanding the various clinical presentations and for guiding therapy.
Nonselective beta-blockers
Propranolol was the first beta-blocker with 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. High lipid solubility leads to a larger volume of distribution and better CNS penetration. Lipophilic beta-blockers are primarily metabolized by the liver. Propanolol 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). Toxicity with sotalol has been reported to result in ventricular dysrhythmias for as long as 2 days postingestion.
Frequency
United States
The 2007 Annual Report of the American Association of Poison Control Centers' (AAPCC) National Poison Data System reported 9291 single exposures to beta-blockers.1
International
Propranolol is the most toxic beta-blocker and the most frequently used in suicide attempts worldwide.
Mortality/Morbidity
In 2007, the AAPCC reported 413 minor outcomes, 631 moderate outcomes, 61 major outcomes, and 3 fatalities for beta-blocker exposure.1
Beta-blocker type: Beta-blockers that are lipid soluble and have marked antidysrhythmic (ie, quinidine-like) effects are more lethal (eg, propranolol, sotalol, oxprenolol).
Co-ingestions and state of health: 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.
Sex
According to the 2004 AAPCC toxic exposure review, 51% of all exposures and 47.6% of all overdose fatalities are in women.2
Age
Of the fatalities reported to the AAPCC, 68% were associated with individuals younger than 50 years. Forty-three percent of all fatalities reported to the AAPCC in 2004 were associated with children younger than 6 years.2
Clinical
History
- Determining the specific type of beta-blocker, quantity, and time of the overdose is ideal. Unfortunately, these details are often not immediately available.
- Information regarding the patient's underlying medical condition may be a clinical clue to the possibility of an overdose.
Physical
The initial evaluation of a comatose patient should include consideration of an occult overdose. If a patient is bradycardic and hypotensive, the clinician should consider a beta-blocker or calcium blocker overdose. Other associated symptoms may include hypothermia, hypoglycemia, and seizures. Myocardial conduction delays with decreased contractility typify the acute beta-blocker ingestion.
- Cardiac output may diminish with resulting hypotension from bradycardia and negative inotropy. Hypotension due to the beta2-receptor blockade can be profound and jeopardize myocardial perfusion, creating a downward spiral of events.
- Beta-blockers that are not sustained-release formulations are all rapidly absorbed from the gastrointestinal tract.
- The first critical signs of overdose can appear 20 minutes postingestion but are more commonly observed within 1-2 hours.
- All clinically significant beta-blocker overdoses develop symptoms within 6 hours.
- Although the half-life of these compounds is usually short (2-12 h), half-lives in the overdose patient may be prolonged because of a depressed cardiac output, reduced blood flow to the liver and kidneys, or because of the formation of active metabolites.
- Saturation kinetics prolong elimination at the type of high plasma concentrations that typically occur with overdose. Delayed absorption from long-acting preparations can significantly increase the apparent elimination half-life. Thus, prolonged effects (>72 h) after massive overdoses are not uncommon.
- Asymptomatic intoxication occurs mainly in healthy persons with tolerance to these drugs who ingest beta-blockers lacking membrane-stabilizing effects or having a partial agonist effect (eg, pindolol). Individual sensitivity to beta-blockade may be significantly reduced in those patients who have tolerated therapeutic doses of up to 4 g of propranolol daily and in patients who have sustained deliberate overdoses of both practolol and propranolol without serious adverse effects.
- Conversely, circulatory collapse may occur in patients with preexisting cardiac failure when sympathetic drive is inhibited by even a small dose of a particular beta-blocker.
- Intermediate toxicity results in a moderate drop in blood pressure (systolic BP >80 mm Hg) and/or bradycardia (heart rate <60 BPM).
- Bradycardia with associated hypotension and shock (systolic BP <80 mm Hg, heart rate <60 BPM) defines severe beta-blocker toxicity. Patients with severe toxicity often manifest extracardiac manifestations of intoxication.
- Bradycardia, by itself, is not necessarily helpful as a warning sign because slowing of the heart rate and damping of tachycardia in response to stress is observed at therapeutic doses.
- Although case reports have documented hypotension in the absence of bradycardia, blood pressure usually does not fall before the onset of bradycardia.
- Bradycardia may be isolated or accompanied by mild conduction disturbances.
- A depressed level of consciousness and seizures may occur as a result of cellular hypoxia from poor cardiac output, a direct CNS effect caused by sodium channel blocking, or even as a result of hypoglycemia. The lipid-soluble agents have increased distribution into the brain, and these agents are associated with severe CNS toxicity.
- Patients who have taken lipid-soluble beta-blockers, such as propranolol, frequently present with seizures after an overdose.
- Seizures are generalized and may be multiple but are usually brief, lasting seconds to minutes. Seizures occasionally have been reported after therapeutic use of esmolol and with overdose of alprenolol, metoprolol, and oxprenolol. Seizures are far more common after propranolol overdose.
- Coma may be prolonged, depending on the half-life of the agent involved and the coexisting morbidity.
- Severe memory impairment developed in an 81-year-old woman taking propranolol 20 mg 3 times per day. Effects were associated with an elevated propranolol blood level (163 mcg/L) and resolved after discontinuation of the drug.
- Bronchospasm is a rare complication of beta-blocker therapy or overdose but is more likely in patients who already have bronchospastic disease. Sudden fatality following administration of therapeutic doses of beta-blocker has been reported in 4 patients with asthma. Pulmonary edema had been reported to occur as a result of cardiac failure. Respiratory arrest has also been described with beta-blocker intoxication, especially with propranolol, and is thought to be secondary to a central drug effect.
- Hypoglycemia is relatively uncommon but described in patients with unstable diabetes and in children. Beta-blocking drugs may cause hypoglycemia by inhibiting glycogenolysis.
Causes
- 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.
More on Toxicity, Beta-blocker |
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Further Reading
Keywords
beta-blocker toxicity, beta-blocker poisoning, beta-blocker overdose, beta-adrenergic antagonist overdose, beta-adrenergic antagonist toxicity, hypertension, postmyocardial infarction, migraine headaches, essential tremors, thyrotoxicosis, glaucoma, anxiety, propranolol, nadolol, timolol, pindolol, acebutolol, labetalol, sotalol, oxprenolol, practolol, esmolol, alprenolol, metoprolol, quinidinelike effects, Vaughan-Williams class I antiarrhythmic effects, QT interval prolongation, prolonged QT interval, multifocal premature ventricular contractions, PVCs, bigeminy, ventricular tachycardia, ventricular fibrillation, torsade de pointes, seizures, hypoglycemia
