Beta-blockers act by competitively inhibiting the binding of epinephrine and norepinephrine to β-adrenergic neuroreceptors in the heart (β₁), blood vessels, bronchioles (β₂), and other organs (Table 125.1). Binding to the β receptor (G-protein–coupled receptor) activates phosphodiesterase and increases cytoplasmic cyclic adenosine monophosphate (cAMP). This in turn leads to modification of cellular processes and changes in ionic channel conductance. By reducing the activity of β receptors, the production of cAMP is decreased and β effect is diminished [2].

Beta-blockers are usually rapidly absorbed after oral administration. The beta-blocker dose required to produce a toxic effect is variable, depending on the sympathetic tone and metabolic capacity of the person and the pharmacologic properties of the particular beta-blocker [2]. The first signs of toxicity may appear 20 minutes after ingestion, with peak effects typically occurring 1 to 2 hours after an immediate-release preparation overdose. Absorption of modified-release formulations may be erratic after an overdose, however, and clinical
toxicity may be significantly delayed. The duration of toxicity may be several days [2].

The pharmacologic and pharmacokinetic properties of beta-blockers are variable (Table 125.2). Cardioselectivity tends to be lost at high doses, and membrane-stabilizing effects, which are minimal at therapeutic doses, assume a more important role [2]. Membrane dysfunction may account for many of the central nervous system (CNS) and myocardial depressant effects in patients poisoned by membrane-active drugs such as propranolol. The half-life may be significantly prolonged in patients with decreased hepatic and renal perfusion [2]. Intrinsic heart, kidney, and liver disease as well as the concomitant use of drugs with similar activity increase the risk of toxicity.

The major manifestations relate to the cardiovascular system and CNS. Respiratory, peripheral vascular, and metabolic (hypoglycemic and hyperkalemic) effects have been infrequently reported [2,3].

Patients with severe poisoning frequently present with hypotension and bradycardia. Tachycardia and hypertension have been reported with agents possessing intrinsic sympathomimetic activity, however, particularly pindolol [2]. Congestive heart failure and pulmonary edema have infrequently been reported and mainly occur in patients with underlying heart disease [4]. Electrocardiographic manifestations may include prolonged PR interval, intraventricular conduction delay, progressive atrioventricular heart block, nonspecific ST-segment and T-wave changes, early repolarization, prolonged corrected QT (QTc) interval, and asystole [5,6,7]. Sotalol poisoning may result in ventricular tachycardia, torsade de pointes, ventricular fibrillation, and multifocal ventricular extrasystoles [8,9]. Labetalol, which also has mild β-receptor–blocking properties, may cause profound hypotension, possibly from decreased peripheral resistance.

Depression in the level of consciousness, ranging from drowsiness to coma with seizures, is another common feature of beta-blocker poisoning. Significant CNS depression has been reported in the absence of cardiovascular compromise [2] or hypoglycemia and may be due to direct membrane effects [10]. Cerebral hypoperfusion, hypoxia, and metabolic or respiratory acidosis frequently contribute to CNS toxicity. Beta-blockers with high lipid solubility (e.g., propranolol, penbutolol, metoprolol) appear more likely to cause CNS effects than those with low lipid solubility (e.g., atenolol) [11,12].

Bronchospasm is a relatively rare consequence of beta-blocker poisoning and usually occurs more frequently in patients with preexisting reactive airway disease. In most instances, respiratory depression appears to be secondary to a CNS effect [13,14,15,16].

Although it does occur, hypoglycemia is not a common complication of beta-blocker poisoning [17]. It appears to be more common in diabetics, children, and uremic patients and it is the consequence of impaired glycogenolysis and hepatic gluconeogenesis [18]. A blunted tachycardic response to hypoglycemia may occur in patients with beta-blocker toxicity, although other symptoms of hypoglycemia appear unaffected.

Oliguric renal failure has been reported as a complication of labetalol poisoning [19]. Mesenteric ischemia and subsequent cardiovascular collapse have occurred after propranolol overdose [20].

Sudden discontinuation of long-term beta-blocker therapy may precipitate angina pectoris and myocardial infarction. This is the result of the “beta-blocker withdrawal phenomenon,” explained by the theory that long-term beta-blocker therapy not only diminishes receptor occupancy by catecholamines but also increases the number of receptors sensitive to adrenergic stimulation. When beta-blockers are suddenly withdrawn, the increased pool of sensitive receptors responds more readily to the stimulation of circulating catecholamines [17].

The history should include the time, amount, and formulation of drugs ingested; the circumstances involved; time of onset and nature of any symptoms; and treatments rendered before arrival, as well as underlying health problems. Beta-blocker poisoning may be difficult to recognize, especially when multiple drugs have been ingested [2]. Beta-blocker poisoning should be suspected in a patient in whom hypotension or seizures suddenly develop or who has bradycardia resistant to the usual doses of chronotropic drugs [21]. Evaluation of patients with suspected beta-blocker poisoning should begin with a complete set of vital signs, continuous cardiac rhythm monitoring, and a 12-lead electrocardiogram. Physical examination should focus on the cardiovascular, pulmonary, and neurologic systems. Vital signs and physical examination should be frequently repeated.

Serum drug levels may help confirm the diagnosis but are rarely available quickly enough to be clinically useful. In addition, differences in individual patient metabolism and sympathetic tone may make interpretation of blood levels difficult [2,3]. A serum and urine specimen can be saved for later analysis in forensic cases. Continuous cardiac rhythm monitoring, interpretation of 12-lead electrocardiograms, and measurement of oxygen saturation should be routine. Laboratory evaluation of symptomatic patients should include electrolytes, blood urea nitrogen, creatinine, bicarbonate, and glucose. Arterial blood gas and a chest film should be obtained as clinically indicated. Serum acetaminophen and aspirin levels should be obtained in patients with suicidal ideation.

The differential diagnosis of beta-blocker toxicity includes antidysrhythmic drugs, calcium channel blockers, cholinergic agents, clonidine, digitalis, narcotics, sedative hypnotics, and tricyclic antidepressants. Anaphylactic, cardiogenic, hypovolemic, and septic shock should also be considered.

The prognosis associated with beta-blocker intoxication is generally positive. A review of two regional poison control centers [22] found that 15% of patients developed cardiac toxicity, and only 1.4% died. The only factor associated with increased

morbidity was coingestion of cardioactive drugs such as calcium channel blockers, cyclic antidepressants, and neuroleptics [22].