Chapter 118: Cardiovascular Drugs

High-Yield Facts

• β-Blocker and calcium channel blocker poisoning have significant morbidity, and their hallmark is bradycardia and hypotension.

• If standard Pediatric Advance Life Support Protocols (PALS) do not restore adequate cardiovascular function, stepwise administration of glucagon, hyperinsulinemia–euglycemia therapy (HIE) and lipid emulsion should be considered.

• Administration of specific anti-digoxin Fab antibody fragments is a highly effective treatment for digoxin poisoning.

• Consider naloxone if PALS protocols fail to reverse clonidine toxicity.

β-Adrenergic Blocking Agents

In 2011, the American Association of Poison Control Centers documented 3.229 β-blocker exposures in children younger than 5 years and 723 in 6- to 19-year-olds.¹ Those producing the greatest morbidity were metoprolol, atenolol, and propranolol. β₁- and β₂-receptor antagonism, intrinsic sympathomimetic activity, and membrane-stabilizing activity are responsible for the clinical effects of these drugs. α-Antagonist activity is seen with labetalol and carvedilol.²

Pharmacology

The pharmacologic effects of β-blocking drugs are mediated through modulation of intercellular signals and calcium secondary to inhibited adrenergic activation.³ β₁-Antagonism produces decreased cardiac contractility and conduction. β₂-Antagonism produces increased smooth muscle tone, which may manifest as bronchospasm, increased peripheral vascular tone, and increased gut motility. Although many β-blockers are β₁-selective at therapeutic doses, these drugs have both β₁- and β₂-effects in overdose.

Intrinsic sympathomimetic properties of some β-blockers produces agonist–antagonist activity, which may blunt the bradycardic response in some patients.^2,4 Drugs with intrinsic sympathomimetic activity include acebutolol, carteolol, oxprenolol, penbutolol, and pindolol. The membrane-stabilizing activity characteristic of some β-blockers is a quinidine-like effect, resulting in inhibition of fast sodium channels, decreased contractility, and ventricular arryhythmias.⁵ This effect is additive to the β₁-toxic effects.

β-Blockers with increased intrinsic sympathomimetic activity and decreased membrane-stabilizing properties demonstrate less toxicity than those with increased membrane-stabilizing properties.^5–8 Drugs with significant membrane-stabilizing properties include propranolol, acebutolol, and oxprenolol.⁹

Sotalol is a β-blocker, which has class III antiarrhythmic properties.¹⁰ In overdose, it may prolong the QT interval, resulting in ventricular arrhythmias, including torsades de pointes. Each β-blocker may have only some of the described activities, and the clinical manifestations may vary.

Pharmacokinetics

The absorption, distribution, and elimination of β-blockers vary with the drug. Extended-release formulations can have a marked delay of onset of toxic effects. Conversely, standard release β-blockers are rapidly absorbed, with 30% to 90% bioavailability. Only penbutolol and propranolol exhibit high lipid solubility. The elimination half-life varies from 2 to 24 hours, but can be significantly increased in overdose.

Pathophysiology

Toxicity from acute β-blocker overdose largely results from suppression of the cardiovascular system. Negative inotropic and chronotropic effects result in bradycardia and hypotension. Respiratory compromise in β-blocker overdose can result from ...