β-blocker overdose can cause life-threatening cardiac depression, with propranolol and sotalol posing the highest risk of severe toxicity. Management priorities include early decontamination and ensuring adequate circulation to prevent complications.

There are a number of ways to classify β-blockers. A simple functional classification for therapeutic use is described in the table below ^[1]. Importantly, receptor selectivity is lost in overdose.

Excess competitive inhibition at β-adrenergic receptors primarily cause bradycardia and hypotension for all drugs in this class. There is a loss of receptor selectivity in overdose.

β1-receptors are found primarily in cardiac tissue, and when stimulated results in increased chronotropy, inotropy, automaticity, and dromotropy. β-antagonists depress these effects, and toxicity primarily manifests as suppression of cardiac functions with bradycardia, hypotension, and cardiogenic shock.

β2-receptors are found in peripheral smooth muscle vasculature, airway smooth muscle, liver, GI tract, pancreas, uterus, and to a lesser extent cardiac tissue. When stimulated, vasodilation and bronchodilation occur. The toxic effects of β-antagonists can manifest as bronchospasm in susceptible individuals.

β-blockers may also cause hypoglycemia by inhibition of hepatic glycogenolysis and pancreatic glucagon release. Counter-regulation by adrenaline is also diminished by β-blockade, further compounding hypoglycemia.

Individual drugs in this class differ based on their unique pharmacological properties, which include:

• Cardioselectivity
• Intrinsic sympathomimetic activity
• Class I antiarrhythmic effects
• Class III antiarrhythmic effects
• Vasodilatory activity
• Lipid solubility
• Renal/hepatic clearance

While β1-selectivity can influence adverse effects in therapeutic use, it becomes less relevant in overdose situations because selectivity is lost at high drug concentrations.

Some β-blockers have ISA due to partial β agonism and may result in tachycardia and hypertension. This partial agonist effect rarely leads to significant problems and probably protects to some extent from the more serious class I and III antiarrhythmic effects. Drugs with ISA include acebutolol, pindolol, labetalol, and celiprolol.

The membrane-stabilizing activity of some β-blockers is due to the inhibition of fast Na+ channels (class I anti-arrhythmic activity). These effects usually only occur at high drug concentrations. Propranolol has the most membrane-stabilizing activity of the β-blockers and can result in impaired AV conduction, widened QRS interval, ventricular tachyarrhythmias, coma, and seizures.

Some β-blockers block the delayed rectifier outward K+ channel which is responsible for cell repolarization. This prolongs the action potential duration and prolongs the QT interval, which can predispose to arrhythmias. Examples of these β-blockers include sotalol and acebutolol.

The vasodilatory activity of certain β-blockers can theoretically enhance the hypotensive effects in cases of β-blocker overdose.

Only lipid soluble drugs will lead to direct CNS effects as they are able to penetrate the blood brain barrier, though CNS symptoms may occur secondary to cardiac effects and decreased cerebral perfusion. Lipid solubility alone will not lead to CNS effects and they may relate to Na+ channel blocking effects as they are particularly common with propranolol.

This is occasionally important in therapeutics but is largely irrelevant in overdose.

The toxic dose of β-blockers is variable and depends on individual susceptibility and drug type. Factors associated with increased risk of toxicity include:

• Ingestion of propranolol or sotalol
  • Ingestions of > 2 g propranolol is commonly associated with sodium channel blocking effects including seizures and coma ^[2]
• Coingestion/regular treatment of additional cardiac medications (especially calcium channel blockers or digoxin)
• Underlying cardiovascular disease
• Old age
• Late presentation / ineffective GI decontamination

Most beta-blockers are rapidly absorbed from the small intestine except esmolol (IV administration) and atenolol (~50% GI absorption). However, most have relatively low oral bioavailability due to high first-pass metabolism except sotalol and bisoprolol (both 90% bioavailable). In overdose, bioavailability increases because the enzymes responsible for first-pass metabolism become saturated. Under therapeutic conditions, peak drug concentrations are typically reached within 1-4 hours.

All β-blockers have moderate to large volumes of distribution, roughly proportional to their lipid solubility. The drug's lipid solubility also determines the degree of CNS penetration. Most are also relatively highly protein-bound.

Most β-blockers undergo extensive hepatic metabolism except atenolol, sotalol, and esmolol. The half-life of most beta-blockers at therapeutic doses is less than 12 hours. In overdose, the half life of β-blockers vary and are prolonged due to reduced cardiac output (reduced blood flow to liver and kidneys) and/or the formation of active metabolites.

The more water-soluble β-blockers (atenolol, sotalol) are primarily excreted unchanged by the kidneys. The more lipid-soluble β-blockers undergo extensive hepatic metabolism, and their metabolites are excreted via the urine or bile.

The principal clinical effects of β-blocker toxicity are hypotension and bradycardia.

CVS:

• Bradydysrhythmias: varying degrees (sinus, 1°-3° heart block, junctional/ventricular bradycardia, asystole). Vagal stimuli may precipitate cardiac arrest. QRS and QT prolongation are a measure of severity.
• Pump failure / direct myocardial depression
• Hypotension: due to combination of bradycardia and pump failure

CNS:

• CNS depression: drowsiness commonly due to cardiovascular depression and decreased cerebral perfusion, and may respond to correction of hypotension.
• Seizures: lipophilic β-blockers (e.g. propranolol) disproportionately implicated. Risk factors for seizures in propranolol overdose include ingestion of > 2 g of propranolol and QRS width >100 ms ^[3].

Resp:

• Bronchospasm: due to β2 antagonism particularly in individuals with underlying reactive airway disease.

Metabolic:

• Hypoglycemia: β-blocking drugs may cause hypoglycemia by inhibiting glycogenolysis.

β-blockers can cause hypoglycemia in overdose.

A basic biochemistry panel is used to assess for electrolyte derangements and renal function.

Serial 12-lead ECGs with continuous cardiac monitoring is used to identify signs of cardiotoxicity. These include:

• Bradyarrhythmia
• AV nodal blocks
• QT interval prolongation (K+ channel blockade)
• QRS widening, large terminal R wave in aVR (Na+ channel blockade)

Cardiac POCUS or comprehensive TTE are used to diagnose and categorize the degree of myocardial dysfunction. This will guide cardiovascular therapies.

There are a number of drugs that can lead to a patient presenting with profound hypotension and bradycardia. Correct diagnosis is important as these drugs have different specific treatments.

• Digoxin toxicity causes bradycardia, hypotension, and hyperkalemia.
• Calcium channel blocker toxicity causes bradycardia, hypotension, and hyperglycemia.

Propranolol is the only beta-blocker that frequently causes seizures in overdose. It is more toxic due to its lipophilic and membrane-stabilizing properties. In one series, of those who ingested more than 2 g of propranolol, two thirds had a seizure. It also causes more severe cardiovascular effects and death more commonly than other widely used beta-blocking drugs due to its inverse agonist effects. Propranolol also appears to be over-represented in beta-blocker poisoning when corrected for frequency of prescription ^[3]. This presumably relates to propranolol being taken by a younger age group for predominantly non-cardiac indications (anxiety, stress, migraine).

Sotalol may frequently cause significant QT prolongation and torsade de pointes (occasionally reported with propranolol) as well as the usual manifestations of beta-blockade. Other factors relate to its intrinsic sympathomimetic (partial agonist) activity and lipid solubility (resulting in CNS effects).

Invasive mechanical ventilation is indicated in refractory cardiovascular instability or reduced level of consciousness compromising airway and breathing. Administer atropine before intubation to block the vagal response to intubation, except in cases of cardiac arrest.

Continuous ECG monitoring with serial 12-lead ECGs are indicated for all except minor β-blocker poisonings. Echocardiography is recommended to characterize the relative contributions of negative inotropy and vasodilation to the hypotension, and thus guide choice of treatment. There are a number of drugs that will antagonize some of the cardiac effects of beta-blockers. All these treatments may be used simultaneously if required.

• Hypotension: IV fluid resuscitation (with normal saline or balanced crystalloid) should be initiated as first line management of hypotension.
• Bradycardia: for bradycardia associated with hypotension, treat initially with atropine boluses. If bradycardia persists, consider infusion of adrenaline or isoprenaline.
• Cardiogenic shock: β-blockers can result in impaired myocardial contractility. In these cases, initiate an adrenaline infusion ± HIET.

• Seizures: Glucose should be only given if hypoglycemic. Otherwise, they should be treated conventionally with benzodiazepines (eg diazepam) and a status epilepticus protocol.
• Arrhythmias: Ventricular tachycardia (polymorphic VT, torsades de pointes) may occur with sotalol. Conventional treatment is with magnesium, isoprenaline, or cardiac pacing. Magnesium has calcium channel blocking effects and may further impair cardiac conduction and contractility, thus should be used with great caution. Isoprenaline or cardiac pacing may be used to achieve a heart rate of 100-120 bpm, to reduce the QT interval and thus the risk of torsades de pointes.

Oral activated charcoal should be given to all patients ingesting any overdose of a β-blocking drug who present within 2 hours, or 4 hours if a modified release preparation has been ingested.

Whole bowel irrigation may be considered in patients who have ingested sustained-release preparations.

The drugs that are water soluble are predominantly renally cleared, namely sotalol and atenolol. Among these drugs, sotalol has significant 'antiarrhythmic' effects (via K+ channel blockade) and frequently causes life-threatening poisoning.

Extracorporeal treatment with renal replacement therapies (intemittent hemodialysis preferred) can be considered in patients who have all of the following ^[4]:

• Sotalol or atenolol toxicity
• Significant renal impairment
• Refractory cardiotoxic effects (bradycardia, hypotension, recurrent polymorphic VT)

There are no specific antidotes for β-blocker toxicity.

Admit all patients with symptomatic β-blocker toxicity, particularly those with:

• Large ingestions
• Deliberate ingestions
• Unintentional ingestions of > 2x daily dose of a β-blocker

Duration of observation:

• 6 hours after ingestion of an immediate-release preparation
• 12 hours after ingestion of a modified-release prepration

Occasional late complications/deterioration have been reported generally in patients who have had significant poisoning. It is likely that these relate to too rapid withdrawal of treatment. Long term sequelae have not been reported and no follow up is required after resolution of the clinical signs or ECG findings, unless the patient has been profoundly hypotensive.

Further Reading:

• Lip GY, Ferner RE. Poisoning with anti-hypertensive drugs: beta-adrenoceptor blocker drugs. J Hum Hypertens 1995; 9(4):213-221.
• Love JN, Howell JM, Litovitz TL, Klein-Schwartz W. Acute beta blocker overdose: factors associated with the development of cardiovascular morbidity. J Toxicol Clin Toxicol 2000; 38(3):275-281.
• Pentel PR, Salerno DM. Cardiac drug toxicity: digitalis glycosides and calcium-channel and beta-blocking agents. Med J Aust 1990; 152(2):88-94.
• Albertson TE, Dawson A, de Latorre F, Hoffman RS, Hollander JE, Jaeger A, Kerns WR 2nd,Martin TG,Ross MP;American Heart Association;International Liaison Committee on Resuscitation.AnnEmergMed.
• TOX-ACLS: toxicologic-oriented advanced cardiac life support 2001 Apr;37(4 Suppl):S78-90
• O'grady J, Anderson S, Pringle D.Successful treatment of severe atenolol overdose with calcium chloride. CJEM. 2001 Jul;3(3):224-7.
• Kerns W. Management of beta-adrenergic blocker and calcium channel antagonist toxicity. Emerg Med Clin North Am 2007, May;25(2):309-31; abstract viii.