• β-blockers are commonly prescribed for hypertension, coronary artery disease, arrhythmias, glaucoma, anxiety.
• β-blocker toxidrome: bradycardia, hypotension, hypoglycemia.
• β-blocker receptor selectivity is lost in overdose.
• Morbidity and mortality are due to cardiovascular collapse from ↓ inotropy (direct myocardial depression) and ↓ chronotropy (impaired myocardial conduction).

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

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-adrenergic antagonism
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-adrenergic antagonism
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

Cardioselectivity (β1-selectivity)
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.

Intrinsic sympathomimetic activity (ISA)
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.

Membrane-stabilizing activity / class I antiarrhythmic effects
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.

K+ channel blockade / class III antiarrhythmic effects
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.

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

Lipid solubility
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.

Renal/hepatic clearance
This is occasionally important in therapeutics but is largely irrelevant in overdose.

The prognosis correlates best with the degree of heart block/bradycardia. Factors in the history that increase the severity of the overdose are:

• Ingestion of propranolol/sotalol
• 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.

The cardiovascular manifestations of β-antagonist poisoning typically are bradydysrhythmias, cardiac conduction defects, hypotension, and circulatory shock.

Bradyarrhythmias and cardiac conduction defects
Varying degrees of bradyarrhythmia may occur (sinus bradycardia, 1st to 3rd degree heart block, junctional or ventricular bradycardia, or asystole) and deterioration may occur rapidly and without warning. Vagal stimuli (gastric lavage, emesis, intubation) and seizures are precipitants for cardiac arrest. Atropine pretreatment should be used prior to any intervention that could enhance vagal tone. Other ECG changes including QRS and QT prolongation occur and are a measure of severity.

Pump failure
Direct myocardial depression due to the negative inotropy effects of β-blockers can complicate circulatory shock.

Hypotension
Hypotension occurs due to a combination of bradycardia (with or without heart block) and direct myocardial depression. Toxicity develops over the first few hours. Intractable hypotension with extreme bradycardia and/or asystole is the usual mode of death.

The two primary neurologic manifestations of β-blocker toxicity are CNS depression and seizures.

CNS depression
Drowsiness is commonly due to cardiovascular depression and decreased cerebral perfusion, and may respond to correction of hypotension.

Seizures
Seizures are primarily linked to overdoses of the lipophilic β-blockers with propranolol being disproportionately implicated. Risk factors for seizures in propranolol overdose include ingestion of > 2 g of propranolol and QRS width >100 ms ^[2].

Bronchospasm
β-blocker overdose can result in bronchospasm as a result of β2 antagonism, particularly in individuals with underlying reactive airway disease.

Hypoglycaemia
β-blocking drugs may cause hypoglycemia by inhibiting glycogenolysis.

Hyperglycaemia, due to a combination of glucagon treatment and impaired insulin release (due to beta blockade) may also occur.

Two problems here.
(1) The above are contradictory.

(2) Need to check this - never seen this elsewhere:
There are some reports of patients responding to glucose with “normal” blood glucose measurements. Therefore, it is worth giving a bolus of 50% glucose to any patient with CNS effects. 

Blood glucose level
β-blockers can cause hypoglycemia in overdose.

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

Serum paracetamol and salicylate levels
This is done to rule out common co-ingestants. Serum β-blocker concentrations are generally unhelpful because they cannot be obtained in time to be clinically useful.

ECG
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)

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
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. Propranolol also appears to be over-represented in beta-blocker poisoning when corrected for frequency of prescription ^[2]. This presumably relates to propranolol being taken by a younger age group for predominantly non-cardiac indications (anxiety, stress, migraine).

Sotalol
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).

IV access and IV fluid resuscitation (with normal saline or balanced crystalloid) should be initiated. ECG monitoring in intensive care is indicated for all but the most trivial propranolol or sotalol poisonings. Glucose should be given to any patient with decreased consciousness or seizures regardless of a normal blood sugar.

Again the empirical glucose administration needs to be checked.

Gastric lavage should be considered in large ingestions of propranolol or sotalol if patients present within one hour of ingestion. Atropine should be given prior to lavage and in any patient who is vomiting.

Oral activated charcoal should be given to all patients ingesting any overdose of a β-blocking drug who present within 2 hours.

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

Induction of emesis (e.g. with syrup of ipecac) is contraindicated in β-blocker toxicity due to risk of airway compromise (from aspiration and reduced consciousness) and vagal stimulation which may worsen bradycardia.

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 ^[3]:

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

I have removed the argument where sotalol is the only one which should be dialyzed, in light of ExTRIP recommendation to consider atenolol also. - Review to keep changes.

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.

• Atropine
• Glucagon
• Isoprenaline
• Dextrose & Insulin

Atropine
This should be tried in all patients with bradycardia. It should be given prior to intubation, lavage, or any other procedure that might increase vagal tone and in patients who are nauseated or vomiting.

Glucagon
IV glucagon had been used as antidote for beta-blocker poisoning in the past but its use has been largely superseded by HIET. Glucagon increases intracellular cAMP and activates myosin kinase independent of β-receptors.
* 💊 Glucagon IV 5-10 mg as a bolus, then an IV infusion titrated against heart rate and blood pressure (starting at 5-10 mg/hour, or the 'reponse dose' per hour).

Isoprenaline
Isoprenaline is a non-selective competitive β-agonist. Doses should also be titrated against cardiac parameters and the dose required may be ten or twenty fold larger than normally used. As both the agonist and antagonist are competing for the same receptors, much larger doses are needed to reach the same level of receptor occupancy. Dose requirements will fall rapidly as the β-blocking drug is metabolised.

HIET
Patients who require inotropics support should be commenced on Dextrose & Insulin. This should be implemented in patients not responding to isoprenaline.

This section has been reworked 08/01. Goldfrank's has a discussion of calcium, general catecholamines (other than isoprenaline), and lipid emulsion.
Do we want to include those in?
Also, in what order should we include them?

Seizures
Glucose should be given regardless of a normal blood sugar. Otherwise, they should be treated conventionally with benzodiazepines (eg diazepam). If seizures are refractory, use phenobarbitone.

Why phenobarb instead of usual status epilepticus protocol?

Arrhythmias
Ventricular tachycardia (polymorphic VT, torsades de pointes) may occur with sotalol or occasionally propranolol. Conventional treatment is with magnesium, isoprenaline, or cardiac pacing. Magnesium has calcium channel blocking effects and is potentially hazardous as it may further impair cardiac conduction and contractility. It should be used with great caution if at all. Isoprenaline or cardiac pacing to achieve a heart rate of 120-140 bpm is the safest option.

 Unsure about this due to very high target HR, and probably should caveat with needing invasive BP monitoring? 

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.

Useful general references:

• 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.