62: β-Adrenergic Antagonists
Jeffrey R. Brubacher
HISTORY
In 1948, Raymond Alquist postulated that the cardiovascular actions of epinephrine, hypertension
and tachycardia, were best explained by the existence of two distinct sets of receptors that he
generically named α and β receptors. At that time, the contemporary “antiepinephrine” xenobiotics
such as phenoxybenzamine reversed the hypertension but not the tachycardia associated
with epinephrine. According to Alquist’s theory these xenobiotics acted at the α receptors. The β
receptors, in his schema, mediated catecholamine induced tachycardia. The British pharmacist, Sir
James Black was influenced by Alquist’s work and recognized the potential clinical benefit of a β-
adrenergic antagonist. In 1958, Black synthesized the first β-adrenergic antagonist, pronethalol. This
drug was briefly marketed as Alderlin, named after Alderly Park, the research headquarters of ICI
Pharmaceuticals. Pronethalol was discontinued because it produced thymic tumors in mice.
Propranolol was soon developed and marketed as Inderal (an incomplete anagram of Alderlin) in the
United Kingdom in 1964.22,199 and in the United States in 1973. Prior to the introduction of β-
adrenergic antagonists, the management of angina was limited to medications such as nitrates,
which reduced preload through dilation of the venous capacitance vessels and increased myocardial
oxygen delivery by vasodilation of the coronary arteries. Propranolol gave clinicians the ability to
decrease myocardial oxygen utilization. This new approach proved to decrease morbidity and
mortality in patients with ischemic heart disease.112 New drugs soon followed and by 1979 there were
ten β-adrenergic antagonists available in the United States.54 Unfortunately it soon became apparent
that these medications were dangerous when taken in overdose and by 1979 cases of severe
toxicity and death from β-adrenergic overdose were reported.54 Today there are nineteen β-
adrenergic antagonists approved by the US Food and Drug Administration, and other β-adrenergic
antagonists are available worldwide (Table 62–1). The pharmacology, toxicology, and poison
management issues discussed in this chapter are applicable to all of these drugs. They are
commonly used in the treatment of cardiovascular disease: hypertension, coronary artery disease,
and tachydysrhythmias. Additional indications for β-adrenergic antagonists include congestive heart
failure, migraine headaches, benign essential tremor, panic attack, stage fright, and hyperthyroidism.
Ophthalmic preparations containing β-adrenergic antagonists are used in the treatment of
glaucoma.80
TABLE 62–1. Pharmacologic Properties of the β-Adrenergic Antagonists
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EPIDEMIOLOGY
Intentional β-adrenergic antagonist overdose, although relatively uncommon, continues to account
for a number of deaths annually. From 1985 to 1995, there were 52,156 β-adrenergic antagonist
exposures reported to the American Association of Poison Control Centers (AAPCC; Chap. 136).
These exposures accounted for 164 deaths of which β-adrenergic antagonists were implicated as
the primary cause of death in 38. The other fatalities could not be clearly ascribed to β-adrenergic
antagonists due to cardioactive coingestants such as calcium channel blockers or other factors.
Children under the age of 6 accounted for 19,388 exposures, but no fatalities were reported in this
age group. The youngest fatality reported in this series was aged 7 years. It is interesting to note that
more than one-half of the fatalities developed cardiac arrest after reaching health care
personnel.133 The number of exposures to β-adrenergic antagonists reported to the AAPCC has
increased annually from 9500 in 1999 to more than 23,000 in 2010. Just under one-half of these
exposures were single substance ingestions. Each year since 2006, single substance exposures to
β-adrenergic antagonists have resulted in between 54 and 70 cases with major morbidity and three
to six fatalities (Chap. 136).
Compared with the other β-adrenergic antagonists, propranolol accounts for a disproportionate
number of cases of self-poisoning36,167 and deaths.109,133 This may be explained by the fact that
propranolol is frequently prescribed to patients with diagnoses, such as anxiety, stress,
hyperthyroidism, and migraine, who may be more prone to suicide attempts.167 Propranolol is also
more lethal due to its lipophilic and membrane stabilizing properties.75,167
PHARMACOLOGY
Cardiac Cycle
Normal cardiac electrical activity involves a complex series of ion fluxes that result in myocyte
depolarization and repolarization. Cardiac electrical activity is coupled to myocyte contraction and
relaxation respectively by increases and decreases in intracellular calcium concentrations. Cardiac
electrical and mechanical activity is closely regulated by the autonomic nervous system.
Under normal conditions, heart rate is determined by the rate of spontaneous discharge of
specialized pacemaker cells that comprise the sinoatrial (SA) node (Fig. 62–1). Pacemaker cells are
also found in the atrioventricular (AV) node and in Purkinje fibers. Spontaneous pacemaker cell
depolarization has traditionally been ascribed to inward cation current through “pacemaker
channels.”2,43 Recent research suggests that spontaneous depolarization of pacemaker cells involves
several mechanisms including a “membrane clock,” consisting of “pacemaker channels” and other
inward cation channels located on the cell membrane, and a “calcium clock,” which is driven by
rhythmic release of calcium from the sarcoplasmic reticulum.35,111,117,140β-Adrenergic stimulation
significantly increases the rate of pacemaker cell depolarization by phosphorylating proteins within
the sarcoplasmic reticulum, thereby increasing the rate of the “calcium clock.” There is also a direct,
phosphorylation-independent action of cyclic adenosine monophosphate (cAMP) at the pacemaker
channels, which increases the rate of the “membrane clock.”35 Depolarization of cells in the SA node
spreads to surrounding atrial cells where it triggers the opening of fast sodium channels. This
initiates an electric current that spreads from cell to cell along specialized pathways to depolarize the
entire heart. This depolarization, referred to as cardiac excitation, is linked to mechanical activity of
the heart by the process of electrical–mechanical coupling described below (Chap. 16).
FIGURE 62–1.
Cardiac conduction system: A. The cardiac cycle begins when pacemaker cells in the sinoatrial node depolarize
spontaneously. Traditionally, this depolarization has been attributed to inward “pacemaker” currents (If). There is
recent evidence that that pacemaker cell depolarization may also be driven by cyclical calcium release from a
“calcium clock” in the sarcoplasmic reticulum (SR). β-Adrenergic stimulation increases both the frequency of the
“calcium clock” by a phosphokinase A (PKA) mediated effect and the magnitude of the pacemaker current secondary
to a direct effect of cAMP. These effects both increase the heart rate. Cholinergic stimulation has the opposite effects
and results in bradycardia. Pacemaker cells lack fast sodium channels. Pacemaker cell depolarization triggers the
opening of voltage sensitive L-type calcium channels (ICa-L) and the impulse is transmitted to surrounding cells.
B. Coordinated SA nodal depolarization generates an impulse sufficient to open fast sodium channels in surrounding
atrial tissue and the impulse spreads along specialized pathways to depolarize the atria and ventricles.
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Myocyte Calcium Flow and Contractility
During systole, voltage sensitive slow calcium channels (L-type channels) on the myocyte
membrane open in response to cell depolarization allowing calcium to flow down its concentration
gradient into the myocyte (Fig. 62–2). Invaginations of the myocyte membrane, known as T-tubules,
place L-type calcium channels in close approximation to calcium release channels (ryanodine
receptors {RyRs}) on the sarcoplasmic reticulum (SR). The local increase in calcium concentration
that follows the opening of a single L-type calcium channel on the cell membrane triggers the
opening of the associated RyR channels, resulting in a large release of calcium from the SR, a
phenomenon known as calcium-induced calcium release.67,224 Myocytes contain tens of thousands
of couplons, clusters of L-type calcium channels and RyR channels. The calcium released from
one couplon is not sufficient to trigger firing of neighboring couplons.30 Organized myocyte
contraction requires synchronized release of calcium from numerous couplons throughout the
myocyte. This process depends on membrane depolarization to synchronize opening of L-type
channels and subsequent calcium release. This occurs rapidly throughout an extensive network of
T-tubules that spans the myocyte.86 Following release from the sarcoplasmic reticulum, cytosolic
calcium binds to troponin C and allows actin myosin interaction and subsequent myocyte
contraction. The strength of contraction is proportional to the amount of calcium release from the SR
during depolarization, which depends, in part, on the magnitude of SR calcium stores. Actin–myosin
interaction is also modulated by β-adrenergic–mediated troponin phosphorylation, ischemia,
intracellular pH, and myofilament stretch.9,17,19,209
FIGURE 62–2.
Fluctuations in calcium concentrations couple myocyte depolarization with contraction and myocyte repolarization
with relaxation. [1] Depolarization causes voltage sensitive calcium channels to open and calcium to flow down its
concentration gradient into the myocyte. [2] This calcium current triggers the opening of calcium release channels in
the sarcoplasmic reticulum and calcium pours out of the sarcoplasmic reticulum (SR). The amount of calcium
released from the SR is proportional to the initial inward calcium current and to the amount of calcium stored in the
SR. [3] At rest, actin–myosin interaction is prevented by troponin. When calcium binds to troponin, this inhibition is
removed, actin and myosin slide relative to each other, and the cell contracts. Following contraction, calcium is
actively removed from the myocyte to allow relaxation. [4] Most calcium is actively pumped into the SR where it is
bound to calsequestrin. Calcium stored in the SR is thus available for release during subsequent depolarizations. The
sarcoplasmic calcium ATPase is inhibited by phospholamban (Fig. 62–3). [5] The calcium sodium antiporter couples
the flow of three molecules of sodium flow in one direction to that of a single molecule of calcium in the opposite
direction. This transporter is passively driven by electrochemical gradients which usually favor the inward flow of
sodium coupled to the extrusion of calcium. Extrusion of calcium is inhibited by high intracellular sodium or
extracellular calcium concentrations and by cell depolarization. Under these conditions, the pump may “run in
reverse.” [6] Some calcium is actively pumped from the cell by a calcium ATPase. [7] As myocyte calcium
concentrations fall, calcium is released from troponin and the myocyte relaxes.
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During diastole, several ion pumps actively remove calcium from the cytoplasm (Fig. 62–2). The
most important of these are the sarcoplasmic reticulum calcium ATPase that pumps cytosolic
calcium into the SR, and the calcium–sodium transporter that exchanges one calcium ion for three
sodium ions with the extracellular fluid. The SR calcium ATPase is important for maintaining SR
calcium stores and is modulated by β-adrenergic stimulation (see below). When calcium
concentrations drop during diastole, calcium dissociates from troponin and relaxation occurs.15,17,18,19,187
β-Adrenergic Receptors and the Heart
β-Adrenergic receptors are divided into β1, β2, and β3 subtypes. In the healthy heart, approximately
80% of human cardiac β-adrenergic receptors are β1 and 20% are β2. Human hearts may also
contain a small number of β3-adrenergic receptors.28,60,61,150,177 The relative density of cardiac β2-
adrenergic receptors increases with heart failure.28,200β1-Adrenergic receptors mediate increased
inotropy by a well-described pathway involving cyclic AMP and protein kinases (Fig. 62–3). β1-
Adrenergic receptors are coupled to Gs proteins that activate adenylate cyclase when the receptor is
stimulated. This increases intracellular production of cAMP, which binds to and activates protein
kinase A and other cAMP-dependent protein kinases.122 Protein kinase A, in turn, phosphorylates
important myocyte proteins, including phospholamban, the voltage sensitive calcium channels, the
calcium release (RyR) channels, and troponin.17,28,70,187,204,209 Phosphorylation of the L-type calcium
channel increases contractility by increasing the influx of calcium during each cell depolarization
triggering greater release of calcium from the sarcoplasmic reticulum.169,190,197Phospholamban inhibits
the SR calcium ATPase. Phosphorylation of phospholamban removes this inhibition and increases
the activity of the sarcoplasmic calcium ATPase, resulting in increased SR calcium stores and hence
enhanced contractility.40,204 Improved activity of the SR calcium ATPase will also result in more rapid
removal of cytoplasmic calcium during diastole and aid in myocyte relaxation. Phosphorylation of the
RyR channels results in more rapid release of calcium from SR stores.17,187,209 Troponin
phosphorylation facilitates calcium unbinding and thus improves cardiac performance by enhancing
myocyte relaxation.3,15,123,204β1-Adrenergic receptors increase chronotropy by an incompletely
understood mechanism that may involve phosphorylation of SR proteins, resulting in an increased
rate of calcium discharge from the SR140, 141, and 142 in addition to direct cAMP interaction with membrane
bound pacemaker channels.2,26 Although β-adrenergic stimulation acutely improves cardiac function,
chronic β-adrenergic stimulation, acting through β1-adrenergic receptors, results in a number of
detrimental effects, including calcium overload, increased risk of dysrhythmias, impaired excitation-
contraction coupling, and myocyte apoptosis.17,28,230
FIGURE 62–3.
β1-adrenergic agonists are positive inotropes by virtue of their ability to activate protein kinase A (PKA). [1] β1-
adrenergic receptors are coupled to GS proteins, which activate adenyl cyclase when catecholamines bind to the
receptor. This causes increased formation of cAMP from ATP. [2] Increased cAMP concentrations activate PKA,
which mediates the ultimate effects of β-adrenergic receptor stimulation by phosphorylating key intracellular proteins.
[3] Phosphorylation of phospholamban disinhibits the sarcoplasmic reticulum (SR) calcium ATPase resulting in
increased SR calcium stores available for release during subsequent depolarizations and phosphorylation of SR
calcium release channels enhances calcium release from SR stores during contraction. [4] Phosphorylation of voltage
sensitive calcium channels increases calcium influx through these channels during systole. [5] Troponin
phosphorylation improves cardiac performance by facilitating calcium unbinding during diastole. β2 Receptors are also
coupled to GS proteins and mediate positive inotropy through a cAMP mechanism.Increased cAMP directly increases
heart rate (Fig. 62–1).
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Cardiac β2-adrenergic receptors are dually linked to both excitatory Gsproteins and inhibitory
Gi proteins.101,175,231 Under normal conditions, the Gs pathway predominates in human cardiac β2-
adrenergic receptors and β2-adrenergic stimulation increases contractility, relaxation, and
chronotropy through the protein kinase A pathway described above. However, in the failing heart,
the inhibitory Gi protein pathway becomes dominant and β2-adrenergic stimulation inhibits cardiac
function.28,73,187Chronic β2-adrenergic stimulation may prevent myocyte apoptosis.230
Noncardiac Effects of β-Adrenergic Receptor Activation
β-Adrenergic agonists have important noncardiac effects. β-Adrenergic receptors mediate smooth
muscle relaxation in several organs. Relaxation of arteriolar smooth muscle predominately by β2-
adrenergic stimulation reduces peripheral vascular resistance and decreases blood pressure. This
counteracts α–adrenergic–mediated arteriolar constriction. In the lungs, β2-adrenergic receptors
mediate bronchodilation. Unfortunately, chronic β-adrenergic stimulation may cause adverse
pulmonary effects, including mucous cell proliferation, hyperreactive airways, and
inflammation.37 Third-trimester uterine tone and contractions are inhibited by β2-adrenergic agonists,
and gut motility is decreased by both β1- and β2-adrenergic stimulation. Chronic, high-dose β2-
adrenergic stimulation causes skeletal muscle hypertrophy.104
β-Adrenergic receptors play a role in the immune system. Mast cell degranulation is inhibited by β2-
adrenergic stimulation, explaining the role of epinephrine in aborting and treating severe allergic
reactions. Polymorphonuclear leukocytes demarginate in response to β-adrenergic stimulation,
resulting in the increased white blood cell counts with catecholamine infusions or with increased
endogenous release ofepinephrine that occurs with pain or physiologic stress.
β-Adrenergic agonists also have important metabolic effects. Insulin secretion is increased by β2-
adrenergic receptor stimulation. Despite increased insulin concentrations, the net effect of β2-
adrenergic receptor stimulation is to increase glucose due to increased skeletal muscle
glycogenolysis and hepatic gluconeogenesis and glycogenolysis. β2-Adrenergic receptors also cause
glucagon secretion from pancreatic α cells.110β-Adrenergic agonists act at fat cells to cause lipolysis
and thermogenesis. Stimulation of adipocyte β-adrenergic receptors results in breakdown of
triglycerides and release of free fatty acids. Skeletal muscle potassium uptake is increased by β2-
adrenergic stimulation resulting in hypokalemia, explaining the role of β2-adrenergic agonists in the
treatment of hyperkalemia. Finally, renin secretion is increased by β1-adrenergic stimulation,
resulting in increased blood pressure.223
Effects of β-Adrenergic Antagonists
β-Adrenergic antagonists competitively antagonize the effects of catecholamines at β-adrenergic
receptors and blunt the chronotropic and inotropic response to catecholamines. Bradycardia and
hypotension may be severe in patients who take additional medications that impair cardiac
conduction or contractility or in those with underlying cardiac or medical conditions that make them
reliant on sympathetic stimulation. In addition to slowing the rate of SA node discharge, β-adrenergic
antagonists inhibit ectopic pacemakers and slow conduction through atrial and AV nodal tissue. β-
Adrenergic antagonists block the detrimental effects of chronic adrenergic overstimulation and have
become standard of care for patients with all stages of compensated chronic heart failure, including
patients with stable NYHA (New York Heart Association) class III or IV disease.1,66,226β-Adrenergic
blockade may exacerbate symptoms in patients with decompensated congestive heart failure but, in
the absence of cardiogenic shock or symptomatic bradycardia, β-adrenergic antagonists should not
be routinely discontinued in heart failure patients admitted to hospital.229β-Adrenergic antagonists
prevent adverse cardiac events in patients with recent myocardial infarctions but may be ineffective
in patients with prior myocardial infarction, stable coronary artery disease, or risk factors for coronary
artery disease.13
The antihypertensive effect of β-adrenergic antagonists is counteracted by a reflex increase in
peripheral vascular resistance. This effect is augmented by the β2-adrenergic antagonism of
nonselective β-adrenergic antagonists. By causing increased peripheral vascular resistance, β2-
adrenergic antagonists may rarely worsen peripheral vascular disease.
Patients with reactive airways disease may suffer severe bronchospasm after using β-adrenergic
antagonists due to loss of β2-adrenergic–mediated bronchodilation. Catecholamines inhibit mast cell
degranulation through a β2-adrenergic mechanism. Interference with this may predispose to life-
threatening effects following anaphylactic reactions in atopic individuals.89β2-Adrenergic antagonists
impair the ability to recover from hypoglycemia and may mask the sympathetic discharge that serves
to warn of hypoglycemia. This combination of effects is dangerous for patients with diabetes at risk
for hypoglycemic episodes.223
β2-Adrenergic antagonism inhibits catecholamine-mediated potassium uptake at skeletal muscle.
This may cause slight elevations in serum potassium especially after exercise. Although β2-
adrenergic stimulation augments insulin release, β-adrenergic antagonists seldom lower insulin
concentrations and may actually cause hypoglycemia by interference with glycogenolysis and
gluconeogenesis. These effects are important in patients with diabetes at risk for hypoglycemia. β-
Adrenergic antagonists also alter lipid metabolism. Although the release of free fatty acids from
adipose tissue is inhibited, patients taking nonselective β-adrenergic antagonists typically have
increased plasma concentrations of triglycerides and decreases in high-density lipoproteins.223
PHARMACOKINETICS
The pharmacokinetic properties of the β-adrenergic antagonists depend in large part on their
lipophilicity. Propranolol is the most lipid soluble of the β-adrenergic antagonists and atenolol is the
most water soluble. The oral bioavailability of the β-adrenergic antagonists ranges from
approximately 25% for propranolol to almost 100% for pindolol and penbutolol.
The highly lipid-soluble drugs cross lipid membranes rapidly and concentrate in adipose tissue.
These properties allow rapid entry into the central nervous system (CNS), and typically result in large
volumes of distribution. In contrast, highly water-soluble drugs, cross lipid membranes slowly,
distribute in total body water, and tend to have less CNS toxicity. Volumes of distribution range from
about 1 L/kg for atenolol to more than 100 L/kg for carvedilol.
The highly lipid soluble β-adrenergic antagonists are highly protein bound and poorly excreted by the
kidneys. They require hepatic biotransformation before they can be eliminated and accumulate in
patients with liver failure. By contrast, the water-soluble β-adrenergic antagonists tend to be slowly
absorbed, poorly protein bound, and renally eliminated. They accumulate in patients with kidney
failure. Esmolol, although water-soluble, is rapidly metabolized by red blood cell esterases and does
not accumulate in patients with kidney failure. The half-life of esmolol is about 8 minutes. Half-lives
of the other β-adrenergic antagonists range from about 2 hours for oxprenolol to as much as 32
hours for nebivolol. The β-adrenergic antagonists also differ in their β1-adrenergic selectivity, intrinsic
sympathomimetic activity, and vasodilatory properties (Table 62–1).157,166,170,206,223
β1 Selectivity (Acebutolol, Atenolol, Betaxolol, Bisoprolol, Celiprolol, Esmolol, Metoprolol, Nebivolol)
β1-Selective antagonists may avoid some of the adverse effects of the non-selective antagonists.
Short-term use of β1-adrenergic selective antagonists appears to be safe in patients with mild to
moderately severe reactive airways.181 These drugs may be safer for patients with diabetes mellitus
or peripheral vascular disease and may be more effective antihypertensives. Their β1-adrenergic
selectivity, however, is incomplete, and adverses. reactions secondary to β2-adrenergic antagonism
may occur with therapeutic dosage as well as in overdose.124,223
Membrane Stabilizing Effects (Acebutolol, Betaxolol, Carvedilol, Oxprenolol, Propranolol)
β-Adrenergic antagonists that inhibit fast sodium channels (also known as type I antidysrhythmic
activity) are said to possess membrane-stabilizing activity. No significant membrane stabilization
occurs with therapeutic use of β-adrenergic antagonists, but this property can contribute to toxicity in
overdose.
Intrinsic Sympathomimetic Activity (Acebutolol, Carteolol, Oxprenolol, Penbutolol, Pindolol)
These medications act as partial agonists at β-adrenergic receptors and are said to have intrinsic
sympathomimetic activity (ISA). This property is unrelated to β1-adrenergic selectivity. These drugs
may avoid the dramatic decrease in resting heart rate that occurs with β-adrenergic antagonism in
susceptible patients, but their clinical benefit is not demonstrated in controlled trials.50,57
Potassium Channel Blockade (Acebutolol, Sotalol)
Sotalol is a nonselective β-adrenergic antagonist with low lipophilicity, no membrane stabilizing
effect, and no ISA. Sotalol is unique because of its ability to block the delayed rectifier potassium
current responsible for repolarization. This prolongs the action potential duration and is manifested
on the electrocardiogram (ECG) by a prolonged QT interval.81 The prolonged QT interval
predisposes to torsade de pointes and ventricular dysrhythmias may complicate the therapeutic use
of sotalol.108 In patients taking sotalol therapeutically, torsade de pointes is most common in those
who have kidney failure, use other drugs that prolong the QT interval, or have predisposing factors
for QT prolongation such as hypokalemia, hypomagnesemia, bradycardia, or congenital QT
prolongation.38,81 Some authors suggest that QT dispersion is a better predictor of sotalol induced
torsade de pointes than QT prolongation alone (Chap. 17). A difference between the longest and
shortest QT interval on 12-lead ECG of more than 100 milliseconds indicates an increased risk of
torsade de pointes.38Acebutolol also prolongs the QT interval presumably secondary to blockade of
outward potassium channels.125
Vasodilation (Betaxolol, Bucindolol, Carteolol, Carvedilol, Celiprolol, Labetalol, Nebivolol)
Labetalol and the newer “third-generation” β-adrenergic antagonists (betaxolol, bucindolol, carteolol,
carvedilol, celiprolol, nebivolol) are also vasodilators. Labetalol and carvedilol are nonselective β-
adrenergic antagonists that also possess α-adrenergic antagonist activity. Nebivolol is a selective β1-
adrenergic antagonist that causes vasodilation by release of nitric oxide.143 Bucindolol, carteolol, and
celiprolol vasodilate because they are agonists at β2-adrenergic receptors. Celiprolol and carteolol
also vasodilate because of nitric oxide mediated effects. Bucindolol and celiprolol are not FDA
approved. Carteolol is currently available as an ocular preparation. Betaxolol and carvedilol also
have calcium channel blocking properties that result in vasodilation (Table 62–1). β-Adrenergic
antagonists with vasodilating properties may be particularly beneficial for patients with congestive
heart failure.164 These drugs may also have a role in managing patients with coronary artery disease
or peripheral vascular disease. Those drugs with β2-adrenergic agonist activity may prove useful for
patients with reactive airways.
β-Adrenergic antagonists should not be given without appropriate α-adrenergic blockade in
situations of catecholamine excess such as pheochromocytoma. In these conditions, β2–adrenergic–
mediated vasodilation is essential to counteract α-adrenergic–mediated vasoconstriction. β-
Adrenergic antagonists would result in “unopposed α” adrenergic effect causing dangerous
increases in vascular resistance. Even agents with combined α- and β-adrenergic antagonist
properties can cause this problem. Labetalol, for example, is five to ten-fold more potent as a β-
adrenergic antagonist than as an α-adrenergic antagonist. Theoretically, xenobiotics with β2-
adrenergic agonist properties may avoid the “unopposed α” effect, but their use in this situation has
not yet been investigated.48,63,143,210,223
Other Preparations (Ophthalmic Preparations, Sustained Release, Combined Products)
Therapeutic use of ophthalmic solutions containing β-adrenergic antagonists may cause systemic
adverse effects such as bradycardia, high-grade AV block, heart failure, and
bronchospasm.24,56,151,189,191,216,223
An extended-release tablet containing a combination of the calcium channel blocker, felodipine, and
metoprolol has been studied as an antihypertensive medication.69,85 This medication (Logimax,
AstraZeneca) is marketed in more than 35 countries worldwide but is not available in the United
States or Canada. Another combined β-adrenergic and calcium channel antagonist containing
atenolol andnifedipine (Nif–Ten, AstraZeneca) is also used as an antihypertensive.45
PATHOPHYSIOLOGY
Most of the toxicity of β-adrenergic antagonists is due to their ability to competitively antagonize the
action of catecholamines at cardiac β-adrenergic receptors. The peripheral vascular effects of β-
adrenergic antagonism are less prominent in overdose. β-Adrenergic antagonists also appear to
have toxic effects independent of their action at catecholamine receptors. In catecholamine
depleted, spontaneously beating isolated rat hearts, propranolol, timolol and sotalol all decreased
heart rate and contractility.42 Surprisingly, these effects were similar in catecholamine depleted and
nondepleted hearts.114 A membrane depressant effect likely contributes to the cardiac depressant
effects of propranolol but not to that of timolol or sotalol. It may be concluded that β-adrenergic
antagonists cause myocardial depression at least in part by an action independent of catecholamine
antagonism or membrane depressant activity.114 This effect may be mediated by interference with
calcium handling in the sarcoplasmic reticulum.
Other investigators studied the role of extracellular ions and cardiac membrane potential in
modulating β-adrenergic antagonist toxicity. β-Adrenergic antagonists interfere with calcium uptake
into intracellular organelles. This interference with cytosolic calcium handling may stimulate calcium
sensitive outward potassium channels and result in myocyte hyperpolarization and subsequent
refractory bradycardia. Lowering extracellular potassium or raising extracellular sodium
concentrations was conjectured to counteract this effect and, in fact, partially reversed propranolol
and atenolol toxicity in isolated rat hearts.97 In another series of experiments with isolated rat hearts,
calcium improved the function of rat hearts poisoned with β-adrenergic antagonists. This may have
been due to a nonspecific positive inotropic action of calcium.114
Although cardiovascular effects are most prominent in overdose, β-adrenergic antagonists also
cause respiratory depression.115 This effect is centrally mediated and appears to be an important
cause of death in spontaneously breathing animal models of β-adrenergic antagonism
toxicity.116 There is evidence that propranolol is concentrated in synaptic vessels and may impair
synaptic function by inhibition of membrane ion pumps, including the sodium–potassium ATPase,
the calcium ATPase, and the magnesium ATPase. These actions may explain some of the CNS
effects noted in propranolol overdose.64
CLINICAL MANIFESTATIONS
Symptoms of toxicity generally occur within hours after β-adrenergic antagonist overdose.
Propranolol overdose, in particular, may be complicated by the rapid development of hypoglycemia,
seizures, coma, and dysrhythmias. In a retrospective review of published reports of adult β-
adrenergic antagonist overdose there were 39 symptomatic patients with well documented times
from ingestion to symptom onset. Only one patient had ingested a sustained release product. Thirty-
one patients were symptomatic at 2 hours, all but one developed symptoms at 4 hours, and
everyone developed symptoms within the first 6 hours. The authors conclude that there have been
no well documented reports of immediate release β-adrenergic antagonist overdose resulting in
toxicity delayed more than 6 hours after ingestion.126 The authors of an Australian series also noted
that, in their 58 patients with β-adrenergic antagonist overdose, all major symptoms began within 6
hours of ingestion.167 These observations do not apply to sotalol, which is well known to cause
delayed toxicity in overdose, or to sustained-release preparations.
Isolated β-adrenergic antagonist overdose in healthy people is often benign. In several series, one-
third or more of patients reporting a β-adrenergic overdose remained asymptomatic.46,51,127,206 This is
partially explained by the fact that β-adrenergic antagonism is often well tolerated in healthy persons
who do not rely on sympathetic stimulation to maintain cardiac output. In particular, unintentional
ingestions in children rarely result in significant toxicity.16 In fact, a review of published cases found a
few reports of hypoglycemia but no deaths or serious cardiovascular morbidity following β-
adrenergic antagonist ingestion in children younger than 6 years of age.135
β-Adrenergic antagonists severely impair the ability of the heart to respond to peripheral
vasodilation, bradycardia, or decreased contractility caused by other xenobiotics. Therefore even
relatively benign vasoactive xenobiotics may cause catastrophic toxicity when coingested with β-
adrenergic antagonists.58 According to one author, the most important predictor of toxicity in β-
adrenergic antagonist overdose is likely to be the presence of a cardioactive coingestant.129 Isolated
β-adrenergic antagonist overdose is most likely to cause symptoms in persons with congestive heart
failure, sick sinus syndrome, or impaired AV conduction who rely on sympathetic stimulation to
maintain heart rate or cardiac output. Nevertheless, severe toxicity and death may still occur in
healthy persons who have ingested β-adrenergic antagonists alone.54,167,198 This may be explained by
an increased susceptibility of certain persons to β-adrenergic antagonism or by special properties
that increase the toxicity of certain β-adrenergic antagonists (see below). In patients without a
coingestant, toxicity is most likely to occur in those who ingest a β-adrenergic antagonist with
membrane stabilizing activity.129
Patients with symptomatic β-adrenergic antagonist overdose will most often be hypotensive and
bradycardic. Decreased SA node function results in sinus bradycardia, sinus pauses, or sinus arrest.
Impaired atrioventricular conduction manifested as prolonged PR interval or high-grade AV block
occurs rarely. Prolonged QRS and QT intervals may occur and severe poisonings may result in
asystole. Congestive heart failure often complicates β-adrenergic antagonist overdose. Delirium,
coma, and seizures occur most commonly in the setting of severe hypotension but may also occur
with normal blood pressure, especially with exposure to the more lipophilic xenobiotics such as
propranolol.54,167 Respiratory depression and apnea may have an additional role in toxicity.6 In a
review of reported cases, 18% of patients with propranolol toxicity and 6% of those with atenolol
toxicity had a respiratory rate fewer than 12 breaths/min.167 Respiratory depression following β-
adrenergic antagonist overdose typically occurs in patients who are hypotensive and comatose but
is reported in awake patients.153Hypoglycemia may complicate β-adrenergic antagonist poisoning in
children77,135 but is uncommon in acutely poisoned adults. In a series of 15 cases of β-adrenergic
antagonist overdose, none of the 13 adults were hypoglycemic whereas both of the two children had
symptomatic hypoglycemia.54 Bronchospasm is relatively uncommon following β-adrenergic
antagonist overdose and appears to occur only in susceptible patients. In the series mentioned
above, only two of the 15 patients developed bronchospasm54 and in a recent review of 39 cases of
symptomatic adults with β-adrenergic antagonist overdose, only one patient developed
bronchospasm.126 Clinical use of β-adrenergic antagonists slightly increases serum potassium136;
however, significant hyperkalemia is rare.
β1 Selectivity (Acebutolol, Atenolol, Betaxolol, Bisoprolol, Esmolol, Metoprolol, Nebivolol)
In overdose, cardioselectivity is largely lost and deaths due to the β1-adrenergic selective agents
including acebutolol,75 atenolol,133betaxolol,20 and metoprolol172,198 are reported. There have been
single reports of minor toxicity following overdose with bisoprolol212 and nebivolol.74
Membrane-Stabilizing Effects (Acebutolol, Betaxolol, Carvedilol, Oxprenolol, Propranolol)
Propranolol possesses the most membrane stabilizing activity of this class and propranolol
poisoning is characterized by coma, seizures, hypotension, bradycardia, impaired atrioventricular
conduction, and widened QRS interval. A Brugada-pattern on ECG may occur following propranolol
overdose (Chap. 16).168 Ventricular tachydysrhythmias may also occur.4,133 Hypotension may be out of
proportion to bradycardia and deaths from propranolol overdose are well reported.54,75,133Acebutolol,
betaxolol and oxprenolol also possess significant membrane stabilizing activity and have caused
fatalities when taken in overdose.20,75,100,157,165
Lipid Solubility
In overdose, the more lipophilic β-adrenergic antagonists may cause delirium, coma, and seizures
even in the absence of hypotension.54,167Atenolol, the least lipid soluble of β-adrenergic antagonists,
appears to be one of the safer β-adrenergic antagonists when taken in overdose.75In fact, in one
series of β-adrenergic antagonist overdoses, none of the 18 patients with atenolol overdose had
seizures compared with eight out of 28 patients with propranolol overdose.167 Nevertheless, atenolol
overdose may result in severe toxicity and cardiovascular death.133,161,202
Intrinsic Sympathomimetic Activity (Acebutolol, Carteolol, Oxprenolol, Penbutolol, Pindolol)
There is little experience with overdose of these agents, but ISA would theoretically make these
drugs safer than the other β-adrenergic antagonists. Sympathetic stimulation with mild tachycardia
or hypertension often predominates in pindolol overdose, and this class of medications appears to
be relatively safe in overdose.54,109,166 In addition to ISA, acebutolol and oxprenolol have significant
membrane-stabilizing activity, making them dangerous in overdose, and deaths due to acute toxicity
from these β-adrenergic antagonists are reported.54,75,125,165 Overdose with carteolol or penbutolol has
not been reported.
Potassium Channel Blockade (Acebutolol, Sotalol)
In six patients with sotalol overdose, the average QT interval was 172% of normal and five patients
had ventricular dysrhythmias, including multifocal ventricular extrasystoles, ventricular tachycardia,
and ventricular fibrillation.156 Sotalol overdose may also be complicated by hypotension, bradycardia,
and asystole,5,156 and fatalities are well documented.152,160
Sotalol overdose may cause delayed and prolonged toxicity although ECG changes appear to occur
early. In a series of six patients with sotalol overdose, all had prolonged QT interval noted on the
initial ECG taken 30 minutes to 4.5 hours after ingestion. It is not clear whether these patients were
taking sotalol therapeutically prior to the overdose so it is possible that the prolonged QT on the
initial ECG was present prior to the overdose. The greatest QT prolongation occurred 4 to 15 hours
after ingestion, and the risk of ventricular dysrhythmias was highest between 4 and 20 hours. All four
patients who developed ventricular tachycardia did so after 4 hours, and in two patients ventricular
dysrhythmias first occurred 9 hours after ingestion. One patient continued to have ventricular
dysrhythmias at 48 hours, and abnormally prolonged QT intervals were noted as long as 100 hours
after ingestion. In this series the average sotalol half-life was 13 hours, and the average time until
normalization of the QT interval was 82 hours.156 Acebutolol-induced QT interval prolongation may
partially explain the ventricular tachydysrhythmias that occur with severe acebutolol toxicity.44,125,133
Vasodilation (Betaxolol, Bucindolol, Carteolol, Carvedilol, Celiprolol, Labetolol, Nebivolol)
The vasodilatory properties of these drugs would theoretically act in synergy with β-adrenergic
antagonism to increase toxicity. Conversely, the low membrane-stabilizing effect of these drugs may
make them relatively safe in overdose. Betaxolol is the sole drug in this class with membrane
stabilizing properties. Overdose with labetalol appears to be similar to that of other β-adrenergic
antagonists with hypotension and bradycardia as prominent features.103,105,194 Experience with
overdose of the newer vasodilating β-adrenergic antagonists is limited. Similar to conventional β-
adrenergic antagonists, carvedilol overdose causes hypotension and bradycardia.23,68,205 In a case
report from Germany, nebivolol overdose was complicated by bradycardia, lethargy, and
hypoglycemia. The patient received standard treatment and had a benign outcome.74 Another patient
became hypotensive and bradycardic and then experienced cardiac arrest following nebivolol
overdose. That person was successfully resuscitated with lipid emulsion and high-dose
insulin.201 Severe toxicity and death have occurred following betaxolol20,21 and celiprolol176 poisoning.
Overdoses with bucindolol or carteolol have not been reported.
Other Preparations (Ophthalmic Preparations, Sustained Release, Combined Products)
There is very little published experience with overdoses of the sustained release β-adrenergic
antagonists, but it is reasonable to expect that overdose with these agents will result in both a
delayed onset and prolonged duration of toxicity. Acute overdose of ophthalmic β-adrenergic
antagonists has not been reported. Patients who take mixed overdoses with calcium channel
antagonists and β-adrenergic antagonists are difficult to manage because of synergistic
toxicity.180,188,195 Overdoses with combined β-adrenergic antagonist and calcium channel blocker
preparations such as felodipine and metoprolol or atenolol and nifedipine have not been reported,
but these combinations would be expected to be quite dangerous in overdose.
DIAGNOSTIC TESTING
All patients with an intentional overdose of a β-adrenergic antagonist should have a 12-lead ECG
and continuous cardiac monitoring. Serum glucose should be measured regardless of mental status
because β-adrenergic antagonists can cause hypoglycemia. A chest radiograph and assessment of
oxygen saturation should be obtained if the patient is at risk for or suffering symptoms of congestive
heart failure. For patients with bradycardia of uncertain etiology, measurement of thyroid function,
potassium, kidney function, cardiac enzymes, and digoxin concentration may prove helpful. Serum
concentrations of β-adrenergic antagonists are not readily available for routine clinical use but may
prove helpful in making a retrospective diagnosis in selected cases. Lactate concentrations may be
elevated in patients with β-adrenergic antagonist poisoning but are poor predictors of survival.147
MANAGEMENT
Airway and ventilation should be maintained with endotracheal intubation if necessary. Because
laryngoscopy may induce a vagal response, it is reasonable to give atropine prior to intubation of the
bradycardic patient. This is particularly true for children who are more susceptible to this
complication. The initial treatment of bradycardia and hypotension consists of atropine and
intravenous fluids. These measures will likely be insufficient in patients with severe toxicity but may
suffice in patients with mild poisoning or other etiologies for bradycardia.
Gastrointestinal decontamination is warranted for all persons who have ingested significant amounts
of a β-adrenergic antagonist. Induction of emesis is contraindicated because of the potential for
catastrophic deterioration of mental status and vital signs in these patients, and since vomiting
increases vagal stimulation and may worsen bradycardia.196Orogastric lavage is recommended for
patients with significant effects such as seizures, hypotension, or bradycardia if the patient presents
in a time frame when the drug is still expected to be in the stomach. Orogastric lavage is also
recommended for all patients who present shortly after ingestion of large (gram amount) ingestions
of propranolol or one of the other more toxic β-adrenergic antagonists (ie, acebutolol, betaxolol,
metoprolol, oxprenolol, sotalol). Orogastric lavage causes vagal stimulation and carries the risk of
worsening bradycardia so it is reasonable to pretreat patients with standard doses of atropine. We
recommend activated charcoal alone for persons with minor symptoms following an overdose with
one of the more water-soluble β-adrenergic antagonists who present later than one hour following
ingestion. Whole bowel irrigation with polyethylene glycol should be considered in patients who have
ingested sustained release preparations (Antidotes in Depth: A2).
Seizures or coma associated with cardiovascular collapse is treated by attempting to restore
circulation. Seizures in the patient with relatively normal vital signs should be treated with
benzodiazepines followed by barbiturates if benzodiazepines fail. Refractory seizures are rare in β-
adrenergic antagonist overdose.
Specific Management
Patients who fail to respond to atropine and fluids require management with the inotropics discussed
below (Fig. 62–4). When time permits, it is preferable to introduce new medications sequentially so
that the effects of each may be assessed. We recommend glucagon followed by calcium, and high-
dose insulin euglycemia therapy. In the critically ill patient, there may not be enough time for this
approach and multiple treatments may be started simultaneously. If these therapies fail, we suggest
starting a catecholamine pressor and phosphodiesterase inhibitors. Advanced hemodynamic
monitoring, when available, is advisable to guide therapy for all patients receiving catecholamine
pressors or phosphodiesterase inhibitors. Lipid emulsion therapy should be given to patients with
severe toxicity or cardiac arrest. Mechanical life support with intra-aortic balloon pump or
extracorporeal circulation may be lifesaving when medical management fails and is most effective
when started early.
FIGURE 62–4.
Positive inotropes improve cardiac function by a number of mechanisms, which usually result in increased
intracellular calcium. Xenobiotics that [1] increase cAMP: Glucagon receptors and β-adrenergic receptors are coupled
to GS proteins so that receptor binding increases cAMP by activation of adenyl cyclase. Phosphodiesterase inhibitors
increase cAMP by inhibiting its breakdown. [2] increase calcium influx: Calcium salts increase calcium influx through
L-type calcium channels by a direct mass effect. [3] inhibit extrusion of calcium via the sodium-calcium exchange
pump: Those that increase intracellular sodium such as digoxin and sodium channel agonists (eg, aconitine) and
those such as 4-aminopyridine that prolong the action potential duration alter the electrochemical gradients in a way
that hinders the extrusion of calcium. [4] increase the sensitivity of the contractile elements to calcium: Angiotensin II
and endothelin do this by inducing an intracellular alkalosis. The calcium sensitizers, levosimendan and pimobendan
are used to treat heart failure in some countries.
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Glucagon
Cardiac glucagon receptors,220 like β-adrenergic receptors, are coupled to Gs proteins. Glucagon
binding increases adenyl cyclase activity independent of β-adrenergic receptor binding.227 The
inotropic effect of glucagon is enhanced by its ability to inhibit phosphodiesterase and thereby
prevent cAMP breakdown.149
There are no controlled trials of glucagon in humans with β-adrenergic antagonist
poisoning.12,25 Nevertheless, with more than 30 years of clinical use,107,217 glucagon is still recognized
as a useful treatment of choice for severe β-adrenergic antagonist toxicity.96,163,206,222 This is supported
by animal models,62,106,132 and a case series suggesting that glucagon is also effective in correcting
symptomatic bradycardia and hypotension secondary to therapeutic β-adrenergic antagonist
use.134Glucagon is a vasodilator, and in animal models of propranolol poisoning it is more effective in
restoring contractility, cardiac output, and heart rate than in restoring blood pressure.12,132
The initial adult dose of glucagon for β-adrenergic antagonist toxicity is 3 to 5 mg given slowly over 1
to 2 minutes. The initial pediatric dose is 50 µg/kg. If there is no response to the initial dose, higher
doses up to a total of 10 mg may be used. Once a response occurs, a glucagon infusion is started.
Most authors recommend using an infusion of 2 to 5 mg/h, although many authorities recommend
glucagon infusions as high as 10 mg/h. We suggest that the glucagon infusion be started at the
“response dose” per hour. Thus, for example, if the patient receives 7 mg of glucagon before a
response occurs, the glucagon infusion should be started at 7 mg/h. When a full 10 mg dose of
glucagon fails to restore blood pressure and heart rate and the diagnosis of β-adrenergic antagonist
toxicity is probable, we still recommend starting an infusion of glucagon at 10 mg/h as glucagon will
have synergistic effects with subsequent antidotes. Glucagon may cause vomiting with risk of
aspiration. Other adverse events of glucagon in this setting include hyperglycemia and mild
hypocalcemia87 and these should be treated appropriately if they develop. Patients also develop
rapid tachyphylaxis to glucagon, and the need for increasing doses and additional therapies should
be expected, even when patients initially respond (Antidotes in Depth: A18).
Calcium
Calcium salts effectively treat hypotension but not heart rate in animal models of β-adrenergic
antagonist toxicity.114,128 Calcium chloride successfully reverses hypotension in patients with β-
adrenergic antagonist overdose27,161 and in combined calcium channel blocker and β-adrenergic
antagonist toxicity.76 The adult starting dose of calcium gluconate is 3 g of the 10% solution given
intravenously. We recommend using up to 9 g of calcium gluconate if needed. The initial dose of
calcium gluconate in children is 60 mg/kg up to 3 g. This may be repeated up to a total of 180 mg/kg
(Antidotes in Depth: A29).
Insulin and Glucose
High-dose insulin, euglycemia therapy improves cardiac function following cardiac surgery65 and
survival following myocardial infarction.49,137, 138, and 139 There is evidence that high-dose insulin combined
with sufficient glucose to maintain euglycemia is beneficial in β-adrenergic antagonist poisoning. In a
canine model of propranolol toxicity, all six animals treated with insulin and glucose survived
compared with four out of six in the glucagon group, one of six in theepinephrine group, and no
survivors in the sham treatment group.99Insulin plus glucose was markedly more effective
than vasopressin plusepinephrine in a porcine model of propranolol toxicity. In that experiment, all
five animals in the insulin group survived the 4-hour protocol and all five in
the vasopressin plus epinephrine group died within 90 minutes.82 In a rabbit model of severe
propranolol toxicity, high-dose insulin was more effective than lipid emulsion in restoring blood
pressure and heart rate, but there was no difference in survival.71Clinical experience with high-dose
insulin for β-adrenergic antagonist poisoning is increasing but still limited to case reports and case
series.47Improvements in heart rate and blood pressure following high-dose insulin are reported in
patients with isolated overdoses of metoprolol, nebivolol, and propranolol.84,158,201 High-dose insulin
was also effective in combined poisoning with β-adrenergic antagonists and calcium channel
blockers.84,228
High-dose insulin is simple to use, safe (with appropriate monitoring of glucose and potassium), and
does not require invasive monitoring. For these reasons, we recommend using high-dose insulin and
glucose infusions for patients with β-adrenergic antagonist toxicity who have not responded to
fluids, atropine, and glucagon. Although the dose of insulin is not definitively established, therapy
typically begins with a bolus of 1 unit/kg of regular human insulin along with 0.5 g/kg of dextrose. If
blood glucose is greater than 300 mg/dL (16.7 mmol/L), the dextrose bolus is not necessary. An
infusion of regular insulin should follow the bolus starting at 1 unit/kg/h. A continuous dextrose
infusion, beginning at 0.5 g/kg/h should also be started. Glucose should be monitored every 15 to 30
minutes until stable and then every 1 to 2 hours and titrated to maintain the blood glucose between
100 and 250 mg/dL. Cardiac function should also be reassessed every 10 to 15 minutes, and if it
remains depressed, the insulin infusion can be increased up to 10 units/kg/h as required (rarely
higher). The goal of therapy includes improved organ perfusion with improvements in cardiac output,
mental status, urine output, and acid-base abnormalities. The response to insulin is typically delayed
for 15 to 60 minutes so it will usually be necessary to start a catecholamine infusion before the full
effects of insulin are apparent. It is important to continue monitoring glucose and electrolytes for
several hours after insulin is discontinued (Antidotes in Depth: A17).
Catecholamines
Patients who do not respond to the preceding therapies usually require a catecholamine infusion.
The choice of catecholamine is somewhat controversial. Theoretically, the pure β-adrenergic agonist
isoproterenol would seem to be the ideal agent because it can overcome β-adrenergic blockade
without causing any α-adrenergic effects. Unfortunately, this therapy has several potential
drawbacks, which limit its efficacy. In the presence of β-adrenergic antagonism, extraordinarily high
doses of isoproterenol and other catecholamines are frequently required.36,165,171,206,215 Individual case
reports document isoproterenol infusions as high as 800 µg/min.166 At these high doses, the β2-
adrenergic effects of isoproterenol cause peripheral vasodilation and may actually lower blood
pressure.171 Nevertheless, in some animal models, isoproterenol is the most effective catecholamine
and is even more effective than glucagon in reversing β-adrenergic antagonist toxicity.203,219 However,
clinical experience has not shown this to be the case. In a review of reported cases, glucagon
increased heart rate 67% of the time and blood pressure 50% of the time. In contrast, isoproterenol
was effective in increasing heart rate only 11% of the time and blood pressure only 22% of the
time. Epinephrine was more effective than isoproterenol.222 The selective β1-adrenergic agonist
prenalterol may avoid some of the problems associated with isoproterenol and was used
successfully to treat β-adrenergic antagonist overdose.52,109 Prenalterol would be expected to be
especially effective following overdose of the cardioselective β-adrenergic antagonists.52Prenalterol is
not FDA approved and prenalterol therapy is limited as its relatively long half-life (~ 2 hours) makes
titration difficult.173 Dobutamine is a β1-adrenergic agonist with relatively little effect on vascular
resistance that may be useful in this setting. However, experience is limited and dobutamine is not
always effective in patients with β-adrenergic antagonist overdose.165,193 In the setting of β-adrenergic
antagonism, catecholamines with substantial α-adrenergic agonist properties may increase
peripheral vascular resistance without improving contractility, resulting in acute cardiac failure.
Severe hypertension due to lack of β2-adrenergic–mediated vasodilation is another potential adverse
reaction from this so-called “unopposed α-adrenergic” effect.59 Because of these potential problems,
we recommend that catecholamine use be guided by hemodynamic monitoring using noninvasive
techniques such as bioimpedance or echocardiographic monitoring or direct invasive measures of
determining cardiac performance. Catecholamine infusions should be started at the usual rates and
then increased rapidly until a clinical effect is obtained. If advanced monitoring is impossible and the
diagnosis of β-adrenergic antagonist overdose is fairly certain, it is reasonable to begin an
isoproterenol or epinephrine infusion with careful monitoring of the patient’s blood pressure and
clinical status. The infusion should be stopped immediately if the patient becomes more hypotensive
or develops congestive heart failure.
Lipid Emulsion
Lipid emulsion is a promising antidote that has a role in selected cases of severe β-adrenergic
antagonist overdose. Intravenous administration of lipid emulsion is hypothesized to reduce the
toxicity of lipid-soluble xenobiotics by lowering free serum concentrations of these compounds,
because they partition into the lipemic component of blood and improve the bioenergetics of the
heart. Lipid emulsion has proven effective in animal models of poisoning with propranolol, a highly
lipid soluble β-adrenergic antagonist, but not those that are water-soluble such as atenolol or
metoprolol.29,31,32,34 Lipid emulsion was less effective than high-dose insulin in restoring heart rate and
blood pressure in a rabbit model of propranolol poisoning.71 Human experience with the use of lipid
emulsion in β-adrenergic antagonist overdose is limited, but cases of dramatic recovery from cardiac
arrest have been reported.33,90,182,201,205 It is reasonable to administer intravenous lipid emulsion in
patients with severe toxicity from a lipid-soluble β-adrenergic antagonist that does not respond to
usual therapy.34,72 The optimal dose and formulation of lipid emulsion for this purpose is unknown.
One protocol calls for a 1.5 mL/kg of 20% Intralipid followed by an infusion of 0.25 mL/kg/min. The
bolus can be repeated in 3 to 5 minutes if necessary. The total dose should be less than 8
mL/kg221 (Antidotes in Depth: A20).
Phosphodiesterase Inhibitors
The phosphodiesterase inhibitors amrinone, milrinone, and enoximone are theoretically beneficial in
β-adrenergic antagonist overdose since they inhibit the breakdown of cAMP by phosphodiesterase
and hence increase cAMP independently of β-adrenergic receptor stimulation. Phosphodiesterase
inhibitors increase inotropy in the presence of β-adrenergic antagonism in both animal models118 and
in humans.213Although these agents appear to be as effective as glucagon in animal models of β-
adrenergic antagonist toxicity,132,185 controlled dog models were unable to demonstrate an additional
benefit of these agents over glucagon.131,186 Phosphodiesterase inhibitors might be useful in selected
patients who fail glucagon therapy, and have been used clinically to treat β-adrenergic antagonist
poisoned patients.79,103,183,184Therapy with phosphodiesterase inhibitors is often limited by hypotension
secondary to peripheral vasodilation. Furthermore, these drugs are difficult to titrate because of
relatively long half-lives (30– 60 minutes for milrinone, 2–4 hours for amrinone, and ~ 2 hours for
enoximone).94,154 For these reasons the phosphodiesterase inhibitors should generally only be
considered for patients who have arterial and pulmonary artery pressure monitoring.
Ventricular Pacing
Ventricular pacing is not a particularly useful intervention in patients with β-adrenergic antagonist
toxicity, but it will increase the heart rate in some patients.95 Unfortunately, there will frequently be
failure to capture or pacing may increase the heart rate with no increase in cardiac output or blood
pressure.4,109,113,206 In fact, some authors have noticed that ventricular pacing occasionally decreases
blood pressure perhaps secondary to loss of organized atrial contraction or due to impaired
ventricular relaxation.206
Extracorporeal Removal
Extracorporeal removal is ineffective for the lipid-soluble β-adrenergic antagonists due to their large
volumes of distribution. Hemodialysis may remove water-soluble renally eliminated β-adrenergic
antagonists such as atenolol179 and acebutolol.174 Because hemodialysis is often technically difficult in
poisoned patients due to hypotension and bradycardia, it is rarely utilized in patients with β-
adrenergic antagonist overdose but may be considered in selected cases.
Mechanical Life Support
It is important to remember that the patient with circulatory failure from an acute overdose will
typically recover without sequelae if ventilation and circulation are maintained until the xenobiotic is
eliminated. When the preceding medical treatment fails, it is appropriate to consider the use of an
intra-aortic balloon pump or extracorporeal life support (ECLS). Several case reports describe
remarkable recoveries following the use of these therapies for refractory β-adrenergic antagonist
toxicity21,113,146 or combined β-adrenergic antagonist and calcium channel blocker
overdose.53,88,102,162,178,225 In one report, a neonate who developed refractory circulatory collapse from an
iatrogenic overdose of propranolol was supported with extracorporeal membrane oxygenation
(ECMO) for 5 days and survived neurologically intact.41 A case series documents experience with
ECMO for patients with cardiac arrest caused by cardiovascular drug poisoning. In this series of six
patients, two deaths were attributed to delayed institution of ECMO. The other four patients survived
without sequelae.11 In another series, ECLS was used in 17 patients with circulatory failure following
a drug overdose. Eight patients had taken β-adrenergic antagonists either alone or in combination
with other cardiovascular toxins. Thirteen of the 17 patients had long-term survival. The authors
conclude that ECLS is efficient and relatively safe as a last resort treatment for patients with cardiac
arrest or refractory shock following a drug overdose.39 More recently, researchers compared survival
with ECLS versus conventional therapy in poisoned patients with circulatory failure. Six patients in
the ECLS group and ten in the conventional therapy group had ingested β-adrenergic antagonists. In
this series, 12 out of 14 (86%) of the ECLS patients survived compared with 23 out of 48 (48%) in
the conventional therapy group. The authors concluded that ECLS is helpful in critically ill poisoned
patients who do not respond to conventional therapy.144
Experimental Treatment
Vasopressin is a hypothalamic hormone that acts at G protein–coupled receptors to mediate
vasoconstriction (at V1 receptors), water retention (at V2 receptors), and corticotropin secretion (at
V3 receptors), and may also increase the response to catecholamines. Vasopressin analogues have
been used as vasopressors clinically in shock states and for patients in cardiopulmonary
arrest.14,214 Vasopressin was as effective as glucagon but less effective than high-dose insulin in a
porcine model of propranolol toxicity.82,83 There are no reports of vasopressin use for human β-
adrenergic antagonist toxicity.
The calcium sensitizers, levosimendan and pimobendan, interact with the contractile proteins to
improve cardiac function and are used clinically to treat heart failure.7,119,120,159 Levosimendan is both a
positive inotrope and a vasodilator and has a better safety profile than pimobendan. It is approved in
Europe for use in heart failure patients and is as effective as dobutamine in increasing contractility.
Levosimendan infusions allow uptitration of β-adrenergic antagonists in patients with severe heart
failure.229 Levosimendan improved survival in a porcine model of propranolol toxicity121 and improved
cardiac output in a murine model of metoprolol toxicity93 but was not beneficial in a murine model of
propranolol toxicity.92 Calcium sensitizers are not available in the United States or Canada. They may
prove to have a role in managing patients poisoned with β-adrenergic antagonists.
Fructose 1,6-diphosphate (FDP) is an intermediate in the glycolytic pathway. FDP is able to cross
cell membranes and it increases cardiac contractility.155,208 Compared with glucose infusion, FDP
infusion resulted in improved survival in murine models of propranolol toxicity
and verapamil toxicity.91 FDP may prove to have a role in the management of β-adrenergic
antagonist poisoning, but it cannot be recommended at this time.
Special Circumstances
The preceding discussion applies to the generic management of β-adrenergic antagonists. Certain
β-adrenergic antagonists have unique properties that modify their toxicity. The management
considerations for these unique agents are discussed as follows.
Sotalol
In addition to bradycardia and hypotension, sotalol toxicity may result in a prolonged QT interval and
ventricular dysrhythmias including torsade de pointes. Sotalol induced bradycardia and hypotension
should be managed as with other β-adrenergic antagonists. Specific management of patients with
sotalol overdose includes correction of hypokalemia and hypomagnesemia. Overdrive pacing and
magnesium infusions may be effective for sotalol-induced torsade de pointes.8,211 Lidocaine is also
effective for sotalol- induced torsade de pointes.10 In the future, potassium channel openers such as
the cardioprotective drug nicorandil may prove effective for sotalol- induced torsade de
pointes.192,207,218
Peripheral Vasodilation (Betaxolol, Bucindolol, Carteolol, Carvedilol, Celiprolol, Labetalol, Nebivolol)
Treatment of patients who have overdosed with one of the vasodilating β-adrenergic antagonists is
similar to that for patients who ingest other β-adrenergic antagonists. Decisions about the need for
vasopressors should be guided by clinical findings. If vasodilation is a prominent feature, high doses
of vasopressors with α-adrenergic agonist properties (eg, norepinephrine or phenylephrine) may be
required.78 Conversely, if β-adrenergic antagonism is prominent, xenobiotics that act to increase
intracellular cAMP, like glucagon, may be needed.74,103
Membrane Stabilizing Effects (Acebutolol, Betaxolol, Carvedilol, Oxprenolol, Propranolol)
It might be expected that hypertonic sodium bicarbonate would be beneficial in treating the
ventricular dysrhythmias that occur with these β-adrenergic antagonist. Unfortunately there is limited
experience with the use of sodium bicarbonate in this situation, and the experimental data are
mixed. Sodium bicarbonate was not beneficial in a canine model of propranolol toxicity, although
there was a trend toward QRS interval narrowing in the sodium bicarbonate group.130 In models with
propranolol poisoned isolated rat hearts, however, hypertonic sodium chloride proved
beneficial.97,98 Perhaps most compelling is the fact thatsodium bicarbonate appeared to reverse
ventricular tachycardia in a human case of acebutolol poisoning.44 Because sodium bicarbonate is a
relatively safe and simple intervention, we would recommend that it be used in addition to standard
therapy for β-adrenergic antagonist poisoned patients with QRS widening, ventricular dysrhythmias,
or severe hypotension. Sodium bicarbonate would not be expected to be beneficial in sotalol
induced ventricular dysrhythmias and, by causing hypokalemia, may actually increase the risk of
torsade de pointes. The usual dose of hypertonic sodium bicarbonate is 1 to 2 mEq/kg given as an
intravenous bolus. This may be followed by an infusion or repeated boluses may be given as
needed. Care should be taken to avoid severe alkalosis or hypokalemia (Antidotes in Depth: A5).
Observation
All patients who have bradycardia, hypotension, abnormal ECG findings, or CNS toxicity following a
β-adrenergic antagonist overdose should be observed in a intensive care setting until these findings
resolve. Toxicity from regular release β-adrenergic antagonist poisoning other than with sotalol
almost always occurs within the first 6 hours.126,129,167 Therefore patients without any findings of toxicity
following an overdose of a regular release β-adrenergic antagonist other than sotalol may be
discharged from medical care after an observation time of 6 to 8 hours if they remain asymptomatic
with normal vital signs and normal ECG and have had gastrointestinal decontamination with
activated charcoal. Ingestion of extended-release preparations may be associated with delayed
toxicity, and these patients should be observed for 24 hours in an intensive care unit. Patients who
may have delayed absorption because of a mixed overdose or underlying gastrointestinal disease
may also require longer observation. Sotalol toxicity may also be delayed with ventricular
dysrhythmias first occurring as late as 9 hours after ingestion.156 We recommend that all patients with
sotalol overdose be monitored for at least 12 hours. Patients who remain stable without QT
prolongation may then be discharged from a monitored setting.
SUMMARY
β-Adrenergic antagonists are commonly used to treat hypertension, angina,
tachydysrhythmias, tremor, migraine, and panic attacks.
Overdoses of β-adrenergic antagonists are relatively uncommon but continue to cause
deaths worldwide.
Patients who develop symptoms after ingesting regular release β-adrenergic antagonists do
so within the first 6 hours. Sotalol ingestions are an exception to this and may cause delayed
and prolonged toxicity. Extended release formulations may also result in delayed toxicity and
require 24 hour observation.
Patients with consequential β-adrenergic antagonist overdose typically develop bradycardia
and hypotension.
Propranolol and other β-adrenergic antagonists with membrane- stabilizing properties and
high lipid solubility are the most toxic in overdose. These xenobiotics cause prolongation of
the QRS interval, severe hypotension, coma, seizures, and apnea.
Sotalol is unique in its ability to prolong the QT interval and its toxicity often results in
refractory ventricular dysrhythmias, which may respond to overdrive pacing or to magnesium
infusions.
In addition to supportive care, the most important therapy for β-adrenergic antagonist toxicity
is glucagon. High doses of insulin together with glucose provide a promising new treatment
modality. Catecholamine infusions may also be helpful but should be closely monitored and
large doses are typically required. Patients who fail treatment with glucagon, insulin, and
catecholamines are critically ill and may respond to intravenousfat emulsion therapy,
phosphodiesterase inhibitors, or mechanical support of circulation. Fortunately, most patients
respond to simpler measures and this aggressive therapy is rarely required.
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