CV Pharmacology | Beta-Adrenoceptor Antagonists (Beta-Blockers) 9/29/20, 7:11 PM

Beta-Adrenoceptor Antagonists
(Beta-Blockers)
General Pharmacology
Beta-blockers are drugs that bind to beta-adrenoceptors and thereby block
the binding of norepinephrine and epinephrine to these receptors. This
inhibits normal sympathetic effects that act through these receptors.
Therefore, beta-blockers are sympatholytic drugs. Some beta-blockers,
when they bind to the beta-adrenoceptor, partially activate the receptor
while preventing norepinephrine from binding to the receptor. These partial
agonists therefore provide some "background" of sympathetic activity while
preventing normal and enhanced sympathetic activity. These particular
beta-blockers (partial agonists) are said to possess intrinsic
sympathomimetic activity (ISA). Some beta-blockers also possess what is
referred to as membrane stabilizing activity (MSA). This effect is similar to
the membrane stabilizing activity of sodium-channels blockers that
represent Class I antiarrhythmics.

The first generation of beta-blockers were non-selective, meaning that they

blocked both beta-1 (β1) and beta-2 (β2) adrenoceptors. Second generation
beta-blockers are more cardioselective in that they are relatively selective
for β1 adrenoceptors. Note that this relative selectivity can be lost at higher
drug doses. Finally, the third generation beta-blockers are drugs that also
possess vasodilator actions through blockade of vascular alpha-
adrenoceptors.

Heart

Beta-blockers bind to beta-adrenoceptors located in cardiac nodal tissue,

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the conducting system, and

contracting myocytes. The heart has
both β1 and β2 adrenoceptors,
although the predominant receptor
type in number and function is β1.
These receptors primarily bind
norepinephrine that is released from
sympathetic adrenergic nerves.
Additionally, they bind norepinephrine
and epinephrine that circulate in the
blood. Beta-blockers prevent the
normal ligand (norepinephrine or
epinephrine) from binding to the
beta-adrenoceptor by competing for
the binding site.

Beta-adrenoceptors are coupled to a Gs-proteins, which activate adenylyl

cyclase to form cAMP from ATP. Increased cAMP activates a cAMP-
dependent protein kinase (PK-A) that phosphorylates L-type calcium
channels, which causes increased calcium entry into the cell. Increased
calcium entry during action potentials leads to enhanced release of calcium
by the sarcoplasmic reticulum in the heart; these actions increase inotropy
(contractility). Gs-protein activation also increases heart rate (chronotropy).
PK-A also phosphorylates sites on the sarcoplasmic reticulum, which lead
to enhanced release of calcium through the ryanodine receptors
(ryanodine-sensitive, calcium-release channels) associated with the
sarcoplasmic reticulum. This provides more calcium for binding the
troponin-C, which enhances inotropy. Finally, PK-A can phosphorylate
myosin light chains, which may contribute to the positive inotropic effect of
beta-adrenoceptor stimulation.

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CV Pharmacology | Beta-Adrenoceptor Antagonists (Beta-Blockers) 9/29/20, 7:11 PM

Because there is generally some level of sympathetic tone on the heart,

beta-blockers are able to reduce sympathetic influences that normally
stimulate chronotropy (heart rate), inotropy (contractility), dromotropy
(electrical conduction) and lusitropy (relaxation). Therefore, beta-blockers
cause decreases in heart rate, contractility, conduction velocity, and
relaxation rate. These drugs have an even greater effect when there is
elevated sympathetic activity.

Blood vessels

Vascular smooth muscle has β2-adrenoceptors that are normally activated

by norepinephrine released by sympathetic adrenergic nerves or by
circulating epinephrine. These receptors, like those in the heart, are
coupled to a Gs-protein, which stimulates the formation of cAMP. Although
increased cAMP enhances cardiac myocyte contraction (see above), in
vascular smooth muscle an increase in cAMP leads to smooth muscle
relaxation. The reason for this is that cAMP inhibits myosin light chain
kinase that is responsible for phosphorylating smooth muscle myosin.
Therefore, increases in intracellular cAMP caused by β2-agonists inhibits
myosin light chain kinase thereby producing less contractile force (i.e.,

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CV Pharmacology | Beta-Adrenoceptor Antagonists (Beta-Blockers) 9/29/20, 7:11 PM

promoting relaxation).

Compared to their effects in the heart, beta-blockers have relatively little

vascular effect because β2-adrenoceptors have only a small modulatory
role on basal vascular tone. Nevertheless, blockade of β2-adrenoceptors is
associated with a small degree of vasoconstriction in many vascular beds.
This occurs because beta-blockers remove a small β2-adrenoceptor
vasodilator influence that is normally opposing the more dominant alpha-
adrenoceptor mediated vasoconstrictor influence.

Therapeutic Indications
Beta-blockers are used for treating Beta-Blockers
hypertension, angina, myocardial infarction, Cardiac Effects
arrhythmias and heart failure. Decrease contractility
(negative intropy)
Hypertension Decrease relaxation rate
(negative lusitropy)

Beta-blockers decrease arterial blood pressure Decrease heart rate

(negative chronotropy)
by reducing cardiac output. Many forms of
Decrease conduction
hypertension are associated with an increase in velocity
blood volume and cardiac output. Therefore, (negative dromotropy)
reducing cardiac output by beta-blockade can Vascular Effects
be an effective treatment for hypertension, Smooth muscle
especially when used in conjunction with a contraction
(mild vasoconstriction)
diuretic. Acute treatment with a beta-blocker is
not very effective in reducing arterial pressure because of a compensatory
increase in systemic vascular resistance. This may occur because of
baroreceptor reflexes working in conjunction with the removal of β2
vasodilatory influences that normally offset, to a small degree, alpha-
adrenergic mediated vascular tone. Chronic treatment with beta-blockers

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lowers arterial pressure more than acute treatment possibly because of

reduced renin release and effects of beta-blockade on central and
peripheral nervous systems. Beta-blockers have an additional benefit as a
treatment for hypertension in that they inhibit the release of renin by the
kidneys (the release of which is partly regulated by β1-adrenoceptors in the
kidney). Decreasing circulating plasma renin leads to a decrease in
angiotensin II and aldosterone, which enhances renal loss of sodium and
water and further diminishes arterial pressure.

Hypertension in some patients is caused by emotional stress, which causes

enhanced sympathetic activity. Beta-blockers can be very effective in these
patients.

Beta-blockers are used in the preoperative management of hypertension

caused by a pheochromocytoma, which results in elevated circulating
catecholamines. When used for this condition, the blood pressure is first
controlled using an alpha-blocker such as phenoxybenzamine, and then a
beta-blocker can be carefully administered to reduce the excessive cardiac
stimulation by the catecholamines. It is important that a beta-blocker is
administered only after adequate blockade of vascular alpha-adrenoceptors
so that a hypertensive crisis does not occur as a result of unopposed alpha-
adrenoceptor stimulation.

Angina and myocardial infarction

The antianginal effects of beta-blockers are attributed Theraputic Use of

to their cardiodepressant and hypotensive actions. By Beta-Blockers
reducing heart rate, contractility, and arterial pressure, Hypertension

beta-blockers reduce the work of the heart and the Angina

oxygen demand of the heart. Reducing oxygen Myocardial

infarction
demand improves the oxygen supply/demand ratio,
Arrhythmias

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which can relieve a patient of anginal pain that is Heart failure

caused by a reduction in the oxygen supply/demand ratio due to coronary

artery disease. Furthermore, beta-blockers have been found to be very
important in the treatment of myocardial infarction in that they have been
shown to decrease mortality. Their benefit is derived not only from
improving the oxygen supply/demand ratio and reducing arrhythmias, but
also from their ability to inhibit subsequent cardiac remodeling.

Arrhythmias

The antiarrhythmic properties beta-blockers (Class II antiarrhythmic) are

related to their ability to inhibit sympathetic influences on cardiac electrical
activity. Sympathetic nerves increase sinoatrial node automaticity by
increasing the pacemaker currents, which increases sinus rate.
Sympathetic activation also increases conduction velocity (particularly at
the atrioventricular node), and stimulates aberrant pacemaker activity
(ectopic foci). These sympathetic influences are mediated primarily through
β1-adrenoceptors. Therefore, beta-blockers can attenuate these
sympathetic effects and thereby decrease sinus rate, decrease conduction
velocity (which can block reentry mechanisms), and inhibit aberrant
pacemaker activity. Beta-blockers also affect non-pacemaker action
potentials by increasing action potential duration and the effective
refractory period. This effect can play a major role in blocking arrhythmias
caused by reentry.

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Heart failure

The majority of patients in heart failure have a form that is called systolic
dysfunction, which means that the contractile function of the heart is

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depressed (loss of inotropy). Although it seems counterintuitive that

cardioinhibitory drugs such as beta-blockers would be used in cases of
systolic dysfunction, clinical studies have shown quite conclusively that
some specific beta-blockers actually improve cardiac function and reduce
mortality. Furthermore, they have been shown to reduce deleterious cardiac
remodeling that occurs in chronic heart failure. Although the exact
mechanism by which beta-blockers confer their benefit to heart failure
patients is poorly understood, it may be related to blockade of excessive,
chronic sympathetic influences on the heart, which are known to be harmful
to the failing heart.

Different Classes of Beta-Blockers and Specific

Drugs
Beta-blockers that are used clinically can be divided into two classes: 1)
non-selective blockers (block both β1and β2 receptors), or 2) relatively
selective β1 blockers ("cardioselective" beta-blockers). Some beta-
blockers have additional mechanisms besides beta-blockade that
contribute to their unique pharmacologic profile. The two classes of beta-
blockers along with specific compounds are listed in the following table.
Additional details for each drug may be found at www.rxlist.com. The
clinical uses indicated in the table represent both on and off-label uses of
beta-blockers. For example, a given beta-blocker may only be approved by
the FDA for treatment of hypertension; however, physicians sometimes
elect to prescribe the drug for angina because of the class-action benefit
that beta-blockers have for angina.

Clinical Uses
Class/Drug HTN Angina Arrhy MI CHF Comments
Non-
selective β1/

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β2
ISA; long acting; also used
carteolol X
for glaucoma
carvedilol X X α-blocking activity
labetalol X X ISA; α-blocking activity
nadolol X X X X long acting
penbutolol X X ISA
pindolol X X ISA; MSA
MSA; prototypical beta-
propranolol X X X X
blocker
several other significant
sotalol X
mechanisms
timolol X X X X primarily used for glaucoma
β1-selective
acebutolol X X X ISA
atenolol X X X X
betaxolol X X X MSA
bisoprolol X X X X
ultra short acting; intra or
esmolol X X
postoperative HTN
metoprolol X X X X X MSA
relatively selective in most
nebivolol X patients; vasodilating (NO
release)

Abbreviations: HTN, hypertension; Arrhy, arrhythmias; MI, myocardial

infarction; CHF, congestive heart failure; ISA, intrinsic sympathomimetic
activity.

Side Effects and Contraindications

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Cardiovascular side effects

Many of the side effects of beta-blockers are related to their cardiac

mechanisms and include bradycardia, reduced exercise capacity, heart
failure, hypotension, and atrioventicular (AV) nodal conduction block. Beta-
blockers are therefore contraindicated in patients with sinus bradycardia
and partial AV block. The side effects listed above result from excessive
blockade of normal sympathetic influences on the heart. Considerable care
needs to be exercised if a beta-blocker is given in conjunction with cardiac
selective calcium-channel blockers (e.g., verapamil) because of their
additive effects in producing electrical and mechanical depression.
Although this may change with future clinical trials on safety and efficacy of
beta-blockers in heart failure, at present only carvedilol and metoprolol
have been approved by the FDA for this indication.

Other side effects

Bronchoconstriction can occur, especially when non-selective beta-

blockers are administered to asthmatic patients. Therefore, non-selective
beta-blockers are contraindicated in patients with asthma or chronic
obstructive pulmonary disease. Bronchoconstriction occurs because
sympathetic nerves innervating the bronchioles normally activate β2-
adrenoceptors that promote bronchodilation. Beta-blockers can also mask
the tachycardia that serves as a warning sign for insulin-induced
hypoglycemia in diabetic patients; therefore, beta-blockers should be used
cautiously in diabetics.

Revised 01/29/16

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