Expert Review of Respiratory Medicine

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Beta-blockers in asthma: myth and reality

Angelica Tiotiu, Plamena Novakova, Krzysztof Kowal, Alexander Emelyanov,

Herberto Chong-Neto, Silviya Novakova & Marina Labor

To cite this article: Angelica Tiotiu, Plamena Novakova, Krzysztof Kowal, Alexander Emelyanov,
Herberto Chong-Neto, Silviya Novakova & Marina Labor (2019): Beta-blockers in asthma: myth and
reality, Expert Review of Respiratory Medicine, DOI: 10.1080/17476348.2019.1649147

To link to this article: https://doi.org/10.1080/17476348.2019.1649147

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EXPERT REVIEW OF RESPIRATORY MEDICINE
https://doi.org/10.1080/17476348.2019.1649147

REVIEW

Beta-blockers in asthma: myth and reality

Angelica Tiotiua,b,c, Plamena Novakovad, Krzysztof Kowale,f, Alexander Emelyanovg, Herberto Chong-Netoh,
Silviya Novakovai and Marina Labor j,k
a
Department of Pulmonology, University Hospital of Nancy, Nancy, France; bCardio-respiratory regulation, EA3450 DevAH - Development,
Adaptation and Disadvantage. Cardio-respiratory regulations and motor control. University of Lorraine, Nancy, France; cAirways Disease Section,
National Heart and Lung Institute, Imperial College London, London, UK; dClinic of Clinical Allergy, Medical University Sofia, Sofia, Bulgaria;
e
Department of Allergology and Internal Medicine, Bialystok, Poland; fDepartment of Experimental Allergology and Immunology, Medical
University of Bialystok, Bialystok, Poland; gDepartment of Respiratory Medicine, North-Western Medical University, Saint-Petersburg, Russian
Federation; hDivision of Allergy and Immunology, Department of Pediatrics, Federal University of Paraná, Curitiba, Brazil; iAllergy Unit, Internal
Consulting Department, University Hospital “St. George”, Plovdiv, Bulgaria; jDepartment of Pulmonology, University Hospital Centre Osijek, Osijek,
Croatia; kMedical Faculty Osijek, J.J. Strossmayer University, Osijek, Croatia

ABSTRACT ARTICLE HISTORY

Introduction: Patients with asthma often have important co-morbidities which reduce the likelihood of Received 12 April 2019
gaining optimal asthma control. Beta2-blockers are commonly prescribed for the treatment of different Accepted 24 July 2019
clinical indications, including coronary artery disease, cardiac arrhythmia, arterial hypertension, heart KEYWORDS
failure and glaucoma. Asthma outcomes;
Areas covered: The aim of this reviw is to summarize current evidence on the effect of systemic and β-blockers; cardiovascular
local β-blockers on asthma outcomes based on their pharmacologic properties,and to help clinicians comorbidity; glaucoma;
when prescribing for patients with asthma and co-morbidities. Current data suggest that risk of asthma treatment
worsening from systemic and local use of non-selective β-blockers outweighs any potential benefits for
their clinical indications. Recent studies confirm that topical and systemic prescription of cardio-
selective β-blockers is not associated with a significant increased risk of moderate or severe asthma
exacerbations.
Expert opinion: Non-selective β-blockers should not be prescribed for the management of comorbid-
ities in patients with asthma while cardio-selective β-blockers, preferably in low doses, may be used
when strongly indicated and other therapeutic options are not available. More prospective real-life
studies are needed to evaluate the risk of long-term use of β-blockers in patients with asthma.

1. Introduction can induce asthma symptoms/exacerbations in people with

asthma by competing with β2-agonists [12,13]. In this context,
Asthma is a heterogeneous inflammatory disease characterized
the majority of guidelines have, for a long time, recommended
by chronic airway inflammation with history of respiratory symp-
the avoidance of all β-blockers in people with asthma [14,15].
toms (wheezing, dyspnea, chest tightness, and cough) and vari-
Cardio-selective β-blockers have been designed to target
able expiratory airflow limitation [1]. Beta2-adrenoceptor
β1-adrenoreceptors and avoid β2-adrenoreceptors. Even then,
agonists, the most effective bronchodilators ever discovered,
their selectivity is only relative (at therapeutic doses, they
represent the first therapeutic line for rescue during asthma
exert β2-antagonism but less than non-selective β-blockers),
attacks and an important component of asthma controller thera-
and evidence suggests their use in asthma does not cause an
pies in association with inhaled corticosteroids [2].
increase of exacerbations, reduction in airway function or
Patients with asthma are up to three times more likely to have
worsening of quality of life in patients with cardiovascular
significant cardiovascular comorbidities than the general popu-
comorbidity [6,8,12,13,16,17]. Several guidelines now recom-
lation, which reduces the chance for optimal asthma control [3].
mend that cardio-selective β-blockers may be used on a case-
Competitive β-adrenergic receptor antagonists (β-blockers) have
by-case basis in people with asthma after a rigorous consid-
proved clinical benefits for patients with cardiovascular diseases
eration of benefits/risks, along with the initiation of the treat-
(CVD) by decreasing heart rate, reducing blood pressure and
ment under close medical supervision by a specialist [1].
improving left ventricular function [4], therefore they are pre-
Despite this data and strong clinical indication, β-blocker use
scribed for multiple clinical indications (coronary artery disease,
continues to be less than optimal in people with asthma in
cardiac arrhythmia, hypertension, heart failure) [5–8]. Historically,
reason of the previous theory of the complete avoidance and
studies showed that β-blocker administration is associated with
the lack of large studies to evaluate the risk of β-blockers in
increased airway hyperresponsiveness (AHR) and airflow limita-
patients with asthma from real-life settings [8,18,19].
tion in asthmatics but also in the general population [9–11] and

CONTACT Angelica Tiotiu angelica.tiotiu@yahoo.com National Heart and Lung Institute, Imperial College London, Airway Disease Section, Guy Scadding
Building, Cale Street, London SW3, UK
© 2019 Informa UK Limited, trading as Taylor & Francis Group
2 A. TIOTIU ET AL.
Article highlights
● Beta-blockers are largely prescribed in cardio-vascular diseases and
glaucoma which represent frequent comorbidities in patients with
asthma.
● Historically, β-blockers are contraindicated in people with asthma
because they increase airway hyperresponsiveness and may trigger
exacerbations.
● Despite important pharmacological differences, β-blockers are often
regarded as a single class of drugs.
● Cardio-selective β-blockers are now accepted by several guidelines
(but not by all) in patients with asthma who need this treatment but
are underused in practice.
● The prescription of β-blockers in patients with asthma should also
consider other pharmacologic properties of these drugs (i.e. presence
of intrinsic sympathomimetic activity signaling profile of the ligand).
● Low dose initiation with gradual increase is recommended to avoid
the adverse effects.
The purpose of this review is to summarize current evi-
dence about the effects of β-blockers on asthma outcomes
based on their pharmacologic properties to help the clinician
in the decision of this prescription in patients with asthma
who need the treatment. A better knowledge of the bioavail-
ability, cardio-selectivity, vasodilator and metabolic effects of
β-blockers could help us to optimize clinical benefits espe-
cially in patients with asthma and CVD.
2. Pharmacology of β-blockers and impact on
asthma
Beta-blockers occupy β-adrenoceptors (βADR) and antagonize
the effects of catecholamines [20]. According to their distribu-
tion, the βADR has been subdivided into three groups:
β1-predominantly in the heart; β2- in airway, uterine, vascular
smooth muscle, liver, and skeletal muscle; β3- in adipose
tissue [21]. Βeta2-adrenoceptors oscillate between active and
inactive forms, in equilibrium under resting conditions, with
the predominant inactive state [2,21].
A few models of receptor activation were proposed, but at
least two are important in asthma: the G protein cyclic ade-
nosine monophosphate (G-cAMP) pathway, and the β-arrestin
mediated signaling pathway via extracellular signal-regulated
kinases (ERK) activation [2,8,21]. The efficacy of β-blockers is
different according to the ligand ability to selectively promote
specific intracellular signaling pathways [22,23].
According to the affinity for the active/inactive receptor
status, the ligands are classified by agonists, antagonists,
partial and inverse agonists. Full agonists might move the
equilibrium in the direction of active form and lead to
a cellular response [2]. For example, the endogenous ligand
for the β2-adrenoceptor, epinephrine, and agonists used in
asthma like salmeterol and formoterol activate both path-
ways [8]. Partial agonists stabilize the active conformation of
the receptor as a full agonist, although less frequently [21].
Inverse agonists have more affinity for the inactive state and
antagonists block the effects of both agonists and inverse
agonists [2]. For example, alprenolol is a partial agonist at
both pathways while carvedilol and propranolol are inverse
agonists at G-cAMP pathway but partial agonists of ERK
pathway [24]. Nadolol is an inverse agonist at both path-
ways having proved several beneficial effects in asthma,
even though there are currently no large-scale trials to con-
firm these results [2]. In contrast with carvedilol and propra-
nolol, nadolol reduces AHR probably in rapport with its
effect on the arrestin/ERK pathway, in line with the hypoth-
esis of a possible detrimental role of this signaling in asthma
[8,10,22,23,25–27].
Beta2-adrenoceptors have also a constitutive or sponta-
neously active conformation and are capable of signaling even
in the absence of a ligand [2]. Several data suggested that this
constitutive activation of β2-adrenoceptors could be involved in
the development of murine asthma phenotype [2]. These facts
underline the diversity and the complexity of β-blockers, as well
as the importance of complete characterization of the signaling
profiles of different ligands with consequences on the treatment
effectiveness.
Beta-blockers are structurally heterogeneous and share
a common feature: at least one aromatic ring attached to
a side alkyl chain possessing a secondary hydroxyl and
amine groups [5,20]. This structural heterogeneity is reflected
in their pharmacodynamic properties (β-adrenoceptor selec-
tivity, membrane stabilizing activity, intrinsic sympathomi-
metic and vasodilator activities) and in the pharmacokinetic
features (absorption, elimination half-life, route of elimination,
bioavailability) with an important impact on the efficacy, toler-
ability and safety of β-blockers [5,20].
The most clinically recognized pharmacodynamics feature is
the selectivity of β-receptor blockade. First-generation β-blockers,
such as propranolol, timolol, pindolol, nadolol, and sotalol are
non-selective and affect the function of both β1 and β2 adreno-
ceptors. In contrast, second-generation β-blockers (i.e. atenolol,
bisoprolol, metoprolol, acebutolol) selectively bind
β1-adrenoceptor and cause reduced cardiac output [5,20]. Third-
generation or ‘vasodilating’ β-blockers (i.e. carvedilol, labetalol,
nebivolol) are structurally different and characterized by α1- and
β1-blocking, β2-stimulating, nitric oxide-generating, anti-oxidant
and/or anti-inflammatory properties [5,20,28,29]. The presence of
selectivity for β1-adrenoceptor (not blocking the β2-adrenocep-
tors in bronchial and vascular tissue) offers safety advantages with
reduced risk of bronchospasms and peripheral vasoconstriction
but this property is dose-dependent, so the ‘protection’ with
β1-selective agents is not absolute [30]. Table 1 summarizes the
current available β-blockers according to their selectivity and
administration.
Several β-blockers (i.e. acebutolol, labetalol, pindolol) have
weak partial agonist activity on βADR (intrinsic sympathomi-
metic activity ISA). They mimic the effects of catecholamines
(epinephrine and norepinephrine) and protect against adverse
effects, in particular, related to β2-adrenoceptor blockade, but
have a smaller effect in reducing cardiac output and heart
rate [30].
The membrane-stabilizing activity of β-blockers is reflected
by their anti-arrhythmic properties. The effect is achieved by
the blockade of sodium channels by carvedilol, metoprolol

Table 1. Summary of currently available beta-blockers.
Drug Non selective Selective
Sytemic Nadolol Acebutolol
Penbutolol Atenolol
Pindolol Betaxolol
Propranolol Bisoprolol
Sotalol Carvedilol
Timolol Celiprolol
Esmolol
Labetalol
Metoprolol
Nebivolol
Topical Carteolol Betaxolol
Levobunolol
Metipranolol
Timolol
and propranolol, while the potassium channel is blocked by
sotalol [20,30].
Pharmacokinetic features of individual β-blockers are deter-
mined by their lipophilic and hydrophilic properties [5,20,28–
31]. The half-life of most β-blockers is relatively short [30,31].
Water-soluble β-blockers are eliminated via the kidney and
have longer half-lives, while lipid-soluble β-blockers are meta-
bolized in the liver and have shorter half-lives. Their lipophilic
properties facilitate penetration to peripheral tissues, in parti-
cular to the central nervous system with more important local
adverse effects [5,20,31].
Absorption of β-blockers depends on the route of admin-
istration with topical application leading to minimal systemic
bioavailability [5,20,28–31]. As regular therapy of CVD, β-
blockers are administered orally once daily, but in emergency
situations, some β-blockers could be used intravenously with
a rapid increase in their plasma concentration [32]. The
absorption from the gastrointestinal tract occurs by passive
diffusion [20,30,31]. In the blood, they circulate and bind to
plasma albumins and alpha-globulins but the ratio of bound
to free fraction is variable for different β-blockers (i.e. 90% for
sotalol, 20% for propranolol) [30,31]. Lipid-soluble β-blockers
(labetalol, metoprolol, pindolol, propranolol) depend upon
hepatic metabolism for clearance, whereas water-soluble β-
blockers (atenolol) are cleared by the kidney, usually as an
unchanged form [30].
In summary, the high diversity of pharmacological proper-
ties of currently used β-blockers indicates that their effects in
individual clinical conditions cannot be assumed to be a class
effect but are characteristic of a single compound. All phar-
macological properties should be assessed while selecting β-
blockers therapy, in particular in patients at high risk of
adverse effects such as asthma population [33,34]. Adverse
effects to β-blockers vary according to selectivity of the drug,
dose, duration of exposure and clinical response [13].
3. Non-selective β-blockers and asthma
Several safety issues are likely to influence the prescription of
β-blockers in asthma. However, β-blocker exposure is not
uncommon, with 2.2% of patients prescribed each year
despite the risk of exacerbations and propranolol being the
most commonly prescribed non-selective β-blocker [18].
EXPERT REVIEW OF RESPIRATORY MEDICINE 3
Females are more likely to be prescribed non-selective β-
blockers than males. This may represent the increased preva-
lence of conditions associated with non-selective β-blocker
treatment in females such as migraines, thyrotoxicosis and
pre-eclampsia [12,35]. Moreover, the presence of
β2-adrenoceptor antagonism might attenuate the response
to concomitant β2-agonist inhaled treatment which is the
first-line rescue therapy for acute bronchoconstriction.
Non-selective β-blockers are widely used in clinical practice
but are currently contraindicated in asthma – previous data
show acute exposure to propranolol induces rapid broncho-
constriction (in the first 2–3 min after exposure) which could
persist up to 1 h [10,36–38]. The mechanisms suggested in β-
blocker induced bronchospasms are the competitive antagon-
ism of the bronchodilator action of endogenous catechola-
mines and the reduction of the constitutive activity of
β2-adrenoceptor [37]. Both mechanisms are possible, but the
most important may be the pharmacological properties of the
ligand. In this line, a study which compared the bronchial
response to histamine in patients with asthma treated for 3
days by different β-blockers (propranolol 40 mg/day, meto-
prolol 50 mg/day, pindolol 5 mg/day) and a placebo, found
that propranol, the non-selective agent without ISA signifi-
cantly increased the sensitivity to inhaled histamine while
metoprolol, the cardio-selective agent without ISA, and pindo-
lol, the non-selective with this property had effects compar-
able to the placebo [17].
Several years later, a study on a murine model of asthma
showed that nadolol, a non-selective β-blocker without ISA
but an inverse agonist at the β2-adrenoceptors, increased AHR
after acute exposure, while the chronic administration (28-day)
had an opposite effect and anti-inflammatory properties [39].
These initial conclusions led to subsequent open-label stu-
dies [26,27] demonstrating that in steroid-naive patients with
mild asthma, the dose-escalating administration of the non-
selective β-blocker nadolol over 12 weeks was accompanied
by the attenuation of AHR to methacholine along with a small
residual fall in forced expiratory volume in 1 s (FEV1), after an
initial greater fall on first dose exposure. Administration of
salbutamol in those patients was able to reverse methacho-
line-induced bronchoconstriction [26,27].
A randomized placebo-controlled trial (RPCT) evaluated the
effects of chronic propranolol administration on AHR in
patients with stable persistent asthma treated by inhaled
corticosteroids. This study has shown no significant effect of
propranolol compared to the placebo on methacholine or
histamine-induced AHR, but only a partial attenuation of
acute albuterol recovery after challenge. In addition, chronic
propranolol treatment had no effect on asthma control or
quality of life in the studied population [40]. In post-hoc
analysis of a double-blind RPCT, the safety and tolerability of
acute dosing with propranolol in mild-to-moderate asthmatics
on inhaled corticosteroids were evaluated. It was concluded
that up-titration of propranolol to 80 mg could be achieved in
asthma without any significant deterioration in FEV1 and with
no adverse impact on asthma control in the presence of
concomitant tiotropium use [41].
However, a meta-analysis of RPCTs demonstrated that
acute (up to 7 days) oral non-selective β-blocker exposure of
4 A. TIOTIU ET AL.
patients with asthma caused mean falls in FEV1 of 10.2% in
11.1% of patients and attenuation of concomitant β2-agonist
response in 20% of patients. Nevertheless, non-selective β-
blockers varied in relation to mean changes in FEV1 following
acute exposure. Compared with the placebo, labetalol admin-
istration did not cause a statistically significant mean change
in FEV1 (−2.7%, p = 0.43), whereas propranolol did (−17%, p <
0.001) [13].
A more recent study [42] evaluated the risk of asthma
exacerbations with β-blockers prescribed to a population
with asthma and CVD. At high doses, chronic non-selective β-
blocker treatment significantly increased the rate of moderate
and severe asthma exacerbations (incidence rate ratio IRR 2.7,
p = 0.033, respectively, 12.1, p = 0.048). In contrast, low- to
moderate-dose non-selective β-blocker chronic exposure did
not have a significant effect on the relative incidence of
moderate or severe asthma exacerbations. However, the
acute exposure to low/moderate doses of non-selective β-
blockers is associated with a significantly higher relative inci-
dence of moderate asthma exacerbations (IRR 5.2, p = 0.002).
Findings from the study supported current recommendations
that non-selective β-blockers should be avoided in people
with asthma and CVD [42].
An observational study showed that despite possible varia-
tions in the severity of asthma prior to the initiation of β-
blockers (non-selective or selective), no significant increase in
the number of severe asthma exacerbations requiring oral
steroids was observed in the first 4 weeks fellow-up (consid-
ered the highest risk period after prescription) [12].
Nevertheless, life-threatening events resulted from exposure
to non-selective β-blockers in patients with poorly controlled
asthma have been also reported [43].
The present data demonstrate that although some patients
with asthma may tolerate non-selective β-blockers, acute risk
is greater. To reduce this risk, several measures could be
proposed, if this treatment is mandatory, such as the gradual
dose titration and the administration of a long-acting muscari-
nic antagonist to prevent unopposed increased cholinergic
tone uncovered by acute beta-blockade [40]. However, rescue
therapy is less effective and the risk from nonselective β-
blockers outweighs any potential benefits for existing clinical
indications.
4. Selective β-blockers and asthma
Cardio-selective β-blockers such as atenolol, bisoprolol and
metoprolol are at least 20 times more potent to blocking
β1-adrenoceptors than β2-adrenoceptors [6], so at therapeutic
doses, the negative impact on asthma outcomes is lower for
non-selective β-blockers.
Beta blockers are avoided in asthma due to concerns of
acute bronchoconstriction and lack of response to β2-agonist
rescue therapy but several former studies suggested that
selective β-blockers such as metoprolol or celiprolol had
a lower impact on the AHR and FEV1 than non-selective β-
blockers [16,17].
A meta-analysis of randomized, blinded, placebo-controlled
trials of the effects of single dose or continued treatment
cardio-selective β-blockers in patients with reversible airway
disease [6] showed that, compared to the placebo, the first
dose of active treatment produced a small drop in FEV1
(7.46%), which was not an associated respiratory symptom.
After continued treatment from 3 days to 4 weeks, there was
no significant difference in FEV1, symptoms or incidence of
inhaler use compared to the placebo with the maintained
response to β2-agonists. The authors concluded that cardio-
selective β-blockers given in mild to moderate reversible air-
way diseases do not produce adverse respiratory effects and
should not be withheld from such patients [6].
A systematic review of databases was performed to iden-
tify all randomized, blinded, placebo-controlled clinical trials
evaluating acute β-blocker exposure in asthma. It was found
that acute selective β-blockade caused a significant fall in
FEV1 (6.9%, p = 0.001) of ≥20% in 12.5% of patients, with-
out difference concerning the respiratory symptom (affect-
ing 3% of patients), but a significant attenuation in FEV1
concomitant β2-agonist response of 10.2% relative to the
placebo. However, the absolute mean difference in FEV 1
compared to the placebo was lower for selective β-blockers
(−10.2%) than for nonselective (−20.0%), suggesting that
the response to β2-agonists in blocker-induced bronchos-
pasm is partially blunted by selective and completely
blunted by nonselective β–blockade. Findings of this review
suggested that although the mean effects of acute selective
β-blockade were relatively small, there was still a risk for
clinically significant events in a minority of susceptible
patients with exaggerated cholinergic tone. According to
this review, selective β-blockers are better tolerated than
non-selective β-blockers but not completely risk-free [13].
Even in the general population, the administration of car-
dio-selective β-blockers is associated with a significant
decrease in FEV1 without effecting FEV1/FVC [11]. Risk
from acute exposure could be reduced by the smallest
dose possible and by use of β-blockers with a greater
β1-selectivity [13].
Concerning the β-blockers induced exacerbations, an
observational study showed no rise in the number of patients
treated with oral steroids for asthma exacerbation following
the initiation of selective and non-selective β-blocker treat-
ment in this population [12]. More recently, a large case-
control study [42] showed that independently of the dose
(low-to-moderate or high-dose), cardio-selective β-blockers
administration in patients with asthma and CVD was not
associated with a significant increased risk of moderate or
severe asthma exacerbations. Similarly, when evaluated by
dose and duration of exposure, acute or chronic cardio-
selective β-blocker administration did not increase the risk of
moderate or severe asthma exacerbations. The findings were
in contrast with the results for non-selective agents (discussed
in detail before) and suggested that the adverse respiratory
response to β-blockers in asthma depends partly upon cardio-
selectivity, dose and duration of exposure. Consequently, the
cardio-selective β-blockers should not be routinely discontin-
ued in people with asthma if already established and ade-
quate indication. However, dose–response relationships could
occur with acute cardio-selective exposure. If this treatment is
mandatory in patients with asthma, it is reasonable to start

with a low daily dose with a titration up as needed and to
ensure the availability of reliever asthma therapy [42].
Novel selective β1-adrenoceptor antagonists for concomi-
tant cardiovascular and respiratory disease are being devel-
oped. For example, nebivolol, a selective for β1-receptor with
nitric oxide-mediated vasodilatory effects and is metabolically
neutral, is usually well tolerated by patients with arterial
hypertension and asthma or chronic obstructive pulmonary
disease [29]. Similarly, the preliminary results for a highly
selective β1-adrenoceptor antagonist in study showed a lack
of β2-adrenoceptor-mediated adverse effects like bronchos-
pasms and vasoconstriction. Therefore, these
β1-adrenoceptor antagonists are potential candidates for
a highly cardio-selective β-blocker therapy for a large number
of patients with heart and respiratory or peripheral vascular
comorbidities [43].
The recent data suggests that cardio-selective β-blockers
could be the best choice for patients with asthma and con-
comitant CVD. The use of these agents has to be based upon
a risk assessment on an individual patient basis.
5. Topical β-blockers and asthma
Glaucoma is a chronic progressive optic neuropathy character-
ized by degeneration of retinal ganglion cells, secondary to an
increase of the intraocular pressure, whilst gradual reductions
in the visual field ensue. The only proven method to treat the
disease is the reduction of intraocular pressure [44]. Usually,
ocular hypotensive drops are initiated, but other therapies
such as oral drugs, laser trabeculoplasty and surgery are effi-
cient to decrease intraocular pressure in glaucoma patients.
Among these therapies, topical treatments (parasympathomi-
metic drugs, β-blockers, carbonic anhydrase inhibitors, prosta-
glandin analogs, α1-blockers, and α2-adrenergic agonists) are
the first choice because they have the highest efficacy and the
lowest incidence of adverse reactions [44].
The β-blockers reduce aqueous humor production by antag-
onizing ciliary body βADR and could be associated with the
treatment of glaucoma at α1-blockers which accelerate uveoscl-
eral outflow [18]. They are more effective in reducing daytime
than nocturnal intraocular pressure [45]. The topical β-blockers
currently available are timolol, carteolol, betaxolol, metipranolol
and in association with an α1-blocker, nipradilol and levobunolol
[44]. The principal selective ocular β-blocker in the clinical use is
betaxolol [18]. Ocular adverse reactions to β-blockers include
conjunctival allergies and congestion, corneal epithelium disor-
ders, blepharitis, and ocular pemphigoid. Additionally, corneal
sensitivity may be reduced because of the local anesthetic effect
(membrane-stabilizing effect) of betaxolol. Carteolol has ISA, so
administration of this drug is associated with fewer cases of
corneal epithelium disorders than timolol [46].
One major limitation of ocular β-blockers is that they fre-
quently cause systemic side effects. Systemic absorption
occurs via the nasolacrimal system or the conjunctiva, without
undergoing first-pass metabolism [47]. The intraocular admin-
istration of β-blockers worsen asthma attacks so they are
currently contraindicated in these patients [44].
EXPERT REVIEW OF RESPIRATORY MEDICINE 5
Respiratory and cardiovascular effects of three of these
topical β-blockers have been evaluated in asthmatics: 15
patients treated by timolol, 10 patients by carteolol and 10
patients by metipranolol [48]. The functional respiratory para-
meters, blood pressure and heart rate were measured before
the administration of the treatment, and after 15, 30, 45 and
60 min. The three topical drugs induced bronchoconstriction
in the first 15 min and remained during the whole period of
study. The main decrease occurred 45 min after administration
of one of the β-blockers: 11.4% for timolol (p < 0.001); 7% for
carteolol; and 15.1% for metipranolol. Each medication
decreased the heart rate with a maximal effect at 45 min.
From this data, it was recommended to practitioners to care-
fully follow the rules of administration of β-blockers, even in
eye drops [48]. Another study showed that lacrimal occlusion
with intra-canalicular collagen plugs may prevent broncho-
constriction caused by topical timolol (0.5%) in asthmatics by
inhibiting or decreasing systemic absorption of the medication
[49]. Inversely, the administration of prostaglandin F2α ana-
logs in association with β-blockers for reducing intraocular
pressure was associated with a higher risk of asthma (report-
ing odds ratio ROR 28.7) than when administered alone (ROR
4.6 for topical β-blocker, respectively, 4.7 for prostaglandin
F2α analog) [45].
A large study including 693 patients with an obstructive
pulmonary disease using chronic topical anti-glaucoma treat-
ment showed that, despite the risk of bronchoconstriction,
78.5% were treated with topical β-blockers, but only 31.1%
of them received a cardio-selective β-blocker (betaxolol) [50].
Patients treated by topical betaxolol and timolol had 23.1,
respectively, 20.7 hospitalization days per year compared to
a mean of 10 hospitalization days for the patients without β-
blocker treatment (p < 0.0001). The authors concluded that
patients who had used topical β-blocker medication were
more prone to be hospitalized compared to patients receiving
another anti-glaucoma treatment [50].
Despite these results, β-blockers continue to be admini-
strated in people with asthma and glaucoma as showed by
a recent study [18], with a higher prevalence in the prescrip-
tion of non-selective than selective topical agents (23% vs
13.4% in 2012). The same study found that the relative inci-
dence (IRR) of moderate exacerbations increased significantly
with acute non-selective eye drop exposure (IRR 4.8, p = 0.006)
but not with chronic exposure (IRR 1.1, p = 0.517). The admin-
istration of selective topical β-blockers did not have
a significant impact on asthma exacerbation outcomes.
Concerning respiratory function, acute non-selective β-
blocker eye drop exposure caused significant mean falls in
FEV1 of −10.9% (falls of ≥20% affecting 33.3% of patients)
while the corresponding value for selective ocular β-blockers
was −6.3% [18].
Initiating treatment with non-selective β-blocker eye drops
is associated with significant changes in lung function and
increased morbidity in people with asthma and glaucoma.
Selective topical β-blockers seem to be safer in asthma
patients with glaucoma than non-selective β-blockers and
must be prescribed in priority in this population if other
therapeutic options are not available.
6 A. TIOTIU ET AL.
Figure 1. Current strategies for the administration of beta-blockers in asthma.
The presence of intrinsic sympathomimetic activity confers more safety in
asthmatics.
Figure 1 summaries current data about the administration
of β-blockers in asthma.
6. Conclusion
Asthma is frequently associated with CVD and managing this
comorbidity is the norm in modern medicine. Beta-blockers
represent an important therapeutic class in the management of
CVD and glaucoma. Due to safety concerns and fear of adverse
effects, recommended guidelines state that β-blockers should be
contraindicated in patients with asthma. Even then, cardio-
selective β-blockers are only relatively selective, current evidence
support that asthma is not a contraindication for this therapy
(systemic or topical) in patients who have strong clinical indica-
tions for their use. In addition, several non-selective β-blockers
such as nadolol may be a reasonable therapeutic option in
patients with asthma and CVD due to the antagonism of the
arrestin/ERK signaling pathway. Further research is needed to
confirm this hypothesis. However, the initiation of the treatment
should be made under close medical supervision by a specialist,
after the evaluation of risks/benefits, with low dose and gradual
up-titration, according the clinical indication and pharmacologi-
cal proprieties of the β-blocker.
Existing evidence of adverse events come from clinical trials
under controlled conditions in selected patients. Futures studies
are needed to evaluate the risk of β-blockers in asthma from real-
life settings, but also in pharmacology to better understand the
complexity of ligand-β2-adrenoceptor interactions and the addi-
tional signaling pathways which could explain their contradic-
tory effects. By wisely choosing preventive strategies and
treatment options in patients with asthma and CVD, we can
avoid adverse events and optimize patient outcomes.
7. Expert opinion
By their pharmacologic properties, β-blockers are a very effi-
cient treatment for a wide range of cardiovascular diseases
and glaucoma. Historically, they are contraindicated in
patients with asthma because of the reported risk in increas-
ing the airway hyperresponsiveness (even death) in this group
of patients. This is particularly true with the non-selective β-
blockers which antagonize both β1- and β2-adrenoceptors.
Evidence from clinical trials suggests that cardio-selective
β-blockers are reasonably well tolerated in asthma and it is
known that adverse respiratory response to β-blockers varies
according to the degree of cardio-selectivity, dose of admin-
istration and individual response. Even though certain asthma
and cardiology guidelines now recommend that cardio-
selective β-blockers may be prescribed on a case-by-case
basis in people with asthma, their use in clinical practice in
this population continues to be less than optimal.
This review summarizes the published data about the effects of
β-blockers on asthma outcomes to help the clinician’s decision in
prescribing this treatment in patients with asthma and comorbid-
ities who really need it. The choice of the treatment must be done
according to the indication and the pharmacological properties of
the product (cardio-selectivity, the presence of the intrinsic sym-
pathomimetic activity, and the β2-adrenoceptor-activated signal-
ing pathways). The low dose initiation and the gradual increase
are recommended in order to avoid potential adverse effects
because the selectivity is only relative and, at therapeutic doses,
cardio-selective β-blockers exert significant β2-antagonism
though to a lesser extent than non-selective β-blockers. Table 2
summarizes these practical recommendations.
Current evidence of adverse events in asthma patients come
from clinical trials under controlled conditions in selected
patients. Generalization of study results simply regarding β-
blockers as a ‘class’ is not possible when considering their rigor-
ous pharmacological definition and their appropriate clinical
application. In some diseases, all β-blockers are effective, while
in others only certain subgroups have a therapeutic benefit. The
best documented example for only a subset of β-blockers show-
ing clinical efficacy is heart failure, where members of the class
that were considered for a very long time completely ineffective
are now the drugs of choice for treating the disease. There are
remarkable pharmacological similarities between chronic heart
failure and asthma with regards to the temporal effect on
responses to both βADR agonists and inverse agonists. In this
line, clinical studies using nadolol, a non-selective inverse
β2-adrenoceptor agonist, showed a benefit in mild asthma with
an attenuated hyperresponsiveness to methacholine in patients
treated chronically whereas those using propranolol, esmolol or
carvedilol do not have this effect because they activate β-arrestin
/ERK signaling pathway which is detrimental in asthma while
nadolol does the opposite [26,27].
Table 2. Practical recommendations about how to use beta-blockers in patients
with asthma.
1. Non-selective beta-blockers are currently contraindicated in patients with
asthma.
2. If the administration of a beta-blocker is mandatory in patients with
asthma, a selective beta-blocker could be administrated with several
conditions:
- the preferable choice is a highly-selective beta-blocker,
- the presence of intrinsic sympathomimetic activity confers more safety,
- the initiation of the treatment should be made under close medical
supervision by a specialist,
- the treatment must be started by low-doses and an up-titration is
recommended,
- for the most severe patients, by caution, the first dose could be
administrated during a short- time hospitalization for a better monitoring
(24-hours).

The important progress in pharmacology with better
understanding of the different signaling profiles of the various
β2-adrenoceptor ligands, as well as the development of new
highly selective β-blockers will change our clinical practice in
the future regarding prescriptions of β-blockers in asthma
population. Future studies are needed to evaluate the risk/
benefit of β-blockers in asthma from real-life settings, but also
in pharmacology to identify additional signaling pathways and
to design new drugs which could be prescribed in patients
with asthma and a minimal risk of bronchoconstriction.
Acknowledgments
The authors would like to thank the Interasma European Scientific net-
work (INES).
Funding
This paper was not funded.
Declaration of interest
K Kowal reports personal fees from Astra Zeneca, personal fees from Berlin
Chemie, Chiesi, Hal Allergy, Orion Pharma, outside the submitted work.
The authors have no other relevant affiliations or financial involvement
with any organization or entity with a financial interest in or financial
conflict with the subject matter or materials discussed in the manuscript
apart from those disclosed.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other
relationships to disclose.
ORCID
Marina Labor http://orcid.org/0000-0001-5216-8129
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