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Eur Respir J
1990, 3, 228-233
VIEWPOINT
Viewpoint: untoward effects of beta-adrenoceptor
agonists in asthma
J. Morley, S. Sanjar, C. Newth
Viewpoint: untoward effects of beta-adrenoceptor agonists in asthma. J. Morley,
S. Sanjar, C. Newth.
ABSTRACT: Beta-adrenoceptor agonlsts are potent and selective relaxants of airway smooth muscle. They produce symptomatic bronchodUatory
effects and are the most widely used therapy In asthma. In patients with
asthma, they usually effect a reduction of airway resistance, but there have
been several reports of episodes of Increased airway obstruction, arterial
hypoxaemia and even death associated with such therapy. "Anomalous or
paradoxical bronchospasm" are appropriate terminologies to describe this
unexpected phenomenon. Five mechanisms have been proposed to account
for anomalous responses to these substances: 1) reactive myogenic tone;
2) metabolic products with spasmogenic activity; 3) adrenoceptor tachyphylaxis; 4) Increased Inflammatory burden; and 5) Induction of airway
hyperreactlvlty. Following a review of the relative merits of each proposal,
it Is concluded that Increased Inflammatory burden and Induction of airway hyperreactlvity, alone or In combination, provide the most plausible
explanation for paradoxical bronchospasm.
Eur Respir J., 1990, 3, 22fr-233.
Bronchodilatory actions of beta-adrenoceptor
agonists
Beta-adrenoceptor agonists relax isolated airway smooth
muscle, whether tone has developed spontaneously or as
a result of addition of spasmogens, e.g. histamine or
methacholine, to the tissue bath. Relaxation of human
tracheal or bronchial muscle is achieved. when concentrations of (±)isoprenaline exceed 10·9 M [1-3).
The capacity of beta-adrenoceptor agonists to relax
airway smooth muscle has been accounted for by a model,
in which interaction between the agonist and betaadrenoceptors at the surface of airway smooth muscle
induces adenylate cyclase activation and generation of
3', 5' cyclic adenosine monophosphate (cAMP) with
consequent dephosphorylation of protein kinase and
reduced activation of myosin light chain kinase. Activation of adenylate cyclase as a mechanism whereby cells
respond to adrenoceptor agonists is extensively supported
by biochemical studies on a range of cell types [4).
However, elevation of cAMP within airway smooth
muscle only becomes evident at drug concentrations considerably in excess of those needed to achieve maximal
relaxation in vitro [5]. Thus, the bronchorelaxant effect
of beta-adrenoceptor agonists is difficult to explain, other
than by proposing that adenylate cyclase activation is
restricted to certain sub-components, and that the marginal increase in cAMP, associated with relaxation of
smooth muscle, may reflect the low incidence of
Preclinical Research, Sandoz Ltd, Basle, Switzerland.
Correspondence: C.J.L. Newth, Otildren's Hospital Los
Angeles, USC School of Medicine, 4650 Sunset Blvd,
Los Angeles CA 90027 USA.
Keywords: Airway hyperreactivity; asthma; betaadrenoreceptor, side effects.
Received: March 1989; accepted for publication
October 2, 1989.
receptor occupancy needed to achieve physiological or
pharmacological response in this tissue.
Paradoxical bronchospasm
Airway smooth muscle consistently relaxes when betaadrenoceptor agonists are added to the fluid bathing in
vitro preparations. Inhaled or injected beta-adrenoceptor
agonists regularly induce a reduction of airway
obstruction in man or in animals subjected to bronchoconstrictor stimuli. These observations implied that betaadrenoceptor agonists could cause relaxation of airway
smooth muscle in asthma, which clinical investigation
proved to be correct. Nonetheless, there have been intermittent reports of a worsening of asthma with increased
airflow obstruction following administration of betaadrenoceptor agonists, whether by oral [6], intravenous
[7, 8] or inhaled [9-13) routes. Such effects have a very
low incidence or, if widespread, are nullified by bronchodilator effects in most individuals.
"Anomalous bronchospasm" and "paradoxical bronchospasm" are terminologies which seem appropriate in
that an unexpected and unexplained phenomenon is
indicated. Terms such as "rebound bronchospasm" and
"tachyphylaxis" should be avoided, because they imply
specific mechanisms, which may not indicate why the
phenomenon is manifest so infrequently, and may be
difficult to substantiate.
BETA-ADRENOCEPTOR AGONISTS IN ASTHMA
Proposed mechanisms for paradoxical
bronchospasm
Five proposals have been considered to explain "paradoxical bronchospasm" secondary to administration of
drugs that are categorized as beta-adrenoceptor agonists:
1) reactive myogenic tone; 2) metabolic products with
spasmogenic activity; 3) beta-adrenoceptor tachyphylaxis;
4) increased inflammatory burden; 5) induction of airway hyperreactivity.
1) Reactive myogenic tone
It has been suggested that adverse effects of betaadrenoceptor agonists on the airways is due to "rebound
bronchospasm" [7, 14). This term implies that bronchodilator responses to beta-adrenoceptor agonists can induce
a subsequent bronchoconstrictor event Presumably this
concept has its origin in the myogenic constrictor
responses that can be elicited by physical dilatation of
blood vessels [15). Although reactive spasm in response
to abrupt stretching is documented for vascular smooth
muscle, there is no evidence for such a phenomenon in
airway smooth muscle. Clinically, reactive bronchospasm
has not been reported after physical dilatation of locally
constricted tracheal and bronchial areas in children, or
after bronchoalveolar lavage in asthmatics of any age.
Segments of bronchial or tracheal muscle can develop
tone in vitro and such myogenic tone is lost on addition
of beta-adrenoceptor agonists or other relaxants. Following removal of the relaxant by washing, the preparation
recovers tone without exceeding earlier developed
tension. Similar changes can be observed in lung segments perfused via the airway lumen (Chapman et al
unpublished observations). In anaesthetized animals, after
airway obstruction has been induced by intravenous
infusion of spasmogens, spasmolytic agents such as xanthines cause an abrupt reduction of airflow obstruction
which resolves progressively, returning to the original
level of obstruction. Thus, the concept of rebound bronchospasm has no experimental counterpart in vitro or in
vivo.
2)
Metabolic products
When beta-adrenoceptor agonists are administered in
man they are eliminated by metabolic processes, which
raises the possibility that specific metabolites might act
as constrictor agents. For instance, (±)isoprenaline is
metabolized in part by catechol-o-methyl transferase
(COMT) to a 3-methoxy derivative, which has weak
beta-adrenoceptor antagonist activity [16). Although this
metabolite will always attenuate the effect of (±)isoprenaline, the amount required to achieve blockade of betaadrenoceptors considerably exceeds concentrations found
in clinical circumstances [17]. Furthermore, whilst such
events might be proposed to account for anomalous
responses to isoprenaline, this type of explanation cannot
extend to drugs with alternative metabolic pathways and
different metabolic products.
229
3) Beta-adrenoceptor tachyphylaxis
After exposure to an agonist (usually in considerable
excess), certain tissues show diminished response to that
agonist Classically, this reduced responsivity has been
termed tachyphylaxis. The loss of sensitivity may be
accompanied by a reduced incidence of receptors at the
cell surface, a process that has led to introduction of the
term "down-regulation". In asthma patients, changed
responsivity to beta-adrenoceptor agonists at
extra-pulmonary sites (e.g. eye and peripheral blood) can
be detected [18, 19) and such phenomena have been
offered as evidence favouring impaired betaadrenoceptor responsivity in all tissues as a determinant
of asthma pathology. Consequently, it has been widely
presumed that asthmatic airway smooth muscle becomes
desensitized to beta-adrenoceptor agonists, even though
prospective clinical studies in asthmatics fail to detect
such a phenomenon [20, 21]. Animal studies indicate
that tachyphylaxis in airway smooth muscle to betaadrenoceptor agonists occurs only when large doses are
applied over long periods (e.g. 75 mg·kg·1 per day
subcutaneously for three days in rats) [22]. It follows
that loss of responsivity to beta-adrenoceptor agonists is
an improbable outcome of sympathomimetic therapy in
asthma, so that some other explanation must be sought
for diminished responses when these occur. Note that
even if tachyphylaxis to beta-adrenoceptor agonists did
occur in asthmatic airways, it would not provide an
adequate explanation for paradoxical bronchospasm; the
consequence of reduced responsivity is merely a reduced
bronchodilator response, not a bronchoconstrictor
response.
4)
Increased inflammatory burden
The airways of asthmatic patients are characterized by
persistent inflammation with impaired mucociliary clearance and are subject to persistent constrictor stimuli;
hence, inhaled particles encounter turbulent airflow in
major bronchi and impact largely in the central airways
[23]. The relaxant effect of beta-adrenoceptor agonist
drugs reduces obstruction within major airways and so
improves subsequent or concomitant delivery of aerosols
into more peripheral airways (fig. 1). Thus, it has been
recommended that administration of inhaled therapy be
regularly spaced [24), and that beta-adrenoceptor agonists
be used prior to the inhalation of other drugs to decrease
their side-effects [25).
It follows that bronchodilator therapy will increase the
deposition within the airways, not only of other therapeutic agents, but also of noxious particles such as pallens, animal danders and endotoxins, especially as small
doses of beta-adrenoceptor agonists fully inhibit acute
(i.e. early) allergic bronchospasm [26], which might
otherwise restrict ingress of such inflammatory burden.
The consequences of increased allergen deposition in the
airways would only be detected when bronchodilator
responses have waned. Accordingly, it has been reported
that there is an increase in the incidence and intensity of
230
J. MORLEY, S. SANJAR, C. NEWTH
Before exercise ·•
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After bronchodilator
Inhalation
Fig. 1. - Krypton""' ventilation scans and flow-volume loops prior to and following exercise in a 14 yr old girl with asttuna. The top panel
demonstrates nonnal flow-volume and ventilation characteristics. Following exercise, there has been a marked reduction in forced vital capacity
(FVC), forced expiratory volume in one seoond (FE V 1) with the appearance of non-segmental areas of severely reduced ventilation, consistent
with exercise-induced asthma. Over the subsequent 90 m in, there has been sponiJineous improvement in all measured variables although the right
upper lobe remains completely compromised. After inhalation of the beta-adrenoceptor agonist salbuiJimol, the bronchodilator effect reduces obstruction within central airways thereby improving ventilation to the right upper lobe, and also the shape of the flow-volume loop. (Reproduced with
permission: Or Y. likura, National Children's Hospital, Tokyo, Japan).
late-onset reactions following administration of a betaadrenoceptor agonist prior to allergen challenge [27].
Guinea-pig lungs are highly sensitive to airway
spasmogens, hence this phenomenon can be readily demonstrated in sensitized guinea-pigs. In such animals, a
prominent intrapulmonary eosinophilia can be revealed
in resJX)nse to allergen inhalation. This effect can be
inhibited by all classes of anti-asthma drugs [28), with
the notable exception of the beta-adrenoceptor agonist,
salbutamol, (fig. 2) which invariably kills such animals
unless the dose is substantially reduced.
It is frequently stated that beta-adrenoceptor agonists
do not inhibit or diminish late-onset reactions to allergen, but this opinion may prove to be invalid. Beneficial
effects of the drug may be obscured either by decreased
delivery of beta-adrenoceptor agonist during the (late)
periods of airway obstruction, or by an increased
delivery of allergen after the (early) bronchoconstrictor
resJX>nse has been reversed by a beta-adrenoceptor
agonist. The effect of beta-adrenoceptor agonists remains
uncertain, but could be resolved by administration of
constant doses of allergen in the presence and absence of
intravenous administration of beta-adrenoceptor agonists.
Since both the bronchodilator effect of the betaadrenoceptor agonist, and the bronchoconstrictor effect
and airway obstruction due to allergen, can enhance or
restrict drug delivery by inhalation, it is not possible to
control or realistically estimate drug delivery by this route.
Furthermore, ventilatory indices cannot be used to
anticipate aerosol deposition (fig. 1).
5) Induction of airway hyperreactivity
The possibility that beta-adrenoceptor agonists might
induce airway hyperreactivity should have been considered at the time of the asthma death epidemic, for it had
already been demonstrated that systemic treatment with
(±)isoprenaline caused an increased sensitivity of guineapigs to the noxious effect of inhaled histamine [29, 30].
Recently, investigation of the effects of platelet activating factor (P AF) on guinea-pig airways revealed that
(±)isoprenaline intensified PAP-induced airway
hyperreactivity [31). Further investigation has led to the
recognition that (±)isoprenaline per se induces airway
hyperreactivity by a process that cannot be accounted for
by an action on beta-adrenoceptors [32]; thus, increased
airway reactivity is accompanied by little or no loss of
beta-adrenoceptor responsivity in airways; furthermore,
development of airway hyperreactivity is not inhibited
by selective antagonists of beta-adrenoceptors [33] and
is demonstrated equally by both (+) and (-) isomers of
isoprenaline [32]. This latter observation is in contrast to
the bronchorelaxant effect of beta-adrenoceptor occupancy, since (+)isoprenaline has a thousand times less
bronchodilator activity than the(-) isomer. The effect of
BETA-ADRENOCEPTOR AGONISTS IN ASTHMA
231
160
140
40
"'
,..
0
.25..
"',..
0
-
!E.
.r:.
c.
0
c:
X
!E.
8
'(ij
0
-
"iU
Cl)
~
~
~
20
o~--~~~~~~uauu_
Fig. 2. - Deaths and intrapulmonary eosinophilia related to salbutamol in allergen-sensitized guinea-pigs. Following sensitization of guinea-pig
lungs by repeated intra-peritoneal inj ections of ovalbumin, inhalation of allergen produced a prominent intrapulmonary eosinophilia when
srudied at 24 h. This effect could be inhibited by pre·treaunent with 5 day subcutaneous infusions of dexamethasone (1.0 mg·kg ·1 per day),
aminophylline (10 mg·kg· 1 per day) and ketotifen (1.0 mg·kg· 1 per day), (p<O.OS). However, when the beta-adrenoccptor agonist, salbutamol, was
similarly administered in the usual doses of 1.0 mg·kg· 1 per day) the sensitized animals died immediately after challenge (10 deaths in 10
animals), and no record of pulmonary eosinophilia could be made. When the salbutamol dose was reduced to one-tenth (0.1 mg·kg·• per day), there
were less <0.01) rather than inhibited. The brackets after the drug names show the number of animals studied in each group. c=::F control (20);
~: dexamethasone (10); f2522!: ketotifen (10); IIIIIIIIII= aminophylline (9);
salbutamol (4•).
-=
(±)isoprenaline on airway hyperreactivity is only evident
when the vagus is intact , and may be dependent on the
activity of peptidergic neurotransmitters since it is not
influenced by atropine (Morley and Sanjar, unpublished
observations).
The development of increased bronchial hyperreactivity in both paediatric and adult patients with asthma,
after several weeks of therapy with beta-ad.renoceptor
agonists, has been documented in the recent clinical
literature [14, 34, 35].
Discussion
The problem of paradoxical responses during betaad.renoceptor agonist therapy of asthma has been evident
for almost fifty years. This adverse effect has been
infrequently reported [6-13]. leading to the presumption
that it is rare. This may be valid, but the alternative possibility that adverse effects are usually obscured by the
symptomatic efficacy of bronchodilator therapy, is worth
consideration.
Of the mechanisms considered to account for paradoxical bronchospasm, increased inflammatory burden
and induction of hyperreactivity as a direct response to
exposure to the drug seem the most probable explanations. In either circumstance, the occurrence of such a
phenomenon can be expected to remain undetected in a
substantial proportion of patients.
Alternative proposals appear implausible. Rebound
bronchospasm is a concept that is not supported by
laboratory evidence and does not extend to other bronchodilators such as theophylline. Metabolic events could
contribute to such an effect but such an explanation would
only account for effects of specific drugs, such as
isoprenaline.
Tachyphylaxis is also an inadequate explanation, since
the property of decreased beta-ad.renoceptor responsivity
is difficult to demonstrate in airway smooth muscle and,
even if present, it would only contribute to reduced
bronchodilator response, not to airway obstruction.
Since evidence already exists that an increased
incidence of late-onset reactions to allergen follows pretreatment with beta-agonists [27), and since avoidance of
an increased load of environmental allergens is held to
be of clinical benefit [36, 37] and universally prescribed,
the occurrence of an increased allergic or inflammatory
burden secondary to a bronchodilator response must be
a common effect since patients use beta-agonist therapy
for relief of symptoms when exposed to asthmagenic
J. MORLEY, S. SANJAR, C. NEWTH
232
stimuli such as dusts and allergens. Whilst obvious, such
effects would easily be overlooked in patients using
symptomatic bronchodilator therapy because such drugs
produce protracted bronchodilator effects; consequently,
a substantial proportion of patients can have progressive
pathology that remains undetected, or will exhibit a
worsening clinical condition that is attributed to disease
intensification per se. Hitherto, these possibilities have
generally been disregarded, partly because resolution of
this issue would require clinical trials of prophylactic
anti-asthma drugs in which beta-adrenoceptor agonist use
is restricted. Nonetheless, further investigation of these
aspects of beta-adrenoceptor agonist therapy is warranted.
250
Incremental increase in RL
cmH 20 ·t'·sec
200
to allergens or other sensitizing agents, has yet to be
resolved. However, idiosyncratic sensitivity should not
be considered unlikely, as this pattern has been reported
both during study of asthmatics [38, 39] and after accidental administration of beta-adrenoceptor antagonists
[40], which cause a fonn of hyperreactivity in laboratory
animals that is similar to that produced by (±)isoprenaline [41]. Since the capacity of (±)isoprenaline to induce
airway hyperreactivity is independent of beta-adrenoceptor occupancy, it follows that drug applications at higher
frequency during circumstances of increased asthma
symptoms and reduced responsivity to bronchodilator
effects of beta-agonist may unwittingly enhance airway
hyperreactivity. This phenomenon can be readily illustrated in the guinea-pig, where sustained administration
of salbutamol in high doses will cause a reduced
responsivity to beta-adrenoceptor agonists and, at the same
time, an increased responsivity to airway spasmogens
(fig. 3). It is important to ascertain in humans if the
hyperreactivity associated with the use of betaadrenoceptor agonists is also independent of adrenoceptor occupancy in asthma patients.
Conclusion
There is now sufficient evidence to indicate that adverse effects of beta-adrenoceptor agonists in patients
with asthma may intensify disease. The purpose of this
review is to direct the attention of clinical investigators
to this issue, so that the origin of adverse responses may
be resolved on the basis of studies in clinical asthma,
rather than in laboratory models in experimental animals.
150
1 00
Acknowledgement: We a re grateful to E.
Schaeublin, A. Kristerson and L. Mazzoni for undertaking the experiments described in figs 2 and 3, and for
permission to present the data.
50
References
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Saline
Salbutamol
Fig. 3. - Increased airway resistance (RL) resulting from sequential
intravenous injections of histamine (l.O, 1.8 and 3.2 Jlg·kg· ') in
guinea-pigs. In the right panel are the responses to histamine for three
guinea-pigs that have received a sustained subcutaneous infusion
of salbutamoi (lOO Jlg·kg·• per h) over four days. The responses
are markedly enhanced at all three histamine concentrations by
comparison with those in five sham-treated animals (left panel), which
have a histamine sensitivity indistinguishable from that of
untreated animals.~: histamine 0.56 Jlg·kg·1 i.v.; ~histamine
1.0 Jlg·kg·1 i.v.; ~: histamine 1.8 Jlg·kg·• i.v.
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Point de vue: ejfets malincontreux des agonistes des {3 recepteurs dans l'asthme. J. Morley, S. Sanjar, C. Newth.
RESUME: Les agonistes des beta-adreno-recepteurs ont une
action relaxante puissante et selective sur le muscle lisse des
voies aeriennes. De la sorte, ils entrainent des effets bronchodilatateurs perceptibles et sont les plus largemcnt utilises dans le
traitement de l'asthme. Chez les patients atteints d'asthme, ces
produits entrainent habituellement une reduction de la
resistance des voies aeriennes; toutefois, des episodes d'accroissement de !'obstruction des voies aeriennes, de l'hypoxemie
arterielle et meme des deces, ont ete mis en relation avec ce
type de traitement dans toute une serie de rapports des 50
dernieres annees. Une bronchospasme anormal ou paradoxal
est une denomination appropriee pour la description de ce
phenomene inattendu. Cinz mecanismes ont ete proposes pour
expliquer les reponses anormales a ces medicaments: 1) tonus
myogene reactif; 2) produits metaboliques a activite spasmogene;
3) tachyphylaxie des adreno-recepteurs; 4) accentuation de la
charge inflammatoire; 5) induction d'une hyperreactivite des
voies aeriennes. Apres une revue des meritcs relatifs de
chacune des hypotheses, !'on peut conclure qu'une charge
inflanunatoire accrue et !'induction d'une hyperreactivite des
voies aeriennes, seules ou en association. fournissent !'explication la plus plausible du bronchospasme paradoxal.
Eur Respir J., I990, 3, 228-233.