Combination Long-acting b2-agonists with Inhaler Corticosteroid

systemic
Introduction
B2-adrenergic receptor agonists are effective bronchodilators in asthma,
and are important in the management of this disease. Short-acting b2agonists are generally used for symptom relieve, and for the reversal of
acute bronchoconstriction. Long-acting b2-agonists have been proved to
be beneficial in the addition to inhaled corticosteroids for the long-term
management of asthma. However, long-acting b2-agonists should be used
only together with inhaled corticosteroids (ICS), which is the first-line
management of asthma. If a paitnets asthma is not adequately controlled
with ICS therapy alone, the addition of a long-acting b2- agonist can be
considererd. In fact, addition of a long-acting b2-agonist to ICS therapy
leads to greater improvements in lung function than can be achieved
through doubling the dose of ICS and will also reduce the frequency of
asthma exacerbations, making this an important treatment alternative.
The long-acting b2-agonists, formoterol and salmeterol, are commonly
used in the treatment of asthma. These agents have been shown to
improve lung function for at least 12 hours. This article will discuss the
pharmacology and the clinical profile of long-acting b2-agonists, and will
also suggest some ways to use these drugs for successful management of
asthma.(1,2)
Clinical effects of long-acting b2-agonists
Inhlaed formoterol and salmeterol represent important advances in the
management of asthma, in view of their effective bronchodilating effects
and long-term improvement in lung function. Formoterol has been shown
to provide a rapid bronchodilating effect, occurring within minutes after
inhalation of the measured doses of 6-24mg

(4.5-18 mg delivered),

which is more rapid than the effect observed with salmeterol (50 mg
measured). Despite the more rapid onset of action with formoterol, there

apparent to be no difference in the duration of effect between these two

agents up to 12 hours.

(2)

Long-term large multi centre studies have confirmed the beneficial effects
of both salmeterol and formoterol given as regular treatment. Clearly,
lung function was improved to a greater degree with the addition of either
of the long-acting b2-agonsts compared with doubling the dose of of the
inhaled glucocorticoid. In the later study, it was also shown that the
addition of formoterol reduced exacerbations of asthma on top of a low
dose of inhaled glucocorticoid. Furthermore, the same study showed that
quadrupling

the

dose

of

the

inhaled

glucocorticoid

also

reduced

exacerbation frequency. Therefore, overall, it seems that adding a longacting b2- agonist to a lower dose of an inhaled glucocorticoid, may be a
preferred approach. When the regular treatment with formoterol or
salmeterol is directly compared, similar improvement in lung function is
observed over a long observation period. Therefore, for such a therapeutic
approach, there seems to be no difference in the clinical effects of these
drugs.(2,3)
Pharmacology of formoterol and salmeterol
As mentioned, there are some differences in the onset-of-action between
formoterol and salmeterol. The difference in the effects of these drugs
may in part be explained by their different diffusion in the airway
microenvironment. After inhalation of a drug, it is deposited on the
surface of the airway epithelial lining fluid, where it is dissolved.
Subsequently,

these

drugs

diffuse

through

theepithelium

and

the

submucosa to reach the bronchial smooth muscle. Salmeterol and

formoterol are quite lipophilic, and salmeterol is more lipophilic than
formoterol. Therefore, these drugs, and especially salmeterol, with enter
any cell membranes in the microenvironement. The portion of drug that is
present in cell membranes with have a greater difficulty to rapidly pass
through the tissues, and will therefore reach the smooth muscle at

sufficient concentrations at a later time. This simple difference in

chemistry may explain why formoterol has a more rapid onset of action
than salmeterol. Formoterol is thus less lipophilic than salmeterol, and a
portion of this drug will therefore stay outside cell membranes, and will
thus diffuse to the smooth muscle rapidly.(1,3)
The lipophilicity of both formoterol and salmeterol may explain their long
duration of effect. Because high concentrations of these drugs remain in
cell membranes around the smooth muscle for a prolonged time, these
drugs are available for the b2- receptor and receptor activation for at
least 12 h. It has also been argued that salmeterol may have an anchored
binding within the b2-receptor, explaining its long duration of action.
Pharmacological studies using smooth muscle cell preparation from
animals and humans have shown that formoterol has a greater maximal
effect as compared with salmeterol (high pharmacological efficacy/ high
intrinsic activity). Thus, strongly contracted smooth muscle will relax to a
lesserextent with salmeterol compared with formoterol, showing that
salmeterol is a partial agonist at the b2-receptor site in relation to
formoterol. Similarly, in asthma patients in vivo, high doses of formoterol
protects more against methacholineinduced bronchoconstriction than
salmeterol does. Thus, increasing the pre-treatment dose of formoterol up
to 120mg measured dose, caused almost a 5-doubling dose protection
agaist methacholine, whereas the maximal effect of salmeterol was
approximately 2.7 doubling doses. This argues that formoterol can be
given to patients to reverse severe bronchoconstriction, and that
additional effects can be observed by increasing the dose of formoterol.
However, more systemic side effects will be observed in such a case.
Salmeterol, on the other hand, had no clear dose-dependent effect, and
should therefore be used only as a stable regular treatment, without
titrating the dose up and down to any great extent.(1,2)
Theoretically, a partial agonist, such as salmeterol, can inhibit the effect
of a full agonist. However, clinical studies argues against any important

inhibitory effect of salmeterol on the effect of salbutamol. Therefore, both

salmeterol and formoterol seem to be safe in this regard.(3)
Formoterol - an alternative to relieve asthma symptoms?
The rapid onset of effect of formoterol have suggested that this agent
could be used as a relievermedication in patients with asthma. This
possibility is also supported by the high pharmacological efficacy of
formoterol. Formoterol has been approved in the European Union for asneeded treatment of asthma in addition to its use in maintenance
therapy, based primarily on one study that has shown similar or superior
effectiveness compared with the short-acting b2-agonists terbutaline.
Furthermroe, formoterol has a very rapid onset of action, similar to
salbutamol.(1)
Systemic effects of long-acting b2-agonists
Although both short- and long-acting b2-agonists are very safe, systemic
effects such as increase in heart rate and skeletal muscle tremor will
develop when higher doses are given.(3)
Tolerance to b2-agonists
The use of short-acting b2-agonists as regular treatment has been
associated with the induction of tolerance in asthmatic patients. This is
not very obvious when evaluating the bronchodilating effects of for
example salbutamol before and after a period of regular treatment,
whereas the side effects of this treatment shows pronounced tolerance
(thus less side effects during regular treatment). Regular treatment with
the long acting b2-agonists will also result in some reduced effects. The
tolerance is not clear on bronchodilation, but more obvious regarding the
protective effect on bronchial challenges. There is more evidence that
regular long acting b2-agonist treatment causes a decrease in the
protective effect of these drugs on provoked bronchoconstriction, induced
by methacholine, exercise, or allergen. Importantly, however, regular
formoterol will reduce the number of exacerbations of asthma in a large
multi center study.(2,3)

Combining inhaled glucocorticoids and longacting b2-agonists

Both formoterol and salmeterol should be used in combination with ICS
and studies have demonstrated a clear clinical benefit in terms of lung
function for the combination compared with ICS alone. Therefore, two
products combining longacting b2-agonists and inhaled glucocorticoids
have become available (the combination of Fluticasone and Salmeterol;
Seretide, and the combination of Budesonide and Formoterol; Symbicort).
These products have been shown to be highly effective and have become
very popular in the clinical use. It has been argued that these products
will increase the compliance to asthma treatment, because they contain a
symptom reliever (the b2-agonists) and a disease controller (the inhaled
glucocorticoid). However, there is no scientific strong evidence for an
increased compliance, but future studies will be able to prove or disprove
such an hypothesis.(1,2)
Conclusions
Long duration of effect and high tolerability allow formoterol and
salmeterol

to

be

considered

as

beneficial

additions

to

inhaled

glucocorticoids for the management of patients with asthma that are not
fully controlled on a low or a moderate dose of an inhaled glucocorticoid.
Formoterol has a rapid onset of action and a high pharmacological
efficacy, and may therefore be used as a reliever medication. Increasing
the dose of salmeterol over 50mg twice daily causes little additional
benefit, and the dose of this drug should therefore be maintained
constant. Furthermore, the introduction of single inhaler therapy which
combines these two long-acting b2-agonists with highly effective inhaled
glucocorticoids will give us new opportunities to treat asthma, that may
improve compliance to treatment.

Reference
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and inhaled steroids versus higher dose of inhaled steroids in
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2008
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asthma, available from http://www.medicana.kmu.it last update
2001
3. Walters E H, Gibson P G, Lasserason T J, Long-acting beta2-agonists
for chronic asthma in adults and children where background therapy
contains varied or no inhaled corticosteroid, available from
http://www.reseachgate.net last update 2007