DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1040 a marked increase in the risk of death with high doses of all inhaled
2
agonists (Spitzer et al., 1992). The risk was greater with
fenoterol, but when the dose is adjusted to the equivalent dose for
albuterol, there is no significant difference in the risk for these two
drugs. The link between high 2
agonist usage and increased
asthma mortality does not prove a causal association because
patients with more severe and poorly controlled asthma, who are
more likely to have an increased risk of fatal attacks, are more
likely to be using higher doses of 2
agonist inhalers and less likely
to be using effective anti-inflammatory treatment. Indeed, in the
patients who used regular inhaled steroids there was a significant
reduction in risk of death (Suissa et al., 2000).
Regular use of inhaled 2
agonists has also been linked to
increased asthma morbidity. Regular use of fenoterol was associated
with worse asthma control and a small increase in airway hyperresponsiveness
compared with patients using fenoterol “on demand”
for symptom control over a 6-month period (Sears et al., 1990).
However, this was not found in a study with regular albuterol (Dennis
et al., 2000). There is some evidence that regular inhaled 2
agonists
may increase allergen-induced asthma and sputum eosinophilia
(Mcivor et al., 1998). A possible mechanism is that 2
agonists
upregulate expression of PLC 1
, resulting in augmentation of the
bronchoconstrictor responses to cholinergic agonists and mediators
(McGraw et al., 2003). Short-acting inhaled 2
agonists should only
be used on demand for symptom control, and if they are required
frequently (more than three times weekly), an ICS is needed.
The safety of LABA in asthma remains controversial. A large
study of the safety of salmeterol showed an excess of respiratory
deaths and near deaths in patients prescribed salmeterol, but these
deaths occurred mainly in African Americans living in inner cities
who were not taking ICS (Nelson et al., 2006). Similar data have
also raised concerns about formoterol. This may be predictable
because LABA do not treat the underlying chronic inflammation of
asthma. However, concomitant treatment with ICS appears to obviate
such risk, so it is recommended that LABA should only be used
when ICS are also prescribed (preferably in the form of a combination
inhaler so that the LABA can never be taken without the inhaled
corticosteroids) (Jaeschke et al., 2008). All LABA approved in the
U.S. carry a black box warning cautioning against overuse. Studies
are underway to examine their long-term safety profile, especially in
children with asthma. There are less safety concerns with LABA use
in COPD. No major adverse effects were reported in a large study
over 3 years in COPD patients and in several other studies (Calverley
et al., 2007; Rodrigo et al., 2008).
SECTION IV
INFLAMMATION, IMMUNOMODULATION, AND HEMATOPOIESIS
Future Developments
2
Agonists will continue to be the bronchodilators of choice for asthma
in the foreseeable future because they are effective in all patients and
have few or no side effects when used in low doses. It would be difficult
to find a bronchodilator that improves on the efficacy and safety of
inhaled 2
agonists. Although some concerns have been expressed
about the long-term effects of short-acting inhaled 2
agonists, when
used as required for symptom control, inhaled 2
agonists appear safe.
Use of large doses of inhaled 2
agonists indicates poor asthma control;
such patients should be assessed and appropriate controller medication
used. LABA are a very useful option for long-term control in asthma
and COPD. In asthma patients LABA should probably only be used if
the patient is receiving concomitant ICS. There is little advantage to be
gained by improving 2
receptor selectivity because most of the side
effects of these agents are due to 2
receptor stimulation (muscle
tremor, tachycardia, hypokalemia). Several once daily inhaled 2
agonists,
such as indacaterol and carmoterol, are now in clinical development
(Cazzola and Matera, 2008).
METHYLXANTHINES
Methylxanthines, such as theophylline, which are related
to caffeine, have been used in the treatment of asthma
since 1930, and theophylline is still widely used in developing
countries because it is inexpensive. Theophylline
became more useful with the availability of rapid plasma
assays and the introduction of reliable slow-release preparations.
However, the frequency of side effects and the relative
low efficacy of theophylline have led to reduced use
in many countries because inhaled 2
agonists are far more
effective as bronchodilators and ICS have a greater antiinflammatory
effect. In patients with severe asthma and
COPD it still remains a very useful drug, however.
H 3 C
O
N
O
N
Chemistry. Theophylline is a methylxanthine similar in structure to
the common dietary xanthines caffeine and theobromine. Several
substituted derivatives have been synthesized, but only two appear to
have any advantage over theophylline: the 3-propyl derivative,
enprofylline, which is more potent as a bronchodilator and may have
fewer toxic effects because it does not antagonize adenosine receptors;
and doxofylline (7-[1,3-dioxalan-2-ylmethyl] theophylline), a
novel methylxanthine available in some countries (Dini and Cogo,
2001). Doxofylline, which has a dioxolane group at position 7, has
an inhibitory effect on phosphodiesterases (PDEs) similar to that of
theophylline but is less active as an adenosine antagonist and may
have a more favorable side-effect profile. Many salts of theophylline
have also been marketed; the most common is aminophylline, which
is the ethylenediamine salt used to increase its solubility at neutral
pH. Other salts either do not have any advantage (e.g., oxtriphylline
[choline theophyllinate]) or are virtually inactive (e.g., acepifylline).
Thus, theophylline remains the major methylxanthine in clinical use.
Mechanism of Action. The mechanisms of action of theophylline
are still uncertain. In addition to its bronchodilator action, theophylline
has many nonbronchodilator effects that may be relevant to
its effects in asthma and COPD (Figure 36–6). Many of these molecular
effects are seen only at high concentrations that exceed the therapeutic
range, however. Several molecular mechanisms of action
have been proposed:
• Inhibition of phosphodiesterases. Theophylline is a nonselective
PDE inhibitor, but the degree of inhibition is relatively
H
N
N
CH 3
THEOPHYLLINE