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

Table 36–3
Side Effects of Theophylline and Mechanisms
SIDE EFFECT
PROPOSED MECHANISM
Nausea and vomiting PDE4 inhibition
Headaches
PDE4 inhibition
Gastric discomfort
PDE4 inhibition
Diuresis
A 1
receptor antagonism
Behavioral disturbance (?) ?
Cardiac arrhythmias PDE3 inhibition,
A 1
receptor antagonism
Epileptic seizures
A 1
receptor antagonism
PDE, phosphodiesterase; A, adenosine.
routine monitoring of plasma concentrations is usually not
necessary, unless a change in clearance is suspected or evidence
of toxicity emerges.
Clinical Use. In patients with acute asthma, intravenous aminophylline
is less effective than nebulized 2
agonists and should therefore
be reserved for those patients who fail to respond to, or are
intolerant of, agonists. Theophylline should not be added routinely
to nebulized 2
agonists because it does not increase the bronchodilator
response and may increase their side effects (Parameswaran
et al., 2000). Indeed, the role of theophylline in the contemporary management
of asthma and COPD has been questioned. However, there is
good evidence that theophylline may provide an additional bronchodilator
effect even when maximally effective doses of 2
agonist
have been given (Rivington et al., 1995). Thus, if adequate bronchodilation
is not achieved by a agonist alone, theophylline may
be added to the maintenance therapy with benefit. Addition of lowdose
theophylline to either a high or low dose of ICS in patients who
are not adequately controlled provides better symptom control and
lung function than doubling the dose of inhaled steroid (Evans et al.,
1997; Lim et al., 2000; Ukena et al., 1997), although it is less effective
as an add-on therapy than a LABA (Wilson et al., 2000).
Theophylline may be useful in patients with nocturnal asthma
because slow-release preparations are able to provide therapeutic
concentrations overnight, although it is less effective than a LABA
(Shah et al., 2003). Studies have also documented the steroidsparing
effects of theophylline. Although theophylline is less effective
than a 2
agonist and corticosteroids, a minority of asthmatic patients
appears to derive unexpected benefit; even patients on oral steroids
may show a deterioration in lung function when theophylline is
withdrawn (Brenner et al., 1988; Kidney et al., 1995). Theophylline
has been used as a controller in the management of mild persistent
asthma, although it is usually found to be less effective than low doses
of inhaled corticosteroids (Seddon et al., 2006). Although LABA are
more effective as an add-on therapy, theophylline is considerably less
expensive and may be the only affordable add-on treatment when the
costs of medication are limiting (Bateman et al., 2008).
Theophylline is still used as a bronchodilator in COPD, but
inhaled anticholinergics and 2
agonists are preferred (Rabe et al.,
2007). Theophylline tends to be added to these inhaled bronchodilators
in more severe patients and has been shown to give additional clinical
improvement when added to a long-acting 2
agonist (Ram et
al., 2002). Intravenous aminophylline is less effective in treating
acute exacerbations than nebulized 2
agonists and has a much
higher incidence of adverse effects (Barr et al., 2003; Duffy et al.,
2005). As in asthmatics, patients with severe COPD deteriorate when
theophylline is withdrawn from their treatment regimen. A theoretical
advantage of theophylline is that it its systemic administration
may have effects on small airways, resulting in reduction of hyperinflation
and thus a reduction in dyspnea.
Side Effects. Unwanted effects of theophylline are usually related to
plasma concentration and tend to occur at C p
> 15 mg/L. However,
many patients develop side effects even at low plasma concentrations.
To some extent, side effects may be reduced by gradually increasing the
dose until therapeutic concentrations are achieved. The most common
side effects are headache, nausea, and vomiting (due to inhibition of
PDE4), abdominal discomfort, and restlessness (Table 36–3). There
may also be increased acid secretion (due to PDE inhibition) and diuresis
(due to inhibition of adenosine A 1
receptors). Theophylline may
lead to behavioral disturbance and learning difficulties in schoolchildren,
although it is difficult to design adequate controls for such studies.
At high concentrations, cardiac arrhythmias may occur as a consequence
of inhibition of cardiac PDE3 inhibition and antagonism of cardiac
A 1
receptors. At very high concentrations, seizures may occur due
to central A 1
receptor antagonism. Use of low doses of theophylline, targeting
plasma concentrations of 5-10 mg/L, largely avoids side effects
and drug interactions and makes it less necessary to monitor plasma
concentrations (unless checking for compliance).
Summary and Future Developments
Theophylline use has been declining, partly because of
the problems with side effects, but mainly because more
effective therapy with ICS has been introduced. Oral
theophylline remains a useful treatment in some
patients with difficult asthma and appears to have
effects beyond those provided by steroids. Rapidrelease
theophylline preparations are the only affordable
anti-asthma medication in some developing countries.
There is increasing evidence that theophylline has
some anti-asthma effect at doses that are lower than
those needed for bronchodilation, and plasma levels of
5-15 mg/L are recommended.
Given theophylline’s anti-inflammatory effects,
there is a strong scientific rationale for combining lowdose
theophylline with ICS, particularly in patients with
more severe asthma and in COPD. Adding a low dose of
theophylline gives better control of asthma than doubling
the dose of ICS in uncontrolled patients, and is a less
expensive alternative add-on therapy than a LABA or
antileukotriene. Theophylline reverses corticosteroid
resistance in COPD cells by restoring HDAC2 to normal
levels (Cosio et al., 2004) and accelerates the recovery
from acute exacerbations of COPD through this mechanism
(Cosio et al., 2009). In COPD, low-dose theophylline
1043
CHAPTER 36
PULMONARY PHARMACOLOGY