Theophylline is a methylxanthine compound that is used for the
treatment of asthma, chronic obstructive pulmonary disease (COPD;
chronic bronchitis and emphysema), and premature apnea. The bronchodilatory
effects of theophylline are useful primarily for patients with asthma
because bronchospasm is a key component of that disease state.1 The
use of theophylline in patients with chronic obstructive pulmonary
disease is more controversial because these diseases have different
pathophysiologic profiles, although some patients do exhibit a mixed
disease profile with a limited reversible airway component. Even
COPD patients without significant bronchospasm demonstrate clinical improvement
when taking theophylline.2–4 Theophylline is also
a central nervous system stimulant which explains its usefulness
in the treatment of premature apnea.
In the chronic management of asthma or chronic obstructive pulmonary
disease patients, theophylline is now considered to be adjunctive
therapy.5–8 Asthma is now recognized as an inflammatory
disease, and inhaled corticosteroids are considered the mainstay
of therapy.8 Inhaled selective β2-agonists
are used as bronchodilators in asthmatic patients. Other drugs that
are useful in patients with asthma are cromolyn, nedocromil, oral
corticosteroids, inhaled anticholinergics, and leukotriene modifiers.
Inhaled bronchodilators are the preferred treatment for COPD patients
with selective β2-agonists or anticholinergics
considered first line agents.6 Theophylline is considered
for use in asthmatic patients and chronic obstructive pulmonary
disease patients after their respective therapies have commenced.
Theophylline is also useful in these patients when they are unable
or unwilling to use multiple metered dose inhaler (MDI) devices
or if an intravenous drug is needed. For the treatment of premature
apnea, most clinicians prefer to use caffeine, a related methylxanthine
agent, instead of theophylline because of smoother apnea control
and reduced adverse effects.
The bronchodilatory response via smooth muscle relaxation in
the lung to theophylline is postulated to occur by several mechanisms.9 Of
these, the two predominate mechanisms of action are inhibition of
cyclic nucleotide phosphodiesterases which increases intracellular
cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate
(cGMP), and antagonism of adenosine receptors. In addition to bronchodilation,
theophylline increases diaphragmatic contractility, increases mucociliary
clearance, and exerts some antiinflammatory effects. Theophylline
is a general central nervous system stimulant and specifically stimulates
the medullary respiratory center. These are the reasons why it is
a useful agent in the treatment of premature apnea.
The generally accepted therapeutic ranges for theophylline are
10–20 μg/mL for the treatment
of asthma or COPD, or 6–13 μg/mL
for the treatment of premature apnea. Clinical guidelines suggest
that for initial treatment of pulmonary disease, clinical response
to theophylline concentrations between 5–15 μg/mL
should be assessed before higher concentrations are used.5,7 Many
patients requiring chronic theophylline therapy will derive sufficient
bronchodilatory response with a low likelihood of adverse effects
at concentrations of 8–12 μg/mL.
However, theophylline therapy must be individualized for each patient
in order to achieve optimal responses and minimal side effects.
In the upper end of the therapeutic ...