THEOPHYLLINE

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
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.

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 The bronchodilatory response via smooth muscle
relaxation in the lung to theophylline is
postulated to occur by several mechanisms. 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.
Bauer, 2008 : 745
 THERAPEUTIC AND TOXIC
CONCENTRATIONS
The generally accepted therapeutic ranges for
theophylline are 1020 g/mL for the treatment
of asthma or COPD, or 613 g/mL for the
treatment of premature apnea.
In the upper end of the therapeutic range (>15
g/mL) some patients will experience minor
caffeine-like side effects owing to theophylline
treatment. These adverse effects include nausea,
vomiting, dyspepsia, insomnia, nervousness, and
headache
Theophylline concentrations exceeding 2030
g/mL can cause various tachyarrhythmias
including sinus tachycardia
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 At theophylline concentrations above 40
g/mL, serious life-threatening adverse effects
including ventricular arrhythmias (premature
ventricular contractions, ventricular
tachycardia or fibrillation) or seizures can
occur.
Seizures caused by theophylline therapy have
been reported to occur in patients at
theophylline concentrations as low as 25
g/mL

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CLINICAL MONITORING PARAMETERS
Measurement of pulmonary function tests are an
important component of assessing response to
bronchodilator therapy in patients with asthma
or chronic obstructive pulmonary disease.
Forced expiratory volume over 1 second (FEV1)
should be measured on a regular basis for
asthmatic patients, and peak-flow meter
monitoring can be routinely performed by these
individuals at home. Successful bronchodilator
therapy will increase both of these values.
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 Patients should also be monitored for clinical
signs and symptoms of their disease states
including frequency and severity of following
events: dyspnea, coughing, wheezing,
impairment of normal activity
Theophylline serum concentration monitoring
is mandatory in patients receiving the drug. If
a patient is experiencing clinical signs or
symptoms that could be due to a theophylline
adverse effect, a theophylline serum
concentration should be obtained at that time
to rule out drug-induced toxicity
Bauer, 2008 : 747
 For dose adjustment purposes, theophylline
serum concentrations should be measured at
steady state after the patient has received a
consistent dosage regimen for 35 drug half-
lives.
Theophylline half-life varies from 3 to 5 hours
in children and tobacco-smoking individuals to
50 hours or more in patients with severe heart
or liver failure.

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 BASIC CLINICAL PHARMACOKINETIC
PARAMETERS
Theophylline is primarily eliminated by hepatic
metabolism (>90%).
About 10% of a theophylline dose is recovered in the
urine as unchanged drug
Three different forms of theophylline are available.
Aminophylline is the ethylenediamine salt of
theophylline, and anhydrous aminophylline contains
about 85% theophylline while aminophylline dihydrate
contains about 80% theophylline
The oral bioavailability of all three theophylline-based
drugs is very good and generally equals 100%.

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 EFFECTS OF DISEASE STATES AND CONDITIONS ON
THEOPHYLLINE PHARMACOKINETICS AND DOSING

Normal adults without the disease states and

conditions given later in this section with normal liver
function have an average theophylline half-life of 8
hours and volume of distribution of 0.5 L/kg
In patients who smoke these substances, the average
theophylline half-life is 5 hours. When patients stop
smoking these compounds, theophylline clearance
slowly approaches its baseline level for the patient
over a 6- to 12-month period if the patient does not
encounter second-hand smoke produced by other
users.

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 Patients with liver cirrhosis or acute hepatitis have
reduced theophylline clearance which results in a
prolonged average theophylline half-life of 24 hours
Heart failure causes reduced theophylline clearance
because of decreased hepatic blood flow secondary to
compromised cardiac output
Obviously, the effect that heart failure has on
theophylline pharmacokinetics is highly variable and
difficult to accurately predict. It is possible for a patient
with heart failure to have relatively normal or grossly
abnormal theophylline clearance and half-life.
For heart failure patients, initial doses are meant as
starting points for dosage titration based on patient
response and avoidance of adverse effects.
Theophylline serum concentrations and the presence
of adverse drug effects should be monitored frequently
in patients with heart failure.
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 Obese patients (>30% above ideal body weight or IBW)
should have volume of distribution estimates based on
ideal body weight
Patient age has an effect on theophylline clearance and
half-life. Newborns have decreased theophylline
clearance because hepatic drugmetabolizing enzymes
are not yet fully developed at birth.
Children between the ages of 19 years have
accelerated theophylline clearance rates resulting in an
average half-life of 3.5 hours
As children achieve puberty, their theophylline
clearance and half-life approach the values of an adult.
For elderly patients over the age of 65, some studies
indicate that theophylline clearance and half-life are
the same as in younger adults while other
investigations have found that theophylline clearance is
slower and half-life is longer
Bauer, 2008 : 752
 DRUG INTERACTIONS
Cimetidine given at higher doses (1000
mg/d) on a multiple daily dosage schedule
decreases theophylline clearance by 3050%.
Other cimetidine doses (800 mg/d) given
once or twice daily decrease theophylline
clearance by 20% or less
Ciprofloxacin and enoxacin, both quinolone
antibiotics, and troleandomycin, a macrolide
antibiotic, also decrease theophylline
clearance by 3050%.
Bauer, 2008 : 753
 Estrogen and estrogen-containing oral
contraceptives, propranolol, metoprolol,
mexiletine, propafenone, pentoxifylline,
ticlopidine, tacrine, thiabendazole, disulfiram,
nefazodone, interferon, zileuton, and fluvoxamine
can also decrease theophylline clearance by this
extent.
The calcium channel blockers, verapamil, and
diltiazem, have been reported to cause decreases
in theophylline clearance by 1525%
Clarithromycin and erythromycin, both macrolide
antibiotics, and norfloxacin, a quinolone
antibiotic, can also decrease theophylline
clearance by this magnitude
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