THEOPHYLLINE, also known as 1,3-DIMETHYLXANTHINE, is a methylxanthine
drug used in therapy for respiratory diseases such as chronic
obstructive pulmonary disease (COPD) and asthma under a variety of
brand names. As a member of the xanthine family, it bears structural
and pharmacological similarity to theobromine and caffeine , and is
readily found in nature, and is present in tea (
Camellia sinensis )
and cocoa (
Theobroma cacao ). A small amount of theophylline is one of
the products of caffeine metabolic processing in the liver .
* 1 Medical uses
* 1.1 Uses under investigation
* 2 Adverse effects
* 3 Mechanisms of action
* 4 Natural occurrences
* 5.1 Absorption
* 5.2 Distribution
* 5.3 Metabolism
* 5.4 Elimination
* 6 History
* 7 References
* 8 External links
The main actions of theophylline involve:
* relaxing bronchial smooth muscle
* increasing heart muscle contractility and efficiency; as a
* increasing heart rate: (positive chronotropic )
* increasing blood pressure
* increasing renal blood flow
* anti-inflammatory effects
* central nervous system stimulatory effect mainly on the medullary
respiratory center .
The main therapeutic uses of theophylline are aimed at:
* chronic obstructive pulmonary disease (COPD )
* infant apnea
* Blocks the action of adenosine ; an inhibitory neurotransmitter
that induces sleep, contracts the smooth muscles and relaxes the
USES UNDER INVESTIGATION
A clinical study reported in 2008 that theophylline was helpful in
improving the sense of smell in study subjects with anosmia .
The use of theophylline is complicated by its interaction with
various drugs and by the fact that it has a narrow therapeutic window
. Its use must be monitored by direct measurement of serum
theophylline levels to avoid toxicity . It can also cause nausea,
diarrhea, increase in heart rate, abnormal heart rhythms , and CNS
excitation (headaches, insomnia , irritability, dizziness and
lightheadedness ). Seizures can also occur in severe cases of
toxicity, and are considered to be a neurological emergency. Its
toxicity is increased by erythromycin , cimetidine, and
fluoroquinolones , such as ciprofloxacin . It can reach toxic levels
when taken with fatty meals, an effect called dose dumping .
Theophylline toxicity can be treated with beta blockers . In addition
to seizures , tachyarrhythmias are a major concern.
MECHANISMS OF ACTION
Like other methylated xanthine derivatives , theophylline is both a
* competitive nonselective phosphodiesterase inhibitor , which
raises intracellular cAMP , activates PKA , inhibits TNF-alpha and
inhibits leukotriene synthesis, and reduces inflammation and innate
* nonselective adenosine receptor antagonist, antagonizing A1, A2,
and A3 receptors almost equally, which explains many of its cardiac
Theophylline has been shown to inhibit
TGF-beta -mediated conversion
of pulmonary fibroblasts into myofibroblasts in COPD and asthma via
cAMP-PKA pathway and suppresses COL1 mRNA, which codes for the protein
It has been shown that theophylline may reverse the clinical
observations of steroid insensitivity in patients with COPD and
asthmatics who are active smokers (a condition resulting in oxidative
stress ) via a distinctly separate mechanism.
Theophylline in vitro
can restore the reduced HDAC (histone deacetylase) activity that is
induced by oxidative stress (i.e., in smokers), returning steroid
responsiveness toward normal. Furthermore, theophylline has been
shown to directly activate
HDAC2 . (Corticosteroids switch off the
inflammatory response by blocking the expression of inflammatory
mediators through deacetylation of histones, an effect mediated via
histone deacetylase-2 (HDAC2). Once deacetylated, DNA is repackaged so
that the promoter regions of inflammatory genes are unavailable for
binding of transcription factors such as
NF-κB that act to turn on
inflammatory activity. It has recently been shown that the oxidative
stress associated with cigarette smoke can inhibit the activity of
HDAC2, thereby blocking the anti-inflammatory effects of
Theophylline is naturally found in cocoa beans . Amounts as high as
3.7 mg/g have been reported in Criollo cocoa beans.
Trace amounts of theophylline are also found in brewed tea , although
brewed tea provides only about 1 mg/L, which is significantly less
than a therapeutic dose.
When theophylline is administered intravenously, bioavailability is
100%, as with all intravenously administered drugs.
Theophylline is distributed in the extracellular fluid, in the
placenta, in the mother's milk and in the central nervous system. The
volume of distribution is 0.5 L/kg. The protein binding is 40%. The
volume of distribution may increase in neonates and those suffering
from cirrhosis or malnutrition, whereas the volume of distribution may
decrease in those who are obese .
Theophylline is metabolized extensively in the liver (up to 70%). It
N-demethylation via cytochrome P450 1A2 . It is metabolized
by parallel zero order and Michaelis-Menten pathways. Metabolism may
become saturated (non-linear), even within the therapeutic range.
Small dose increases may result in disproportionately large increases
in serum concentration.
Methylation to caffeine is also important in
the infant population. Smokers and people with hepatic (liver)
impairment metabolize it differently. Both THC and nicotine have been
shown to increase the rate of theophylline metabolism.
Theophylline is excreted unchanged in the urine (up to 10%).
Clearance of the drug is increased in children (age 1 to 12),
teenagers (12 to 16), adult smokers, elderly smokers, as well as in
cystic fibrosis , and hyperthyroidism . Clearance of the drug is
decreased in these conditions: elderly, acute congestive heart
failure, cirrhosis, hypothyroidism and febrile viral illness.
The elimination half-life varies: 30 hours for premature neonates, 24
hours for neonates, 3.5 hours for children ages 1 to 9, 8 hours for
adult non-smokers, 5 hours for adult smokers, 24 hours for those with
hepatic impairment , 12 hours for those with congestive heart failure
NYHA class I-II, 24 hours for those with congestive heart failure NYHA
class III-IV, 12 hours for the elderly.
Theophylline was first extracted from tea leaves and chemically
identified around 1888 by the German biologist
Albrecht Kossel .
Seven years later, a chemical synthesis starting with 1,3-dimethyluric
acid was described by Emil Fischer and Lorenz Ach . The Traube purine
synthesis , an alternative method to synthesize theophylline, was
introduced in 1900 by another German scientist,
Wilhelm Traube .
Theophylline's first clinical use came in 1902 as a diuretic . It
took an additional 20 years until it was first reported as an asthma
treatment. The drug was prescribed in a syrup up to the 1970s as
Theostat 20 and Theostat 80, and by the early 1980s in a tablet form
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