Theophylline and other methylxanthines are often used for their performance-enhancing effects in sports, as these drugs increase alertness, bronchodilation, and increase the rate and force of heart contraction.[9] There is conflicting information about the value of theophylline and other methylxanthines as prophylaxis against
exercise-induced asthma.[10]
Adverse effects
The use of theophylline is complicated by its interaction with various drugs and by the fact that it has a narrow
therapeutic window (<20 mcg/mL).[2] 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).[2][11]Seizures can also occur in severe cases of toxicity, and are considered to be a neurological emergency.[2]
Its toxicity is increased by
erythromycin, cimetidine, and
fluoroquinolones, such as
ciprofloxacin. Some lipid-based formulations of theophylline can result in toxic theophylline levels when taken with fatty meals, an effect called
dose dumping, but this does not occur with most formulations of theophylline.[12] Theophylline toxicity can be treated with
beta blockers. In addition to seizures, tachyarrhythmias are a major concern.[13] Theophylline should not be used in combination with the
SSRIfluvoxamine.[14][15]
Spectroscopy
UV-visible spectroscopy
Theophylline is soluble in 0.1N NaOH and absorbs maximally at 277 nm with an extinction coefficient of 10,200 (cm−1 M−1).[16]
Proton nuclear magnetic resonance spectroscopy (1H-NMR)
The characteristic signals, distinguishing theophylline from related methylxanthines, are approximately 3.23δ and 3.41δ, corresponding to the unique methylation possessed by theophylline. The remaining proton signal, at 8.01δ, corresponds to the proton on the imidazole ring, not transferred between the nitrogen. The transferred proton between the nitrogen is a variable proton and only exhibits a signal under certain conditions.[17]
Carbon nuclear magnetic resonance spectroscopy (13C-NMR)
The unique methylation of theophylline corresponds to the following signals: 27.7δ and 29.9δ. The remaining signals correspond to carbons characteristic of the xanthine backbone.[18]
Natural occurrences
Theophylline is naturally found in
cocoa beans. Amounts as high as 3.7 mg/g have been reported in
Criollo cocoa beans.[19]
Trace amounts of theophylline are also found in brewed
tea, although brewed tea provides only about 1 mg/L,[20] which is significantly less than a therapeutic dose.
nonselective
adenosine receptor antagonist, antagonizing A1, A2, and A3 receptors almost equally, which explains many of its cardiac effects.[2][26] Theophylline activates
histone deacetylases.[2]
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%.[medical citation needed]
Metabolism
Theophylline is metabolized extensively in the liver.[2] It undergoes
N-demethylation via
cytochrome P450
1A2. It is metabolized by parallel
first 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.[2] Cigarette and marijuana smoking induces metabolism of theophylline, increasing the drug's metabolic clearance.[28][29]
Excretion
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 illnesses.[2]
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.[medical citation needed]
History
Theophylline was first extracted from tea leaves and chemically identified around 1888 by the German biologist
Albrecht Kossel.[30][31] Seven years later, a
chemical synthesis starting with 1,3-dimethyluric acid was described by
Emil Fischer and
Lorenz Ach.[32] The
Traube purine synthesis, an alternative method to synthesize theophylline, was introduced in 1900 by another German scientist,
Wilhelm Traube.[33] Theophylline's first clinical use came in 1902 as a
diuretic.[34] It took an additional 20 years until it was first reported as an asthma treatment.[35] 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 called Quibron.
References
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^Belliardo F, Martelli A, Valle MG (May 1985). "HPLC determination of caffeine and theophylline in Paullinia cupana Kunth (guarana) and Cola spp. samples". Zeitschrift für Lebensmittel-Untersuchung und -Forschung. 180 (5): 398–401.
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External links
Media related to
Theophylline at Wikimedia Commons