|Trade names||Theolair, Slo-Bid|
|oral, IV, rectal|
|Protein binding||40% (primarily to albumin)|
|Metabolism||Hepatic to 1-methyluric acid|
|Elimination half-life||5–8 hours|
|CompTox Dashboard (EPA)|
|Chemical and physical data|
|Molar mass||180.167 g·mol−1|
|3D model (JSmol)|
Theophylline, also known as 1,3-dimethylxanthine, is a phosphodiesterase inhibiting 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, being 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.
The main actions of theophylline involve:
- relaxing bronchial smooth muscle
- increasing heart muscle contractility and efficiency (positive inotrope)
- 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 cardiac muscle.
- Treatment of post-dural puncture headache. 
Uses under investigation
The use of theophylline is complicated by its interaction with various drugs and by the fact that it has a narrow therapeutic window.[quantify] 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. 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. Theophylline toxicity can be treated with beta blockers. In addition to seizures, tachyarrhythmias are a major concern. Theophylline should not be used in combination with the SSRI fluvoxamine.
Theophylline is soluble in 0.1N NaOH and absorbs maximally at 277 nm with an extinction coefficient of 10,200 (cm−1/M).
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.
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.
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 immunity
- nonselective adenosine receptor antagonist, antagonizing A1, A2, and A3 receptors almost equally, which explains many of its cardiac effects
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 collagen.
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 corticosteroids.)
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 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. 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 illnesses.
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 called Quibron.
Theophylline, despite its adverse effects and narrow therapeutic range, as discussed above, is still a potent bronchodilator. Current research regarding theophylline-based therapies are oriented towards employing theophylline, as well as other methylxanthines as natural scaffolding for new bronchodilatory pharmaceuticals. In 2017, Mohammed, et al. demonstrated potential derivitization of methylxanthines to produce significant broncodilatory effects in a small mouse study group. However, additional work is oriented towards limiting the interactions of theophylline-based therapies with other drugs and structures, as theophylline has been demonstrated as an effective adjunctive therapy in various diseases. These interactions include maintaining, for example, its activity with HDAC, but eliminating its stimulatory behavior (or rather its adenosine-antagonist behavior). Recently, new study investigated the potential beneficial effects of theophylline to skin as anti-aging agent. In this study, theophylline (10 or 100 μM) was administered to the culture medium of full thickness human skin ex vivo for 24 or 72 h. This treatment strongly enhanced mRNA levels of collagen I and III, which have great impact on maintaining dermal stability. It stimulated melatonin secretion, the most potent ROS-protective and DNA damage repair neuromediator and upregulated expression of its receptor (MT1). It was also found that it has a protecting effect against keratinocyte apoptosis induced by excessive ROS production, in addition to stimulatory effect on the expression of antioxidant metallothionein in human epidermis Another study indicated that topical application of plant extracts containing xanthine derivatives and xanthine derivatives themselves: caffeine, theobromine, and theophylline significantly prevented photo damage including wrinkle formation and contributed to suppression of collagen crosslinks caused by UV irradiation. It was suggested that these compounds markedly prevented neutrophils migration into the skin which is considered to be one the major factors in photoaging
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