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20-September-2008 09:55:50 - Theophylline Theophylline Systematic IUPAC name 1,3-dimethyl-7H-purine-2,6-dione Identifiers CAS number 58-55-9 ATC code R03DA04 PubChem 2153 DrugBank APRD00082 Chemical data Formula C7H8N4O2 Mol. mass 180.164 g/mol SMILES eMolecules PubChem Pharmacokinetic data Bioavailability 100% Protein binding 40%, primarily to albumin Metabolism hepatic to 1-methyluric acid Half life 5-8 hours Excretion ? Therapeutic considerations Pregnancy cat. AAU CUS Legal status PUK â„ž-onlyUS Routes oral, IV Theophylline, also known as dimethylxanthine, is a methylxanthine drug used in therapy for respiratory diseases such as COPD or asthma under a variety of brand names. Due to its numerous side-effects, these drugs are now rarely administered for clinical use. As a member of the xanthine family, it bears structural and pharmacological similarity to caffeine. It is naturally found in tea, although in trace quantities ~1 mg/L,1 significantly less than therapeutic doses.2 The main actions of theophylline involve: relaxing bronchial smooth muscle increasing heart muscle contractility and efficiency: positive inotropic increasing heart rate: positive chronotropic increasing blood pressure increasing renal blood flow some anti-inflammatory effects central nervous system stimulatory effect mainly on the medullary respiratory center. Contents 1 History 2 Pharmacokinetics 2.1 Absorption 2.2 Distribution 2.3 Metabolism 2.4 Elimination 3 Indications 4 Mechanisms of action 5 Side-effects 6 Synthesis 7 References History Theophylline was first extracted from tea leaves around 1888 by the German biologist Albrecht Kossel. The drug was chemically identified in 1896, and eventually it was synthesized by another German scientist, Wilhelm Traube. Theophylline's first clinical use in asthma treatment came in the 1950s. Pharmacokinetics Absorption Bioavailability is 100%. However, taking the drug late in the evening may slow the absorption process, without affecting the bioavailability. Taking the drug after a meal high in fat content will also slow down the absorption process, without affecting the bioavailability. There is one exception. Taking UniphylTM, a long-acting theophylline formulation, after a meal high in fat content will increase its bioavailability. Distribution 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 suffering from obesity. Metabolism 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 in caffeine is also important in the infant population. Smokers and people with hepatic liver impairment metabolize it differently. Elimination Theophylline is excreted unchanged in the urine up to 10%. Clearance of the drug is increased in these conditions: children 1 to 12, teenagers 12 to 16, adult smokers, elderly smokers, cystic fibrosis, 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. Indications The main therapeutic uses of theophylline are aimed at: chronic obstructive diseases of the airways chronic obstructive pulmonary disease COPD bronchial asthma infant apnea. Mechanisms of action The main mechanism of action of theophylline is that of adenosine receptor antagonism. Theophylline is a non-specific adenosine antagonist, antagonizing A1, A2, and A3 receptors almost equally, which explains many of its cardiac effects and some of its anti-asthmatic effects. Another proposed mechanism of action includes a non-specific inhibition of phosphodiesterase enzymes, producing an increase in intracellular cyclic AMP; however, this is not known with certainty.345 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.6 It has been shown that theophylline may reverse the clinical observations of steroid insensitivity in patients with COPD and asthmatics that 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.7 Furthermore, theophylline has been shown to directly activate HDAC2.8 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 NFï?«B 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. Thus theophylline could prove to be a novel form of adjunct therapy in improving the clinical response to steroids in smoking asthmatics.citation needed Side-effects The use of theophylline is complicated by the fact that it interacts with various drugs, chiefly cimetidine and phenytoin, and that it has a narrow therapeutic index, so its use must be monitored to avoid toxicity. It can also cause nausea, diarrhea, increase in heart rate, arrhythmias, and CNS excitation headaches, insomnia, irritability, dizziness and lightheadedness 910. Its toxicity is increased by erythromycin, cimetidine, and fluoroquinolones. It can reach toxic levels when taken with fatty meals, an effect called dose dumping.11 Synthesis Theophylline can be prepared synthetically starting from dimethylurea and ethyl 2-cyanoacetate. Image:Theophylline synthesis.png References ^ MAFF Food Surveillance Information Sheet ^ RXlist dosage and administration information for theophylline ^ Theophylline at Priory.com ^ Ito K, Lim S, Caramori G, et al 2002. A molecular mechanism of action of theophylline: Induction of histone deacetylase activity to decrease inflammatory gene expression. Proc. Natl. Acad. Sci. U.S.A. 99 13: 8921-6. doi:10.1073/pnas.132556899. PMID 12070353. ^ RxList.com ^ Yano, Biochem and Biophys Res Comm V341-3, 2006 ^ Ito et al., 2002a ^ Ito et al., 2002b ^ MedlinePlus Drug Information: Theophylline ^ THEOPHYLLINE - ORAL 24 HOUR TABLET Uni-Dur side effects, medical uses, and drug interactions ^ Food-induced dose-dumping from a once-a-day theophylline product as a cause of theophylline toxicity. v d e Drugs for obstructive airway diseases: asthma/COPD R03 Adrenergics, inhalants Short acting β2-agonists Salbutamol/Levosalbutamol Fenoterol Terbutaline Pirbuterol Procaterol Bitolterol Rimiterol Carbuterol Tulobuterol Reproterol Long acting β2-agonists LABA Arformoterol Bambuterol Clenbuterol Formoterol Salmeterol Ultra LABA: Indacaterol other Epinephrine Hexoprenaline Isoprenaline Isoproterenol Orciprenaline Metaproterenol Glucocorticoids Beclometasone Budesonide Ciclesonide Fluticasone Mometasone Anticholinergics/ muscarinic antagonist Ipratropium Tiotropium Mast cell stabilizers Cromoglicate Nedocromil Xanthines Aminophylline Doxofylline Theobromine Theophylline Leukotriene antagonists Montelukast Pranlukast Zafirlukast Lipoxygenase inhibitor Zileuton Thromboxane receptor antagonists Ramatroban Seratrodast Combination products Budesonide/formoterol Fluticasone/salmeterol Ipratropium/salbutamol Retrieved from http://en..org/wiki/Theophylline Categories: Xanthines | Bronchodilators | Bitter compoundsHidden categories: All articles with statements | Articles with statements since March 2008 Views Article Discussion this page History Personal tools Log in / create account Navigation Main page Contents Featured content Current events Random article Search Go Search Interaction Community portal Recent changes Contact Donate to Help Toolbox What links here Related changes Upload file Special pages Printable version Permanent link Cite this page Languages Deutsch Español Français Galego Italiano Magyar 日本語 Polski Português Română РуÑ?Ñ?кий SlovenÄ?ina Suomi Svenska УкраїнÑ?ька ä¸æ–‡ This page was last modified on 18 June 2008, at 00:55
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