Theophylline 62996 220044625 2008-06-18T00:55:31Z Sbmehta 765172 capitalization {{drugbox | IUPAC_name = 1,3-dimethyl-7H-purine-2,6-dione | image = Theophyllin_-_Theophylline.svg | image2 = Theophylline-3D-balls.png | width = 167 | CAS_number = 58-55-9 | ATC_prefix = R03 | ATC_suffix = DA04 | ATC_supplemental = | PubChem = 2153 | DrugBank = APRD00082 | smiles = CN1C(=O)N(C)c2nc[nH]c2C1=O | C=7 | H=8 | N=4 | O=2 | molecular_weight = 180.164 g/mol | bioavailability = 100% | protein_bound = 40%, primarily to albumin | metabolism = [[hepatic]] to 1-methyluric acid | elimination_half-life = 5-8 hours | pregnancy_AU = A | pregnancy_US = C | pregnancy_category = | legal_AU = | legal_CA = | legal_UK = P | legal_US = Rx | legal_status = | routes_of_administration = oral, [[intravenous|IV]] }} '''Theophylline''', also known as '''dimethylxanthine''', is a [[methylxanthine]] drug used in therapy for [[respiratory disease]]s 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),<ref>[http://archive.food.gov.uk/maff/archive/food/infsheet/1997/no103/table2a.htm MAFF Food Surveillance Information Sheet]</ref> significantly less than therapeutic doses.<ref>[http://www.rxlist.com/cgi/generic/theosr_ids.htm RXlist dosage and administration information for theophylline]</ref> 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 [[kidney|renal]] blood flow * some [[inflammation|anti-inflammatory]] effects * [[central nervous system]] stimulatory effect mainly on the medullary [[respiratory center]]. ==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 Uniphyl<sup>TM</sup>, 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 pathway|first order]] and [[Michaelis-Menten kinetics|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]] * [[Apnea of prematurity|infant apnea]]. ==Mechanisms of action== The main [[mechanism of action]] of theophylline is that of [[adenosine receptor]] [[receptor antagonist|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]] [[enzyme]]s, producing an increase in intracellular [[cyclic AMP]]; however, this is not known with certainty.<ref>[http://www.priory.com/cmol/theo.htm Theophylline at Priory.com]</ref><ref>{{cite journal |author=Ito K, Lim S, Caramori G, ''et al'' |title=A molecular mechanism of action of theophylline: Induction of histone deacetylase activity to decrease inflammatory gene expression |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue=13 |pages=8921–6 |year=2002 |pmid=12070353 |doi=10.1073/pnas.132556899}}</ref><ref>[http://www.rxlist.com/cgi/generic/theosr_cp.htm RxList.com]</ref> 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]].<ref>Yano, Biochem and Biophys Res Comm V341-3, 2006</ref> 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.<ref>Ito et al., 2002a</ref> Furthermore, theophylline has been shown to directly activate [[HDAC2]].<ref>Ito et al., 2002b</ref> ([[Corticosteroid]]s 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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.{{Fact|date=March 2008}} ==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]]) <ref>[http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a681006.html MedlinePlus Drug Information: Theophylline<!-- Bot generated title -->]</ref><ref>[http://www.medicinenet.com/theophylline-oral_24_hour_tablet/article.htm THEOPHYLLINE - ORAL 24 HOUR TABLET (Uni-Dur) side effects, medical uses, and drug interactions<!-- Bot generated title -->]</ref>. Its toxicity is increased by [[erythromycin]], cimetidine, and [[fluoroquinolones]]. It can reach toxic levels when taken with fatty meals, an effect called [[dose dumping]].<ref>[http://www.chestjournal.org/cgi/content/abstract/87/6/758 Food-induced "dose-dumping" from a once-a-day theophylline product as a cause of theophylline toxicity].</ref> == Synthesis == Theophylline can be prepared synthetically starting from dimethylurea and ethyl 2-cyanoacetate.<br/> [[Image:Theophylline synthesis.png]] ==References== {{Reflist}} {{Asthma and copd rx}} [[Category:Xanthines]] [[Category:Bronchodilators]] [[Category:Bitter compounds]] [[de:Theophyllin]] [[es:Teofilina]] [[fr:Théophylline]] [[gl:Teofilina]] [[it:Teofillina]] [[hu:Teofillin]] [[ja:テオフィリン]] [[pl:Teofilina]] [[pt:Teofilina]] [[ro:Teofilină]] [[ru:Теофиллин]] [[sk:Teofylín]] [[fi:Teofylliini]] [[sv:Teofyllin]] [[uk:Теофілін]] [[zh:茶碱]]