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 NFB 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]]
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