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Theophylline
From Wikipedia, the free encyclopedia
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Theophylline
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| Systematic (IUPAC) name | |
| 1,3-dimethyl-7H-purine-2,6-dione | |
| Identifiers | |
| CAS number | |
| ATC code | R03 |
| PubChem | |
| DrugBank | |
| Chemical data | |
| Formula | C7H8N4O2 |
| Mol. mass | 180.164 g/mol |
| SMILES | search in , |
| 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. | |
| Legal status |
P(UK) |
| 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 used clinically. 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 are:
- relaxing of bronchial smooth muscle
- positive inotropic (increasing heart muscle contractility and efficiency)
- positive chronotropic (increasing heart rate)
- increase of blood pressure
- increase of renal blood flow
- some anti-inflammatory effects
- central nervous system stimulatory effect mainly on the medullary respiratory center.
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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.
Bioavailability = 100%. However, taking the drug late in the evening may slow the absorption process, without affecting the bioavailability. Taking the drug after a fat meal will also slow down the absorption process, without affecting the bioavailability. There is one exception. Taking UniphylTM, a long-acting theophylline formulation, after a fat meal will increase its bioavailability.
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 these conditions : neonates, cirrhosis, malnutrition. The volume of distribution may decrease in this condition : obesity.
It is metabolized extensively in the liver (up to 90%). It undergoes N-demethylation via cytochrome P450 1A2. It is metabolized by parallel first order and Michaelis-Menton 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.
It 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, kystic 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 may change. 30 hours, premature neonates; 24 hours, neonates; 3,5 hours, children 1 to 9; 8 hours, adults non-smokers; 5 hours, adults smokers; 24 hours, hepatic impairment; 12 hours, congestive heart failure NYHA class I-II; 24 hours, congestive heart failure NYHA class III-IV; 12 hours, elderly.
The main therapeutic uses of theophylline are:
- chronic obstructive diseases of the airways
- chronic obstructive pulmonary disease (COPD)
- bronchial asthma
- infant apnea
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. Many of its cardiac effects and some of its anti-asthmatic effects can be explained through this.
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.[3][4][5]
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 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.[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 rewound around histones and 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.
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. Its toxicity is increased by erythromycin, cimetidine and fluoroquinolones. It can reach toxic levels when taken with fatty meals, an effect called dose dumping.[9]
Theophylline can be prepared synthetically starting from dimethylurea and ethyl 2-cyanoacetate. 
- ^ 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
- ^ Food-induced "dose-dumping" from a once-a-day theophylline product as a cause of theophylline toxicity.
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| Adrenergics, inhalants | Short acting β2-agonists: Salbutamol/Levosalbutamol • Fenoterol • Terbutaline Long acting β2-agonists (LABA): Bambuterol • Clenbuterol • Formoterol • Salmeterol other: Epinephrine • Isoproterenol • Orciprenaline |
| Glucocorticoids | Beclometasone • Budesonide • Ciclesonide • Fluticasone • Mometasone |
| Anticholinergics | Ipratropium • Tiotropium |
| Mast cell stabilizers | Cromoglicate • Nedocromil |
| Xanthines | Aminophylline • Theobromine • Theophylline |
| Leukotriene antagonists | Montelukast • Pranlukast • Zafirlukast |
| Combination products | Budesonide/formoterol • Fluticasone/salmeterol • Ipratropium/salbutamol |