Theophylline

Theophylline, also known as 1,3-dimethylxanthine, is a methylxanthine drug used in therapy for respiratory diseases such asCOPD 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.

Adverse effects[edit]

The use of theophylline is complicated by its interaction with various drugs, chiefly as cimetidine and phenytoin, and that it has a narrow therapeutic index, so 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, arrhythmias, and CNS excitation (headaches, insomnia, irritability, dizziness andlightheadedness).^[3][4] Seizures can also occur in severe cases of toxicity and is considered to be a neurological emergency.^[5] Its toxicity is increased by erythromycin, cimetidine, and fluoroquinolones, such as ciprofloxacin. It can reach toxic levels when taken with fatty meals, an effect called dose dumping.^[6] Theophylline toxicity can be treated with beta blockers. In addition to seizures, tachyarrhythmias are a major concern.^[7]

Mechanisms of action[edit]

Like other methylated xanthine derivatives, theophylline is both a

1. competitive nonselective phosphodiesterase inhibitor,^[8] which raises intracellular cAMP, activates PKA, inhibits TNF-alpha^[9][10] and inhibits leukotriene ^[11] synthesis, and reduces inflammation and innate immunity ^[11]
2. nonselective adenosine receptor antagonist,^[12] 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.^[13]

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.^[14]Furthermore, theophylline has been shown to directly activate HDAC2.^[14] (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 asNF-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.) Thus theophylline could prove to be a novel form of adjunct therapy in improving the clinical response to steroids in smoking asthmatics.