Pharmacodynamics Like other methylated xanthine derivatives,<unk>  is both a # competitive nonselective phosphodiesterase inhibitor, which raises intracellular cAMP, activates PKA, inhibits TNF-alpha and inhibits leukotriene synthesis, and reduces inflammation and innate immunity # nonselective adenosine receptor antagonist, antagonizing A1, A2, and A3 receptors almost equally, which explains many of its cardiac effects<unk>  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<unk> e protein collagen. It has been shown<unk> at<unk>  may reverse<unk> e 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.<unk>  in vitro can restore<unk> e reduced HDAC (histone deacetylase) activity<unk> at is induced by oxidative stress (i.e., in smokers), returning steroid responsiveness toward normal. Furthermore,<unk>  has been shown to directly activate HDAC2. (Corticosteroids switch off<unk> e inflammatory response by blocking<unk> e expression of inflammatory mediators<unk> rough deacetylation of histones, an effect mediated via histone deacetylase-2 (HDAC2). Once deacetylated, DNA is repackaged so<unk> at<unk> e promoter regions of inflammatory genes are unavailable for binding of transcription factors such as NF-κB<unk> at act to turn on inflammatory activity. It has recently been shown<unk> at<unk> e oxidative stress associated with cigarette smoke can inhibit<unk> e activity of HDAC2,<unk> ereby blocking<unk> e anti-inflammatory effects of corticosteroids.) Pharmacokinetics Absorption When<unk>  is administered intravenously, bioavailability is 100%. Distribution<unk>  is distributed in<unk> e extracellular fluid, in<unk> e placenta, in<unk> e mother's milk and in<unk> e central nervous system.<unk> e volume of distribution is 0.5 L/kg.<unk> e protein binding is 40%.<unk> e volume of distribution may increase in neonates and<unk> se suffering from cirrhosis or malnutrition, whereas<unk> e volume of distribution may decrease in<unk> se who are obese. Metabolism<unk>  is metabolized extensively in<unk> e 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<unk> e<unk> erapeutic range. Small dose increases may result in disproportionately large increases in serum concentration. Methylation to caffeine is also important in<unk> e infant population. Smokers and people with hepatic (liver) impairment metabolize it differently. Both<unk> C and nicotine have been shown to increase<unk> e rate of<unk>  metabolism. Excretion<unk>  is excreted unchanged in<unk> e urine (up to 10%). Clearance of<unk> e drug is increased in children (age 1 to 12), teenagers (12 to 16), adult smokers, elderly smokers, as well as in cystic fibrosis, and hyperthyroidism. Clearance of<unk> e drug is decreased in<unk> ese conditions: elderly, acute congestive heart failure, cirrhosis, hypothyroidism and febrile viral illnesses.<unk> e 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<unk> se with hepatic impairment, 12 hours for<unk> se with congestive heart failure NYHA class I-II, 24 hours for<unk> se with congestive heart failure NYHA class III-IV, 12 hours for<unk> e elderly.
Theophylline
Tiotropium bromide
Salbutamol
Fluticasone
Roflumilast
Levosalbutamol
Formoterol
Arformoterol