- Author: Greg Hymel, MD; Chief Editor: Asim Tarabar, MD more...
Theophylline (1,3-dimethylxanthins) can indirectly stimulate both β1 and β2 receptors through release of endogenous catecholamines. It is used for the treatment of pulmonary conditions, including asthma and chronic obstructive pulmonary disease (COPD). In neonates, theophylline can be used for the treatment of apnea.
Medication, diet, and underlying diseases can alter its narrow therapeutic window. Adverse effects can be evident at therapeutic serum levels. The use of theophylline for the treatment of asthma and chronic obstructive pulmonary disease has decreased significantly in recent years. This has greatly decreased the incidence of theophylline overdose.
Major mechanisms of theophylline therapeutic efficacy and its toxicity are through the excess of catecholamines and adenosine antagonism. Adenosine blockade can theoretically reduce histamine release and indirectly reverse bronchospasm. In addition, high levels of theophylline inhibit phosphodiesterase, resulting in elevation of cyclic adenosine monophosphate (cAMP) and consequent adrenergic stimulation.
Theophylline is absorbed rapidly and completely after oral administration. Peak serum levels for immediate release preparations are relatively rapid and can range from 30-120 minutes. Fasting or large volumes of fluid enhance absorption. Enteric-coated and sustained-release tablets have a delayed absorption with peak between 6 and 10 hours. It is important to recognize that these time intervals are much longer in the setting of overdose. The intravenous form of theophylline (aminophylline) reaches peak serum levels in 30 minutes.
Theophylline is around 60% protein bound and has a distribution volume of 0.5 L/kg. Therapeutic serum levels range from 10-20 mcg/mL. Toxic levels are considered to be higher than 20 mcg/mL; however, adverse effects may be evident within the normal therapeutic range. Severe complications including cardiac dysrhythmias, seizures, and death can be observed with the levels of 80-100 mcg/mL. In chronic exposure, those levels could be lower (40-60 mcg/mL).
Theophylline is eliminated by the hepatic cytochrome P-450 system (85-90%) and by urinary excretion (10-15%). The half-life is 4-8 hours in young adults and is shorter in children and smokers. Diet, cardiac or liver disease, tobacco use, and medications (cimetidine, erythromycin, oral contraceptives) affecting the cytochrome P-450 system (CYP1A2) can affect the half-life.
Theophylline affects the cardiovascular (CV), central nervous (CN), gastrointestinal (GI), pulmonary, musculoskeletal, and metabolic systems. Hypokalemia, hyperglycemia, hypercalcemia, hypophosphatemia, and acidosis commonly occur after an acute overdose.
The 2014 annual report of the American Association of Poison Control Centers' National Poison Data System documented 133 exposures to theophylline, with 14 in children younger than 6 years and 107 in persons older than 19 years. Of the 81 theophylline exposures treated in health care facilities, eight were reported to have major adverse outcomes and two deaths were noted. Documented toxic exposures have decreased markedly over the past decade as the use of theophylline for the management of asthma has diminished.
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