Theophylline Level

Theophylline is a methylxanthine, a class of molecule similar to the xanthines caffeine and theobromine found in a normal diet. ^{[1, 2]} It has a half-life of 8 hours in a healthy person but decreases to 4-5 hours in people who smoke. ^[3] In the blood, 40-50% of theophylline is bound to proteins.

The reference therapeutic ranges of theophylline are listed below.

Reference ranges of theophylline in the treatment asthma vary by age, as follows:

• Adults: 5-15 µg/mL

• Children: 5-10 µg/mL

The reference range of theophylline in the treatment of acute bronchospasm in adults is 10-15 µg/mL.

The reference range of theophylline in the treatment of neonatal apnea is 6-11 µg/mL.

Serum values of theophylline that fall within the established reference ranges allow for the desired therapeutic effect while minimizing the drug’s side effects. ^[1] It also lets the clinician know when the dose of theophylline can be adjusted within this range to achieve a therapeutic effect if the patient is still experiencing symptoms.

A low level of theophylline may not produce the desired outcome. Values below 10 µg/mL have small effects on bronchospasm, and those below 5 µg/mL may not offer benefit in the treatment of asthma. ^[1]

Increased clearance of theophylline and the low levels that result are caused by the consumption of barbecued meats; youth (age 1-16 years); low-carbohydrate, high-protein diets; acidosis; and smoking cigarettes and marijuana. ^{[1, 4, 5]} Concomitant administration of phenytoin, phenobarbital, and rifampin can lead to increased clearance of and therefore low levels of theophylline. ^{[1, 4]}

High serum theophylline levels increase the risk of toxicity. Toxic effects include nausea and vomiting, headaches, gastric discomfort, diuresis, insomnia, cardiac arrhythmias, behavioral disturbances, and epileptic seizures. ^{[1, 4, 6]}

Decreased theophylline clearance and the resulting higher-than-predicted serum levels of the drug are caused by pneumonia; heart failure; infections; influenza vaccination; liver disease; chronic obstructive pulmonary disease (COPD); obesity; a high-carbohydrate, low-protein diet; high levels of dietary methylxanthines (eg, caffeine); and the extremes of age (ie, age 0-1 years and elderly). ^{[1, 4, 5]} Administration of allopurinol, oral contraceptives, cimetidine, erythromycin, quinolone antibiotics, fluvoxamine, zileuton, and zafirlukast has been shown to increase theophylline levels. ^{[1, 4, 5]}

Specimen: Blood

Container: Red-top tube, light-green–top tube

Method: Routine venipuncture

In order to accurately measure serum theophylline levels after oral administration, blood should be drawn 3 days after the initiation of therapy or dose change, when the steady-state peak blood concentration has been reached. This assumes that no doses have been missed or added and that none have been taken at unequal intervals. ^[7] Once this steady state has been achieved, theophylline levels should be measured 1-2 hours after administration of an oral solution or immediate-release tablet or 4-12 hours after administration of an extended-release tablet. ^[7]

If the drug is given intravenously, a sample should be drawn 30 minutes after completion of a loading dose to determine if concentrations are less than 10 µg/mL, indicating the need for another loading dose, or greater than 20 µg/mL, indicating the need for delay in initiating maintenance intravenous therapy. ^[8]

Description

Theophylline is a methylxanthine, a class of molecule similar to the xanthines caffeine and theobromine found in a normal diet. ^[1] It has a half-life of 8 hours in a healthy person but decreases to 4-5 hours in people who smoke. ^[3] In the blood, 40%-50% of theophylline is bound to proteins.

Theophylline is metabolized in the liver by the hepatic P450 system enzymes CYP1A2 and CYP3A4 into its metabolites 1,3-dimethyluric acid, 1-methyluric acid, and 3-methylxanthine before being excreted in the urine. ^[3]

Mechanisms of action

There is no single accepted mechanism of action for theophylline, although many have been proposed.

First and foremost, theophylline is a bronchodilator but also has many molecular-level actions that still may be useful in the treatment of airway disease.

Theophylline nonselectively inhibits phosphodiesterases, which elevates cellular levels of cAMP and cGMP, accounting for the bronchodilator effect seen in the treatment of asthma and COPD. Therapeutic levels of theophylline also antagonize adenosine receptors, also contributing to bronchodilation, since adenosine causes bronchoconstriction in persons with asthma via the release of histamine and leukotrienes.

Theophylline has also been shown to increase the release of interleukin-10, which has many anti-inflammatory effects. Higher theophylline concentrations and inhibition of phosphodiesterase affect gene transcription by preventing translocation of the pro-inflammatory transcription factor NF-kB to the nucleus via a protective effect on the degradation of the inhibitory protein I-kba.

Theophylline has also been shown, in vitro, to promote apoptosis in eosinophils and neutrophils, the cells that perpetuate chronic inflammation in asthma and COPD.

Theophylline also activates histone deacetylase, which enhances the anti-inflammatory effects of corticosteroids, which are often used simultaneously in the treatment of asthma and COPD.

Finally, theophylline has some less-understood and less-studied effects at higher-than-therapeutic concentrations, such as increasing circulating catecholamines, inhibiting calcium influx into inflammatory cells, inhibiting prostaglandin effects, and antagonizing tumor necrosis factor-alpha. ^[1]

Comparison of methylxanthines

A literature review by Rogliani et al indicated that, compared with theophylline, the methylxanthine doxofylline is a safer and more effective asthma therapy. The investigators reported that with regard to efficacy in reducing daily asthma events, the mean difference between doxofylline and theophylline was -0.14, while doxofylline had a relative risk of adverse events, compared with theophylline, of 0.76. However, doxofylline and theophylline did not significantly differ in terms of improving forced expiratory volume in 1 second (FEV₁). ^[9]

Another study, a pooled analysis by Calzetta et al of two double-blind, randomized, placebo-controlled trials, did not find that doxofylline and theophylline differed significantly in improvement of the asthma event rate, but, like the Rogliani study, indicated that the risk of adverse events was greater with theophylline. ^[10]

Indications/Applications

Measuring serum theophylline levels is indicated when initiating therapy to guide final dosage adjustments after titration, before increasing the dosage in patients with persistent symptoms, if manifestations of toxicity are present, upon new or worsening illness, or when a change in treatment regimen alters theophylline clearance. ^{[7, 8]}