14 Aug

Canadian Health and Care Mall: Pharmacodynamics of Theophylline

antiasthmatic effectAsthma

The various studies published on the efficacy and toxicity of theophylline have led to a carefully defined range of serum concentrations, between 10 and 20 fjig/ml, where there is an optimal likelihood of maximal safe effect. It is this optimal range for maximal safe effect that has been commonly termed the “therapeutic range. The connotations of this term have sometimes been misinterpreted to suggest that there is no effect from theophylline at serum concentrations under 10 fJtg/ml and no farther potential for antiasthmatic effect at serum concentrations over 20 jig/ml. Even a cursory examination of the literature, however, would argue that this is not so. A measurable effect of theophylline is apparent at lower serum concentrations, and higher serum concentrations almost certainly would provide more effect for some patients.

However, the studies that have argued for a downward extension of the therapeutic range to 5 jig/ml generally have been limited to demonstration of a bronchodilator effect or some decrease in symptoms at lower serum concentrations and have not demonstrated that the measurable effects were indeed maximal or, alternatively, associated with a lower frequency of side effects than serum concentrations within the 10 to 20 |xg/ml range. Moreover, no studies examining the efficacy of serum concentrations less than 10 |xg/ml have demonstrated the remarkably high degree of efficacy of theophylline in preventing symptoms that interfere with sleep, reduction in need for emergency medications including corticosteroids, and blocking of exercise-induced bronchospasm documented exercise-induced bronchospasmat concentrations above 10 |xg/ml. As to the argument that more effects might be attained for some patients at serum concentrations over 20 |xg/ml, it is acknowledged that this may be so, but not with adequate safety. The 10 to 20 |xg/ml range for serum concentrations most likely to obtain maximal safe clinical effect is well supported by multiple clinical studies and by considerable clinical experience by many clinicians over the past ten years. It appears that to some extent efforts to promote a wider therapeutic range, ie, 5 to 20 |xg/ml, have been motivated by drug companies whose products and/or dosing interval recommendations cannot maintain concentrations within the 10 to 20 |ig/ml range around the clock.

Similarly, arguments for using “low-dose” theophylline in combination with an oral (32 agonist have been based on single-dose studies demonstrating additive bronchodilator effects. There are no studies comparing the relative efficacy and safety of the combination with carefully titrated doses of theophylline alone in suppressing the frequency and severity of asthmatic symptoms. This would be particularly important, since the intensity and duration of bronchodilatation decreases with continued use of oral fj2 agonists, and exercise-induced bronchospasm is not inhibited when these drugs are given orally. Last, on an annual basis, the combination therapy is more expensive and less convenient than a slow-release theophylline product used alone in individualized doses, even when the cost of serum level measurements is included. Theophylline is usually used in asthma treatment. It is the most effective component of ihalers. If you are interested in the idea of knowing more about asthma and other diseases you are welcome More info about diseases and hot news – Canadian health&care Mall – chcm4you.com.

Thus, the issue then is no longer whether or not to target 10 to 20 jig/ml range when optimal likelihood of safe maximal effect is desired, but how to attain, maintain, and sustain these serum concentrations given the interpatient variability, the range of available products, and the realities of patients lifestyles.


Although a definite relationship exists between serum concentration and effect in patients with asthma, serum concentrations correlate poorly with pulmonary function in patients with COPD. Moreover, several double-blind, placebo-controlled studies* have demonstrated little or no difference in symptom control between placebo and theophylline at serum concentrations >10 fig/ml (Fig 1). Jenne et al, for example, investigated the effect of theophylline in patients with emphysema during rest (standing) and exercise (walking). Theoretically, any potential benefit would be most noticeable COPD during walking, since patients with COPD experience a large increase in the work of breathing, particularly during exercise. They found a modest increase in FEVj, a small decrease in lung work, and slight subjective improvement during theophylline at a mean concentration of 12 fxg/ml, but neither spirometric nor subjective improvement correlated with the decrease in lung work. Patients preferred theophylline over placebo in this double-blind study, but the possibility that theophylline altered the perception of dyspnea was not excluded. In another study of COPD patients, where reversible airways obstruction was carefully excluded, theophylline decreased dyspnea to a small and significant degree but did not alter exercise performance. Thus, effects of theophylline can be demonstrated in COPD patients, but there is no evidence that these effects are clinically important in the overall management of this disease. Effects on diaphragmatic contractility, work of breathing, biventricular performance, and stimulation of hypoxic drive might offer some benefit in treating or preventing respiratory failure associated with COPD, but there are no controlled studies to support this conjecture.

Since theophylline is a potentially toxic drug, particularly in COPD patients, who may be more sensitive to its arrythmogenic effects and at risk of accumulating excessive serum concentrations as a result of impaired metabolism from cor pulmonale, the small potential benefit must be weighed against the potential risk of toxicity. If it is used in COPD, greater caution must be exercised to prevent accumulation of toxic serum concentrations. In such patients, it might be prudent to maintain serum concentrations at the lower end of the therapeutic range.


Figure 1. Mean symptom scores from patients with COPD who received placebo and individualized oral doses of theophylline, each for one month, in a double-blind, cross-over manner. (Reproduced with permission of Journal of American Medical Association.)

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