Theophylline is used primarily as a bronchodilating agent for therapy of asthma. Over the therapeutic range there is a reasonably linear correlation between dosage and therapeutic effect. The drug is administered intravenously and orally. Oral medication is available in regular (noncoated or liquid) and slow-release (SR) forms. SR forms are available in twice-daily, and even once-daily, dosages. For most (but not all) regular oral preparations, absorption takes place predominantly in the small intestine, absorption is essentially

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complete, and food usually does not interfere significantly. Absorption rates are more apt to vary, and time to serum peak is less predictable among the different SR preparations. In addition, food (especially a high-fat meal) is more likely to interfere with absorption of some SR preparations. One investigator recommends dose intake 1 hour before or 2 hours after meals when using SR preparations influenced by food. For the regular oral medication, time to peak (for adults) is about 2-3 hours, half-life is 4-6 hours (range, 3-8 hours) and time to steady state is about 15-20 hours. For children, half-life is more variable (1-8 hours) and time to steady state is also more variable (5-40 hours). Time to peak for the oral SR preparation is about 5 hours. About 50%-60% (range, 40%-65%) of theophylline is bound to serum albumin. Binding is less in neonates and at lower pH (acidosis). About 90% is metabolized in the liver, and most of the metabolites, plus about 10%-15% of unchanged theophylline, is excreted by the kidneys. Therefore, except in the first several months of life, renal function is not a major factor in theophylline serum concentration. Adults who smoke tobacco or marijuana and children excrete theophylline somewhat more rapidly (decreased serum half-life) than nonsmoking adults. Factors that reduce theophylline clearance (increased serum half-life) include young infants (ages 0-8 months), congestive heart failure, cor pulmonale, severe liver dysfunction, sustained fever, pneumonia, obesity, cessation of smoking, cimetidine, ciprofloxacin, and erythromycin family antibiotics. Some theophylline assay methods may show partial interference (some false increase in values) from substances present in uremia. Children show more individual differences in theophylline clearance and as a group eliminate theophylline more rapidly than adults. In addition, one report indicated that in children a high-protein diet increased theophylline elimination and a high-carbohydrate diet decreased it.

Besides the factors just mentioned, therapy is complicated by the many theophylline preparations available, many of which vary significantly in theophylline content and the rate it is absorbed. Noncompliance is a constant problem in therapy and in the interpretation of theophylline blood levels, because low levels due to noncompliance may be misinterpreted as due to rapid metabolism or excretion. The reverse mistake can also be made. Another difficulty is the asthmatic who may already have taken one or more extra doses of theophylline before being seen by the physician.

There is a relatively narrow zone between therapeutic range (10-20 µg/ml; 55-110 µmol/L) and values associated with toxicity. The degree of elevation over reference range is not a reliable predictor of toxicity risk except in a very general way, since severe toxicity can develop in some patients at less than twice the upper limit of the reference range. Although there are mild toxic symptoms, severe toxicity may develop without warning. If there is a question about previous drug intake, a specimen for theophylline assay should be obtained before therapy is begun. Therapy can then be started and the dosage modified when assay results become available. Thereafter, when steady state is achieved, serum peak concentration should be measured (30 minutes after the dose for IV theophylline, 2 hours after the dose for regular theophylline, and about 5 hours [range, 3-7 hours, depending on the particular medication] after the dose for sustained-release forms). Theophylline is thus an exception to the general rule that the residual (trough) level is better than the peak level to monitor therapy.