Twenty years ago theophylline (Theo-Dur, Slo-bid, Uniphyl, Theo-24) and its more soluble ethylenedi-amine salt, aminophylline, were the bronchodilators of choice in the United States. Although the β2-adreno-ceptor agonists now fill this primary role, theophylline continues to have an important place in the therapy of asthma because it appears to have antiinflammatory as well as bronchodilator activity.
Smooth muscle relaxation, central nervous system (CNS) excitation, and cardiac stimulation are the prin-cipal pharmacological effects observed in patients treated with theophylline. The action of theophylline on the respiratory system is easily seen in the asthmatic by the resolution of obstruction and improvement in pul-monary function. Other mechanisms that may con-tribute to the action of theophylline in asthma include antagonism of adenosine, inhibition of mediator re-lease, increased sympathetic activity, alteration in im-mune cell function, and reduction in respiratory muscle fatigue. Theophylline also may exert an antiinflamma-tory effect through its ability to modulate inflammatory mediator release and immune cell function.
Inhibition of cyclic nucleotide phosphodiesterases is widely accepted as the predominant mechanism by which theophylline produces bronchodilation. Phos-phodiesterases are enzymes that inactivate cAMP and cyclic guanosine monophosphate (GMP), second mes-sengers that mediate bronchial smooth muscle relax-ation.
The principal use of theophylline is in the management of asthma. It is also used to treat the reversible compo-nent of airway obstruction associated with chronic ob-structive pulmonary disease and to relieve dyspnea as-sociated with pulmonary edema that develops from congestive heart failure.
Theophylline has a narrow therapeutic index and pro-duces side effects that can be severe, even life threaten-ing. Importantly, the plasma concentration of theo-phylline cannot be predicted reliably from the dose. In one study, the oral dosage of theophylline required to produce therapeutic plasma levels (i.e., between 10 and 20 μg/mL) varied between 400 and 3,200 mg/day. Heterogeneity among individuals in the rate at which they metabolize theophylline appears to be the principal factor responsible for the variability in plasma levels. Such conditions as heart failure, liver disease, and se-vere respiratory obstruction will slow the metabolism of theophylline.
The most frequent complaints of patients taking theo-phylline are nausea and vomiting, which occur most fre-quently in patients receiving theophylline for the first time and when the plasma level approaches 20 μg/mL but rarely occur at plasma concentrations below 15 μg/mL. The fact that patients who receive the drug intravenously also have the same complaint suggests that the nausea and vomiting result from an action in the CNS.
When serum concentrations exceed 40 μg/mL, there is a high probability of seizures. Nausea will not always be a premonitory sign of impending toxicity. For in-stance, in children, restlessness, agitation, diuresis, or fever can occur even when nausea does not. A rapid in-travenous injection of theophylline can cause arrhyth-mias, hypotension, and cardiac arrest. Thus, extreme caution should be used when giving the drug by this route. Since it is not possible to predict blood levels on the basis of dosage, toxicity is fairly common by any route of administration. Consequently, plasma concen-trations of theophylline should be determined when a patient begins therapy and then at regular intervals of 6 to 12 months thereafter.
Theophylline should be used with caution in pa-tients with myocardial disease, liver disease, and acute myocardial infarction. The half-life of theophylline is prolonged in patients with congestive heart failure. Because of its narrow margin of safety, extreme caution is warranted when coadministering drugs, such as cime-tidine or zileuton, that may interfere with the metabo-lism of theophylline. Indeed, coadministration of zileu-ton with theophylline is contraindicated. It is also prudent to be careful when using theophylline in pa-tients with a history of seizures.