Mechanisms Of Action

Theophylline has been available for more than 60 years. Thousands of research papers have been written about this drug, and it has been studied in more than 1800 clinical trials. Nevertheless, the specific pharmacologic actions of theophylline in airway disease are not completely known or understood. With the application of new research techniques, the molecular mechanisms responsible for the pharmacologic effects of theophylline are slowly emerging. Theophylline has bronchodilator properties, antiinflammatory effects, and extrapulmonary actions. Bronchodilation is caused by weak, nonselective inhibition of phosphodiesterases 3 and 4 (PDE3, PDE4), which increases the intracellular concentration of cyclic adenosine monophosphate (cAMP).² As a consequence, calcium and potassium channels are modulated, leading to relaxation of airway smooth muscle cells. The result is bronchodilation, although the magnitude of the effect is small compared with that induced by β₂-adrenergic agonists. In addition, theophylline may have beneficial airway effects on mucociliary clearance by increasing ciliary beat frequency.^3,4

Theophylline also appears to have antiinflammatory effects in patients with asthma and COPD.^2,5 The antiinflammatory mechanisms appear to be quite diverse and are related to inhibition of PDE isoenzymes in inflammatory cells, adenosine receptor antagonism, promotion of interleukin (IL)-10 release, inhibition of apoptosis, and inhibition of tumor necrosis factor (TNF) secretion, among other effects.⁶ Evidence for the antiinflammatory effects of theophylline includes reduction in CD4⁺ T lymphocytes in airways exposed to allergens, reduction in neutrophil influx in patients with nocturnal asthma, and reduction in the number of eosinophils in bronchoalveolar lavage (BAL) samples obtained from patients with attacks of severe asthma.^7,8 In subjects with COPD, theophylline reduces total neutrophil count and neutrophil chemotactic responses. The antiinflammatory effects of theophylline are observed when circulating levels of the drug are at the lower end of the therapeutic range, suggesting that lower doses may be beneficial in some patients.^2,9,10

Theophylline possesses extrapulmonary effects including promotion of diuresis and a poorly understood action on respiratory muscles.^2,11,12 Some investigators have demonstrated increased diaphragmatic muscle contractility and reversal of fatigue. The clinical application of these latter effects remains controversial.

Pharmacokinetics And Pharmacodynamics

Theophylline is regarded as having a narrow therapeutic window, and toxicity develops when therapeutic serum concentrations are exceeded by only a relatively small margin. Benefits and risks are related to the serum concentration, which is a function of the dose and clearance of theophylline in individual patients. Because theophylline exhibits a dose-response relationship, drug-drug interactions, and variable pharmacokinetics among critically ill subjects, only clinicians who are experienced with dosing and adjustment of infusions should use it. If theophylline is administered intravenously (IV), there usually is a lag of 15 to 60 minutes between achievement of therapeutic serum concentrations and detection of pulmonary airway responses.^13,14 The relationship between the serum concentration of theophylline and bronchodilation, as measured by improvement in forced expiratory volume over 1 second (FEV₁), is linear. FEV₁ improves by 2% for each 1 mg/L increase in serum theophylline concentration.^13–15 When the drug concentration approaches 20 mg/L, the potential benefit of increased bronchodilation is minimal and must be weighed against the possibility of unwanted adverse events. In 1997, an expert panel report from the National Institutes of Health (NIH) describing guidelines for diagnosis and treatment of asthma reduced the recommended theophylline therapeutic serum concentrations from between 5 and 20 mg/L to between 5 and 15 mg/L.^15,16–18 Few data are available to support the use of serum concentrations above 15 mg/L. Some patients with impending respiratory failure may benefit from serum concentrations approaching 15 mg/L, but the benefit of pulmonary improvement in relation to the risk of adverse events should be carefully considered before maximizing the therapeutic serum concentration. Antiinflammatory properties, prevention of neonatal apnea, and diaphragmatic contractility are seen at concentrations below 10 mg/L.^2,19,20

Theophylline distributes readily into fat tissue in both adults and children (mean volume of distribution 0.45 L/kg). Therefore, total body weight should be used for calculating loading doses and initial IV infusion rates. Morbidly obese patients who exceed ideal body weight by more than 50% may be the exception²⁰; the initial dose should be approached with extreme caution in this patient population. All methylxanthines are eliminated by hepatic metabolism; renal elimination accounts for up to 10% to 15% of the overall excretion in adults.²⁰ Neonates have less developed hepatic metabolism, and renal elimination may approach 50%.²⁰ The primary route of metabolism is mediated via the cytochrome P450 system, and the CYP1A2 microenzyme is the most important pathway for theophylline metabolism.²¹ Less than 10% of theophylline is metabolized to caffeine; however, neonates eliminate caffeine in a more predictable fashion, and this agent maybe used in place of theophylline for preventing apnea. Theophylline’s half-life varies widely (3.4-30 hours), depending on age and underlying physiologic factors. Numerous factors affect the metabolic clearance of theophylline in critically ill patients; variations within and among patients of 25% or more have been observed.^21–23 Factors that influence the activity of hepatic enzyme function involved in theophylline clearance—gender, age, obesity, diet, and history of tobacco use, for example—may influence metabolism and serum concentrations. Concomitant conditions found in ICU patients that may significantly alter theophylline clearance are listed in Table 181-1. Other drugs that either inhibit or stimulate CYP1A2 activity can alter clearance of theophylline and lead to life-threatening adverse events secondary to toxic levels of the drug. Agents known to affect theophylline clearance are outlined in Table 181-2.²³ Clinicians should be vigilant regarding these drug-drug and drug-disease interactions that significantly alter theophylline clearance. Newer drugs used in ICU patients are not routinely assessed for their impact on theophylline clearance, so periodic review of new agents and their impact on CYP1A2 metabolism is also vital. Recognition of these factors is essential to minimize toxicity and maximize efficacy. Careful therapeutic monitoring of serum levels is strongly recommended.^24,25

TABLE 181-1 Physiologic and Environmental Factors That Affect Clearance of Methylxanthines in Critically Ill Patients

TABLE 181-2 Drugs That Significantly Alter Theophylline Clearance

Acute Severe Asthma

Adult asthmatics with an acute exacerbation are frequently admitted to the hospital after evaluation in the emergency department (ED). These patients are routinely treated with supplemental oxygen, short-acting inhaled or nebulized β₂-adrenergic agonists, nebulized ipratropium, and IV glucocorticoids. Routine use of oral or IV aminophylline or theophylline in the management of acute severe asthma has been replaced by use of high doses of short-acting β₂-adrenergic agonists. The 2007 NIH expert guidelines for management of hospitalized adult patients with severe asthma do not include theophylline as a routine treatment option.^1,26,27 β₂-Adrenergic agonists offer a better safety profile and appear to have equal or greater efficacy. In the emergency department, oral or IV theophylline or aminophylline demonstrated no additional benefit over optimal-dosed short-acting β₂-adrenergic agonists (SABA) but did increase adverse events.²⁸ Additionally, this meta-analysis failed to demonstrate a benefit of either aminophylline or theophylline in hospitalized patients. However, patients who received IV aminophylline demonstrated an 8% to 9% improvement in predicted FEV₁. The difference in FEV₁ was primarily related to one study, but improvement in airway function did not result in improved outcomes (shortening of ICU length of stay or reduction of symptoms).²⁹ Patients who received theophylline had a significantly greater number of adverse events and required discontinuation of therapy more often compared to the SABA group.

In a second meta-analysis, addition of aminophylline to other therapies in acute asthma offered little additional efficacy, resulted in higher morbidity related to adverse events, and required more intense monitoring of serum concentrations and meticulous dose adjustments.³⁰ More recently, the Cochrane Database and others^31,32 concluded that aminophylline does not appear to confer additional benefit. Intravenous theophylline or aminophylline should be considered only in adult asthmatics with severe exacerbations who are not responding to other treatment modalities, and in patients with impending respiratory failure.

The role of methylxanthines in the management of acute severe asthma in pediatric patients remains controversial.^33,34 At least seven clinical trials published in the 1990s, all with small sample sizes (range 21-42 subjects), showed no significant benefit when theophylline was added to nebulized albuterol and glucocorticoids in hospitalized patients aged 2 to 18 years.^{31,32,35–40} Most of these studies targeted a theophylline serum concentration of 10 to 20 mg/L and used improvement in a clinical score or FEV₁ as the primary readout.³³ Two small trials (21 and 23 patients) demonstrated improvement in FEV₁ and clinical symptom score when theophylline was added to albuterol and either hydrocortisone or methylprednisolone.^41,42 Two larger randomized trials (163 and 47 patients) evaluated IV aminophylline in pediatric patients with severe acute asthma that was unresponsive to glucocorticoids and nebulized albuterol. Both studies demonstrated improvements in FEV₁ and clinical score, but treatment with aminophylline did not reduce hospital length of stay.^43,44 A recent Cochran meta-analysis confirmed these earlier findings.⁴⁵ Addition of theophylline to other therapies in adult or pediatric patients with exacerbations of severe asthma should be weighed carefully, considering the potential benefits, toxicities, and need for intensive therapeutic drug monitoring.