Theophylline and Other Methylxanthines

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181 Theophylline and Other Methylxanthines

The methylxanthines, theophylline and its water-soluble derivative, aminophylline (theophylline ethylenediamine), have been used in the treatment of acute and chronic asthma for decades. Clinical studies suggest that theophylline offers minimal additional benefit to inhaled bronchodilators and results in a greater frequency of adverse events. Some data propose that theophylline may have a role in the treatment of acute asthma in critically ill patients with impending respiratory failure and in the treatment of severe acute exacerbations of chronic obstructive pulmonary disease (COPD). However, the 2007 National Heart Lung and Blood Institute guidelines on the management of asthma recommends not using methylxanthines in the emergency department and strongly discourages their routine use in hospitalized patients.¹ Theophylline’s role in the treatment of pediatric patients also remains controversial. Caffeine, also a methylxanthine and metabolic derivative of theophylline, is indicated in the prevention of neonatal apnea and is a commonly used agent in the neonatal intensive care unit (ICU).

Pharmacology

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 exception ²⁰; 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

Factor	Effect on Clearance
Hepatic insufficiency	Decreased
Congestive heart failure	Decreased
Fever	Decreased
Age	Decreased
Tobacco/marijuana use	Increased
Congestive heart failure	Decreased
Infection	Decreased or no change
Hypothyroid or hyperthyroid disease	Decreased or increased
Cystic fibrosis	Increased
Hypoxemia	No change or decrease
Viral illness	Decrease

TABLE 181-2 Drugs That Significantly Alter Theophylline Clearance

Decrease Clearance	Increase Clearance
Erythromycin/clarithromycin	Phenobarbital
Diltiazem/verapamil	Phenytoin
Cimetidine	Rifampin
Ciprofloxacin	Ketamine
Propranolol and other β-adrenergic blockers	Isoproterenol
Ticlopidine	Allopurinol
	Methotrexate
	Propafenone

Clinical Utility

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.

Severe Exacerbation Of Chronic Obstructive Pulmonary Disease

As in severe acute asthma, routine use of IV methylxanthines in severe exacerbation of COPD is not supported by large randomized clinical trials.⁴⁶ However, several studies have documented the benefits of using two bronchodilators simultaneously.^47,⁴⁸ The combination usually consists of a β₂-adrenergic agonist and an anticholinergic drug (e.g., ipratropium). In acute severe exacerbations that require hospitalization, these agents should be continued at the highest doses tolerated. If an inadequate response is observed, addition of IV aminophylline or theophylline should be considered.⁴⁹ Patients receiving oral theophylline on presentation to the ED demonstrated deterioration when theophylline was withdrawn.⁴⁸ A study that evaluated 143 patients receiving care in the ED demonstrated a trend toward decreased hospitalization rate when aminophylline was added to the treatment regimen.⁴⁸ These patients did not demonstrate improvement in FEV₁ but may have been aided by the antiinflammatory effects of the drug and by drug-induced improvements in diaphragmatic muscle strength. A study of 80 patients with nonacidotic exacerbations of COPD were evaluated in a prospective trial following randomization to either IV aminophylline therapy or no aminophylline. The primary endpoint was improvement of FEV₁ over the first 5 days of admission to the hospital. Although a difference was demonstrated in acid-base balance, there was no difference in the primary endpoint or secondary endpoint of improvement in clinical course.⁵⁰ Unlike acute severe asthma, addition of theophylline to the regimen of a COPD patient has been shown to improve lung volumes and inspiratory muscle function, but the potential for adverse events is higher, and the benefits must be weighed against the possible risk of toxicities.

Other Clinical Uses

Theophylline has been demonstrated to increase diaphragmatic muscle strength in healthy volunteers. Increased respiratory muscle strength may benefit some patients who are on the verge of needing mechanical ventilation, or it may help wean patients from mechanical ventilation.¹ However, this effect has not been evaluated in a prospective randomized clinical trial. Theophylline at therapeutic serum concentrations increases mucociliary clearance in mechanically ventilated ICU patients, but its routine use is discouraged because of the availability of agents with lower incidences of toxicity.⁴⁹ Finally, theophylline and caffeine have been used for preventing apnea in the neonatal ICU.⁵⁰^–⁵⁴

Adverse Events

Methylxanthines are nonspecific inhibitors of PDE subsets, which results in a wide range of adverse events.⁵⁴ Systemic adverse events and theophylline serum concentrations are directly related.⁵⁴^–⁵⁶ When the serum concentration is 10 mg/L or less, adverse events are minimal but may include nausea, vomiting, and diarrhea.⁵⁷ When the serum concentration is above 10 mg/L, patients often experience tachycardia, tremors, and metabolic abnormalities (electrolytes and glucose). Although these adverse events are generally well tolerated in the outpatient setting, significant morbidity may occur in critically ill patients. An older but historically significant study evaluated IV aminophylline in 48 critically ill patients with COPD. Using standard infusion rates resulted in highly variable serum concentrations that ranged from 7 to 52 mg/L (mean 21.9 mg/L), with the concentration strongly correlated to toxicity in 18 patients.⁵⁸

Management of Acute Toxicity

Despite the declining use of oral theophylline, acute intoxication remains a cause of morbidity and mortality. A review of a clinical toxicology database of U.S. poison control centers from 2008 found 369 total exposures, including 230 single exposures to either aminophylline or theophyllilne.⁵⁹ At least 158 of 197 documented episodes of toxicity were unintentional. A total of 118 episodes required treatment in a healthcare facility, and 59 were classified as either moderate or major toxicities. Significant toxicity can occur if the serum theophylline concentration is greater than 25 mg/L.⁵⁷ Serum concentrations can impart some diagnostic and prognostic information and further define the level of intervention required, regardless of whether the overdose was intentional or unintentional.⁶⁰ Clinical responses to acute theophylline overdose can be classified into neurologic, cardiovascular, and metabolic categories.^61,⁶² Cardiac toxicity, the most common acute manifestation, is evident by the appearance of tachycardia and arrhythmias. Profound hypotension and cardiovascular collapse have been reported with serum concentrations above 50 mg/L.^57,⁶² Seizures are rare unless the serum concentration is over 80 mg/L.^57,⁶¹ Severe metabolic abnormalities including hypokalemia, hypomagnesemia, hypercalcemia, and hyperglycemia are common and can complicate treatment of cardiovascular and neurologic adverse events.^56,^61,⁶² Even at nontoxic doses, clinicians often fail to recognize the impact of theophylline on metabolic disturbances.⁶³

On initial presentation, standard acute overdose therapy should be applied. Initial gastric lavage may be useful. Multidose administration of activated charcoal enhances elimination because theophylline undergoes significant enterohepatic recirculation. If the patient presents with an overdose following ingestion of a sustained-release theophylline formulation, there can be a delay before the appearance of major toxicities. Seizures should be treated with benzodiazepines; if they are refractory, phenobarbital may be effective. Phenytoin can worsen theophylline-induced seizures and should be avoided.⁶⁴ Supraventricular arrhythmias and tachycardia may be managed with β-adrenergic blockers or calcium antagonists, and hypotension with fluids that expand vascular volume.^61,^65,⁶⁶ β-Adrenergic blockers should be used cautiously in patients with underlying COPD or asthma. Ventricular arrhythmias are managed with lidocaine and other standard agents.

In a study of 356 patients with theophylline serum concentrations over 30 mg/L, the most notable finding was tolerance of extremely high theophylline concentrations without development of major toxicity.⁵⁷ Despite these data, when life-threatening conditions such as refractory seizures, hypotension, or arrhythmias are present or the serum concentration is above 80 mg/L, hemodialysis or hemoperfusion with charcoal should be initiated.⁵¹ Institutions that cannot provide charcoal hemoperfusion should institute continuous venovenous hemofiltration, because this intervention results in rapid reduction of theophylline serum concentration and is an acceptable alternative.⁶⁶ Important developments in hemodialysis including high-flux, high-efficiency membranes and albumin dialysis using a molecular adsorbent recirculating system offer possibilities for removing of highly protein-bound drugs such as theophylline.^67,⁶⁸ Theophylline serum concentration should be monitored every 2 hours until declining values are confirmed.