Theophylline: Mechanism, Uses, and Considerations
Theophylline is a methylxanthine bronchodilator with anti-inflammatory properties that has been used for decades to treat airway diseases, but has a narrow therapeutic window requiring careful monitoring due to potential serious side effects. 1, 2
Mechanism of Action
- Bronchodilator effects are primarily mediated through inhibition of phosphodiesterase 3 (PDE3), but require relatively high serum levels which are associated with frequent side effects 1, 2
- At lower doses, theophylline has anti-inflammatory effects, likely mediated through phosphodiesterase 4 (PDE4) inhibition and activation of histone deacetylase 2, which downregulates inflammatory genes 1, 2
- May reverse corticosteroid resistance, which could be valuable in severe asthma and COPD 2
Clinical Indications
- FDA-approved for treatment of symptoms and reversible airflow obstruction associated with chronic asthma and other chronic lung diseases (emphysema and chronic bronchitis) 3
- Suggested by the American College of Chest Physicians as a treatment option for stable COPD patients to prevent acute exacerbations (Grade 2B recommendation) 1
- Used as an add-on therapy in patients with asthma not well controlled on inhaled corticosteroids with or without long-acting β2-agonists 2
- Used in patients with COPD with severe disease not controlled by bronchodilator therapy 2
Dosing Considerations
- For adults without risk factors for impaired clearance:
- For patients with risk factors for impaired clearance, elderly (>60 years), or when monitoring serum levels isn't feasible:
- Final dose should not exceed 400 mg/day 3
- Slow-release formulations are recommended for chronic treatment at 100-400 mg twice daily 4, 3
Monitoring
- Serum theophylline levels should be monitored regularly, with a target therapeutic range of 5-15 mg/L 5, 3
- Dosage adjustments should be guided by serum concentrations:
- <9.9 mcg/mL: If symptoms not controlled and current dose tolerated, increase by about 25% 3
- 10-14.9 mcg/mL: If symptoms controlled, maintain dose 3
- 15-19.9 mcg/mL: Consider 10% decrease in dose for greater safety margin 3
- 20-24.9 mcg/mL: Decrease dose by 25% even if no adverse effects present 3
25 mcg/mL: Skip next dose and decrease subsequent doses by at least 25% 3
Side Effects and Risks
- Common side effects include nausea, vomiting, gastroesophageal reflux, headache, and tachycardia 1, 5, 6
- GI side effects are threefold higher with theophylline compared to other bronchodilators like formoterol 1, 4
- Risk of toxicity increases at serum levels >15 μg/mL 6
- More serious adverse effects at higher concentrations include cardiac arrhythmias and seizures due to adenosine A1-receptor antagonism 2
- In clinical trials, GI side effects led to a 27% withdrawal rate in the first 3 months of treatment 1
Drug Interactions
- Theophylline is metabolized by the hepatic cytochrome P450 system, leading to numerous important drug interactions 1, 5
- Drug interactions can significantly affect theophylline levels and should be considered when monitoring patients 5
Clinical Considerations
- Theophylline is considered less effective than inhaled beta-2 selective agonists for acute bronchospasm 3
- The unfavorable side effect profile compared to inhaled agents makes theophylline less useful as a first-line treatment 1, 7
- Should be used at the lowest effective dose to minimize adverse effects 4
- Use with extreme caution in patients with active peptic ulcer disease or congestive heart failure 4
Pitfalls and Caveats
- Patients on long-term theophylline without regular monitoring may present with vague gastrointestinal symptoms that can be misdiagnosed as other conditions 8
- Theophylline distributes poorly into body fat, so dosing should be calculated based on ideal body weight 3
- Withdrawal of theophylline from patients can cause worsening of disease, even in those taking concomitant glucocorticosteroids 7
- Low-dose theophylline may be useful in reversing corticosteroid resistance in COPD and severe asthma 2