What is the recommended use and dosage of Theophylline for treating asthma and Chronic Obstructive Pulmonary Disease (COPD)?

Theophylline Use and Dosage for Asthma and COPD

For stable patients with COPD, oral slow-release theophylline twice daily is suggested to prevent acute exacerbations of COPD, though it should be considered a third-line therapy due to its narrow therapeutic window and side effect profile. 1

Mechanism of Action and Effects

• Theophylline works through multiple mechanisms including inhibition of phosphodiesterase 3 (bronchodilator effect at higher doses) and phosphodiesterase 4 inhibition with histone deacetylase 2 activation (anti-inflammatory effects at lower doses) 1, 2
• It improves lung function when added to long-acting β-agonists and may reverse corticosteroid resistance in COPD patients 1, 2
• In COPD, theophylline decreases dyspnea, air trapping, and work of breathing, and improves contractility of diaphragmatic muscles, with limited improvement in pulmonary function measurements 3

Recommended Dosing

• For COPD: Oral slow-release theophylline twice daily, titrated to achieve serum levels of 8-20 mg/L measured 3-4 hours after dosing 1
• For asthma: Used as additional therapy when symptoms are not adequately controlled with inhaled beta-agonists and inhaled corticosteroids 4
• Maximum daily dose in patients over 60 years should not exceed 400 mg/day unless the patient remains symptomatic and peak steady-state serum theophylline concentration is <10 mcg/mL 3
• Use the lowest effective dose to minimize adverse effects 1

Place in Therapy

• Theophylline is considered an alternative therapy for asthma and COPD, not first-line treatment 5, 6
• For COPD: Recommended for patients who continue to have exacerbations despite maintenance bronchodilator therapy and inhaled corticosteroids 1
• Current guidelines relegate theophylline to third-line therapy after inhaled bronchodilators and corticosteroids 6, 7

Monitoring Requirements

• Regular monitoring of serum theophylline concentrations is essential due to its narrow therapeutic window 1, 4
• Target serum concentration: 8-20 mg/L (measured 3-4 hours after dosing) 1
• More frequent monitoring required in elderly patients, those with liver disease, heart failure, or during febrile illness 3

Important Drug Interactions and Considerations

• Theophylline is metabolized by the hepatic cytochrome P450 system, leading to numerous important drug interactions 1
• Tobacco smoking increases theophylline clearance by approximately 50% in young adults and 80% in elderly smokers compared to non-smokers 3
• Smoking cessation reduces clearance by approximately 40%, requiring dose adjustment 3
• Fever decreases theophylline clearance, with the magnitude correlating to the degree and duration of fever 3
• Other factors decreasing clearance: third trimester pregnancy, sepsis with multiple organ failure, and hypothyroidism 3
• Factors increasing clearance: hyperthyroidism and cystic fibrosis 3

Side Effects and Cautions

• Common side effects include nausea, vomiting, gastroesophageal reflux, headache, and GI disturbances 1
• Higher doses can lead to cardiac arrhythmias and seizures 2
• Elderly patients are at significantly greater risk of serious toxicity due to reduced clearance and increased sensitivity 3
• GI side effects are approximately three times more common with theophylline than with inhaled bronchodilators 1, 8
• High withdrawal rates (up to 27% in the first 3 months) have been reported due to side effects 1

Special Populations

• Pediatric patients: Dosage must be selected with caution due to highly variable clearance rates across age groups 3
• Infants under one year: Particular attention to dosage selection and frequent monitoring required due to immature metabolic pathways 3
• Elderly patients (>60 years): Reduced clearance and increased sensitivity to toxic effects; maximum daily dose should not exceed 400 mg/day unless necessary and with careful monitoring 3