Theophylline

Theophylline is a bronchodilator used for asthma and stable chronic obstructive pulmonary disease (COPD). It is not generally effective in exacerbations of chronic obstructive pulmonary disease. It may have an additive effect when used in conjunction with small doses of beta 2 agonists. Current British Thoracic Society (BTS) guidelines¹ recommend its use at step 3/4 in asthma management. The combination may increase the risk of side-effects including hypokalaemia.

Theophylline is metabolised in the liver. There may be considerable variation in plasma theophylline concentration particularly in:

• Smokers
• Patients with hepatic impairment or heart failure
• Concomitant use of certain drugs

The plasma-theophylline concentration is increased :

• In heart failure, pulmonary oedema and cor pulmonale
• In hepatic dysfunction, cirrhosis
• During viral infections
• In the elderly
• By drugs that inhibit its metabolism e.g. cimetidine, ciprofloxacin, erythromycin

The plasma theophylline concentration is decreased:

• In smokers
• In chronic alcoholism
• By drugs that induce liver metabolism e.g. phenytoin, carbamazepine, rifampicin

The differences in theophylline half-life are important because its toxic dose is close to the therapeutic dose. In most individuals a plasma theophylline concentration of between 10 to 20 mg/litre is required for satisfactory bronchodilation, although a plasma-theophylline concentration of 10 mg/litre (or less) may be effective.
Adverse effects can occur within the range 10 to 20 mg/litre and effects in both the frequency and severity increase are seen at concentrations above 20 mg/litre.
Due to bioavailability differences between brands, people should be maintained on the same brand of theophylline. To assist this the brand should be specified on the prescription.²

The mechanism of action of theophylline is unknown. It is assumed to relax airway smooth muscle. It may also increase diaphragmatic strength and improve mucociliary clearance in COPD. It also improves cardiac output, which may be beneficial in some people with COPD.
Because of the potential for toxicity and significant drug interaction, theophylline is no longer a first-line therapy. MeReC (June 2006) state theophylline is 5th line treatment in management of COPD. Plasma levels of theophylline must be monitored to ensure they remain in the therapeutic range.

• Theophylline has been found to increase FEV1 and FVC compared with placebo. There was no difference found in wheeze, dyspnoea, walking distance, use of rescue medication, or exacerbation frequency in comparison with placebo.³
• One randomised controlled trial (RCT) found that adding theophylline improved peak expiratory flow rate compared with continuing low dose corticosteroids plus placebo after 6 months in people with mild to moderate, persistent asthma that was poorly controlled with inhaled corticosteroids alone.⁴
• One small RCT found no significant difference in lung function or symptoms between theophylline and formoterol or between theophylline and zafirlukast after 3 months.⁵