Methylxanthines – These should be considered when someone with stable COPD remains symptomatic after using SABA and LABA (with or without ICS) or is unable to use inhalers correctly. Plasma level monitoring along needs to be undertaken when using methylxanthines. Theophylline effectiveness is assessed by symptom improvement, exercise capacity, lung function and the ability to undertake activities of daily living. It is important to prescribe by brand due to bioavailability variations, and once stabilised to remain on that brand.

 

Mechanism of action: Relaxes smooth muscle in bronchial airways and pulmonary blood vessels.  It also reduces the response to histamine and allergens. It competitively inhibits type III and IV phosphodiesterase (PDE) which is responsible for breaking down cAMP, and possibly causes bronchodilation.

 

Aminophylline

• Phyllocontin Continus® (modified-release aminophylline hydrate 225mg) — one tablet twice daily, increased after 1 week to two tablets twice daily according to plasma-theophylline concentration.

• Phyllocontin Continus® Forte (modified-release aminophylline hydrate 350mg) — one tablet twice daily, increased after 1 week to two tablets twice daily if necessary. (suitable for smokers and other people in whom theophylline will have a shorter half-life)

Theophylline

• Nuelin SA® modified release tablets: Nuelin SA®175 tablets — 175mg twice daily, increasing to 350mg if necessary. Nuelin SA®250 tablets — 250 mg twice daily, increasing to 500 mg if necessary.

• Slo-Phyllin® modified-release capsules — 250mg to 500mg every 12 hours.

• Uniphyllin Continus® modified-release tablets — 200 mg every 12 hours. (Can be titrated to 300mg or 400mg depending on response.) – If symptoms are severe consider prescribing a larger evening or morning dose to achieve optimum therapeutic effect. In those who have not received theophylline before the total dose can be given as a single evening or morning dose.

 

Pharmacodynamics: Bronchodilators. Theophylline also has actions typical of xanthine derivatives including diuretic, coronary vasodilator, cardiac and skeletal muscle stimulant. Aminophylline affects inflammatory cells including T-cells and the reduction of eosinophil and neutrophil, these actions may contribute to its anti-inflammatory properties.

Pharmacokinetics: Theophylline is metabolised in the liver, however, this is inhibited when the plasma-theophylline concentration is increased by conditions such as heart failure, hepatic impairment, viral infections and the elderly.  Plasma-theophylline concentration is decreased in smokers which alters the dose (care should be taken as if the patient stops smoking the dose will need to be altered), it is also reduced by alcohol.  This needs to be carefully considered as theophylline has a narrow therapeutic index. In most patients plasma-theophylline concentration of 10-20mg/l (55-110micromol/l) is needed for bronchodilation, although lower levels are sometimes effective.

 

Cautions: Cardiac arrhythmias (and other cardiac diseases), hypertension, hyperthyroidism, peptic ulcer, epilepsy, fever, hypokalaemia risk, adjust dose if smoking started or stopped.

 

Side-effects: Arrhythmias, CNS stimulation, convulsions, diarrhoea, gastric irritation, headahe, insomnia, nausea, palpitations, tachycardia, vomiting.

Overdose – vomiting (may be severe and intractable), agitation, restlessness, dilated pupils, sinus tachycardia, hyperglycaemia. Some are more serious including convulsions, haematemesis, supraventricular/ventricular arrhythmias, severe hypokalaemia (can develop rapidly)

 

Interactions:

• Beta-2-agonists, corticosteroids, diuretics — hypokalaemia risk may be increased. Check serum potassium levels regularly.

• Lithium — Check plasma lithium levels and alter dose if necessary.

• Fluvoxamine — can raise the plasma levels of aminophylline/theophylline. Avoid concomitant use or halve the aminophylline/theophylline dose and monitor levels.

• Plasma levels can be altered by concomitant use with liver enzyme-inhibiting drugs (e.g verapamil, ciprafloxacin, fluconazole, erythromycin, clarithromycin, allopurinol, and cimetidine) and liver enzyme-inducing drugs (e.g. primidone, phenobarbital, carbamazepine, phenytoin, ritanovir, rifampicin, and St John's Wort).

For more interactions see the following: https://www.evidence.nhs.uk/formulary/bnf/current/a1-interactions/list-of-drug-interactions/theophylline  

 

Monitoring: Plasma levels should be checked five days after starting, every 6-12months (more regularly in elderly, heart failure and hepatic impairment) and three days after dose adjustments. Also check if the person starts or stops smoking and if enzyme-inhibiting or inducing drugs are prescribed.