Theophylline

Theophylline is a methylxanthine bronchodilator with a narrow therapeutic index, used as an oral add-on controller in asthma and COPD. Use has declined where inhalers are available, but it remains widely used in East Africa because it is cheap and available.

Classification. Methylxanthine, phosphodiesterase inhibitor.

Mechanism. Non-selective phosphodiesterase inhibition raises cyclic AMP, relaxing airway smooth muscle. Adenosine receptor antagonism contributes to bronchodilation and to side effects. At low concentrations it activates histone deacetylase and has a mild anti-inflammatory effect.

Pharmacokinetics. Modified-release preparations are almost completely absorbed. Metabolised in the liver by CYP1A2 (also CYP2E1 and CYP3A4) with saturable kinetics in the therapeutic range, so small dose increases can produce large rises in level. Half-life is 7 to 9 hours in healthy non-smokers, 4 to 5 hours in smokers and more than 24 hours in severe heart failure or cirrhosis. About 10% is excreted unchanged in urine.

Alternative or add-on, chronic asthma and COPD. Start modified-release 200 mg twice daily (dose by ideal body weight; about 10 mg/kg/day). Check a level after at least 3 to 5 days. Increase in steps of about 25% no more often than every 3 days, directed by level and tolerance. Usual maintenance 200 to 400 mg twice daily. Without level monitoring, do not exceed 900 mg daily.

Target serum level. 10 to 20 mg/L (55 to 110 micromol/L) at steady state, sampled 4 to 6 hours after a morning modified-release dose. Many patients respond at 8 to 15 mg/L, and adverse effects rise over 15 to 20 mg/L.

Dose reduction. Reduce the starting and maintenance dose by 25 to 50% and check levels in older adults, heart failure, cirrhosis, severe respiratory infection, hypoxia and with interacting drugs. Smokers may need higher doses; reduce again if smoking stops.

Children. Specialist use only. Start about 10 mg/kg/day in 2 divided modified-release doses and titrate by level. Clearance varies widely in infants.

First-line, alternative, specialist, emergency. There is no first-line use. It is an alternative add-on when long-acting inhalers are unavailable or unaffordable, and a specialist add-on in severe disease. Emergency use is by the intravenous route only.

Loading and titration. No oral loading dose. Increase the dose in steps of about 25% every 3 days, directed by serum level.

Contraindications. Hypersensitivity to xanthines, uncontrolled arrhythmia, active peptic ulcer, porphyria, untreated epilepsy.

Serious adverse effects. Arrhythmia, seizures (which may occur without earlier warning signs), hypokalaemia, hyperglycaemia, lactic acidosis, severe vomiting.

Toxicity by level. Nausea, vomiting and tremor from about 20 mg/L. Tachyarrhythmia and agitation from about 30 mg/L. Seizures and ventricular arrhythmia over 40 mg/L, or at lower levels in chronic toxicity.

Common adverse effects. Nausea, headache, insomnia, tachycardia, palpitations, tremor.

Interactions. Levels rise with ciprofloxacin (halve the dose), erythromycin, clarithromycin, fluvoxamine (halve the dose), cimetidine, oral contraceptives, allopurinol at high dose, verapamil, zileuton and febuxostat. Levels fall with rifampicin, phenytoin, carbamazepine, phenobarbital, ritonavir, St John's wort, and tobacco or cannabis smoking. Additive hypokalaemia with beta-2 agonists, corticosteroids and diuretics.

Common prescribing errors. Starting at a high dose. Adding ciprofloxacin or a macrolide without reducing the dose. Dosing by actual rather than ideal body weight in obesity. Not rechecking levels after a drug change or infection. Stopping rifampicin without lowering the dose.

Special groups.

• Pregnancy: used if needed; clearance falls in the third trimester, so check levels; neonatal irritability may follow late use. Breastfeeding: small amounts pass into milk and may cause infant irritability; compatible with monitoring.

• Older adults: lower dose and closer monitoring.

• Kidney impairment: no adjustment of theophylline itself. Liver impairment: reduce the dose by 25 to 50% and monitor levels.

• East Africa: rifampicin-containing tuberculosis regimens lower levels substantially, and ritonavir-boosted antiretroviral regimens also alter clearance. Recheck levels when these start or stop.

Formulations. Modified-release tablets and capsules 100, 200, 300 and 400 mg. Immediate-release forms exist but cause level swings.

Administration. Swallow modified-release tablets whole, at the same time each day, consistently with or without food.

Baseline. Heart rate and rhythm, potassium, liver function, smoking status, list of interacting drugs.

Monitoring. Serum level at steady state, after each dose change, after starting or stopping an interacting drug, and with acute illness. Heart rate, potassium and glucose when toxicity is suspected.

Stop and reduce rules. Level 20 to 25 mg/L: reduce the dose by about 10% and recheck. Level over 25 mg/L or symptoms of toxicity: omit doses, reduce the dose by 25 to 50% when restarting and recheck. Level over 30 mg/L, any arrhythmia or seizure: this is an emergency needing poisoning care.

Referral and escalation. Refer urgently for arrhythmia, seizures or levels over 30 mg/L. Refer for specialist review when asthma control needs theophylline at high levels.