Methylxanthines

Methylxanthines (theophylline and aminophylline) are oral and intravenous bronchodilators with a narrow therapeutic window. Aminophylline is theophylline with ethylenediamine and contains about 80 percent theophylline. Use is now a late add-on in asthma and COPD, or the main option where inhalers are unavailable.

Mechanism. Non-selective phosphodiesterase inhibition raises cyclic AMP, and adenosine receptor antagonism adds bronchodilation. At low concentrations they activate histone deacetylase and improve corticosteroid sensitivity, and they raise diaphragmatic strength.

Pharmacokinetics. Absorption from sustained release forms is nearly complete. Clearance is by CYP1A2 and shows saturation near the top of the range, so small dose increases can cause large rises in level. Half life is 8 hours in non-smoking adults, 4 to 5 hours in smokers, 3 to 5 hours in children and over 12 hours in older adults, heart failure and cirrhosis. Neonates clear drug very slowly.

Therapeutic range. 10 to 20 mg/L (55 to 110 micromol/L), with some benefit and fewer effects at 10 to 15 mg/L. Adverse effects rise over 20 mg/L.

Theophylline. Oral sustained release tablets given every 12 hours. Start at 200 mg every 12 hours in adults, with a usual maintenance of 400 to 800 mg daily in two divided doses adjusted to the serum level. Take blood for a level at least 5 days after starting or changing dose, 4 to 6 hours after the morning dose.

Aminophylline intravenous. Loading dose 5 mg/kg over at least 20 minutes, omitted if the patient took oral theophylline or aminophylline in the last 24 hours. Maintenance infusion 0.5 to 0.7 mg/kg/h in adult non-smokers, 0.3 mg/kg/h in older adults, heart failure or liver disease, and 0.8 to 0.9 mg/kg/h in smokers. Use ideal body weight. Check a level 4 to 6 hours after starting.

Differences. Sustained release products are not interchangeable between brands, so keep the same product.

Chronic asthma and COPD. Add-on when inhaled treatment, long acting bronchodilators and other controllers are insufficient, or when inhalers cannot be used or supplied. Oral dosing is cheap, which matters where inhalers are scarce.

Life-threatening asthma. Intravenous aminophylline is a specialist decision in patients not responding to nebulised bronchodilators, steroids and magnesium. It adds little to salbutamol and has more adverse effects.

COPD exacerbation. Not advised routinely, because adverse effects exceed benefit.

Where levels cannot be measured. Use the lower end of the dose range, avoid interacting drugs and stop at the first sign of toxicity.

Toxicity. Nausea, vomiting, tremor, tachycardia and agitation arise over 20 mg/L. Arrhythmia, seizures, hypokalaemia, hyperglycaemia and metabolic acidosis follow at higher levels. Seizures can occur at lower levels in chronic toxicity. Severe toxicity needs intensive care, repeated activated charcoal, correction of potassium, and haemoperfusion or haemodialysis for seizures, life-threatening arrhythmia, shock or very high levels (over 100 mg/L acute, over 60 mg/L chronic).

Raising levels. Ciprofloxacin, erythromycin, clarithromycin, fluvoxamine, cimetidine, zileuton, oral contraceptives, heart failure, liver disease, fever and viral illness. Reduce the dose by about a third and recheck the level.

Lowering levels. Smoking (including cannabis), rifampicin, phenytoin, carbamazepine, phenobarbital and St John's wort. After stopping an inducer or smoking, levels rise over weeks.

Cautions. Arrhythmia, epilepsy, peptic ulcer, thyrotoxicosis, porphyria and hypokalaemia. Beta 2 agonists, diuretics and corticosteroids add to hypokalaemia.

Monitoring. Serum level 4 to 6 hours after the morning dose, heart rate, potassium and symptoms.

Special groups. Pregnancy: acceptable, with levels checked because clearance changes in the third trimester. Breastfeeding: infant irritability can occur. Children: weight-based dosing, with lower doses in infants. Older adults: start low. Hepatic impairment and heart failure: reduce dose and check level early. Renal impairment: no adjustment.

Referral and escalation. Palpitations, seizures, persistent vomiting or a level over 20 mg/L needs urgent hospital care.