Long Acting Beta 2 Agonists

Long acting beta 2 agonists (formoterol and salmeterol) give bronchodilation for about 12 hours and are taken twice daily. They are added to an inhaled corticosteroid in asthma and used alone or with a long acting antimuscarinic in COPD.

Mechanism. Receptor stimulation raises cyclic AMP and relaxes smooth muscle. Long duration comes from lipophilicity: salmeterol anchors at an exosite beside the receptor, and formoterol forms a depot in the cell membrane.

Pharmacokinetics. Salmeterol is cleared by CYP3A4, so strong inhibitors (ritonavir, ketoconazole, itraconazole, clarithromycin) raise exposure. Formoterol is cleared by conjugation and demethylation. Systemic exposure after inhalation is low.

Formoterol. Full agonist with onset in 1 to 3 minutes. Dose 12 mcg twice daily by inhalation; some labels allow 24 mcg twice daily in severe disease.

Salmeterol. Partial agonist with onset in 15 to 30 minutes. Dose 50 mcg twice daily. Not used for acute relief.

Fixed combinations. Budesonide with formoterol, beclometasone with formoterol, mometasone with formoterol and fluticasone propionate with salmeterol, used in asthma and (for some) COPD. Formoterol with glycopyrronium or aclidinium is used in COPD as a long acting beta 2 agonist with antimuscarinic combination.

Key difference. Only formoterol combined with budesonide or beclometasone can serve as both maintenance and reliever in one inhaler.

Asthma. Add when symptoms persist on a low to medium dose of inhaled corticosteroid. A single combination inhaler is preferred, so the patient cannot take the long acting beta 2 agonist alone. In maintenance and reliever regimens the daily total of inhalations is capped by the product label, usually 12 inhalations in 24 hours for budesonide 160 mcg with formoterol 4.5 mcg.

COPD. Use as monotherapy when a long acting antimuscarinic is unavailable or not tolerated. Use with a long acting antimuscarinic for persistent breathlessness. Add an inhaled corticosteroid when exacerbations continue and eosinophils are 300 cells/microlitre or more.

Children. Combination with an inhaled corticosteroid from 6 years in asthma. Labelled age limits differ between products, usually from 4 years for salmeterol and 6 years for formoterol.

Where fixed combinations are unavailable. Separate corticosteroid and long acting beta 2 agonist inhalers may be used. Counsel firmly that the long acting beta 2 agonist is never taken without the corticosteroid.

Boxed-warning level risk. Monotherapy in asthma raises the risk of asthma-related death and intubation. Always combine with an inhaled corticosteroid.

Adverse effects. Tremor, palpitations, headache, cramps, tachycardia, hypokalaemia, QT prolongation. Tolerance to bronchoprotection develops. Paradoxical bronchospasm needs the product stopped.

Cautions. Ischaemic heart disease, arrhythmia, thyrotoxicosis, diabetes, hypertension. Not for acute symptoms.

Interactions. Salmeterol with strong CYP3A4 inhibitors is not advised. Non-selective beta blockers are contraindicated in asthma. Monoamine oxidase inhibitors and tricyclic antidepressants add cardiovascular risk, and QT prolonging drugs add arrhythmia risk.

Monitoring. Symptom control, reliever use, exacerbations, heart rate, potassium if on diuretics or high dose, and technique.

Special groups. Pregnancy: may be continued when needed to control asthma. Breastfeeding: unlikely to harm the infant. Older adults: start low and watch for arrhythmia.

Referral and escalation. Persistent poor control on a medium dose inhaled corticosteroid with a long acting beta 2 agonist needs adherence and technique check, then specialist review. Any life-threatening exacerbation needs emergency treatment.