Beta 2 Agonists

Beta 2 agonists are sympathomimetic drugs that stimulate beta 2 adrenergic receptors and relax airway smooth muscle. They are the most effective rapid bronchodilators and underpin reliever and maintenance treatment of asthma and COPD. Salbutamol also has a non-respiratory use in hyperkalaemia.

Mechanism. Receptor activation raises cyclic AMP, activates protein kinase A, opens large conductance potassium channels and lowers intracellular calcium, so smooth muscle relaxes. They also stabilise mast cells, speed mucociliary clearance and reduce microvascular leak, but they do not suppress eosinophilic airway inflammation.

Receptor behaviour. Regular use desensitises beta 2 receptors and reduces protection against bronchoconstrictor challenge, while the bronchodilator response is largely kept. Corticosteroids partly restore receptor expression and function.

Pharmacokinetics. Inhaled drug acts locally, and the swallowed fraction is absorbed and undergoes first pass metabolism. Oral salbutamol bioavailability is about 50 percent. Salmeterol is cleared by CYP3A4, so strong inhibitors such as ritonavir and ketoconazole raise exposure and the risk of QT prolongation.

Stereochemistry. Salbutamol is a racemic mixture in which the R enantiomer is active. Levosalbutamol has no proven clinical advantage in routine use.

Efficacy. Formoterol is a full agonist with rapid onset. Salmeterol is a partial agonist with slow onset and a ceiling effect.

Less selective agents. Fenoterol has more beta 1 activity and cardiac toxicity and is not preferred. Oral and injectable beta 2 agonists cause more systemic effects than inhaled drug and are used only when inhalation is not possible.

Asthma reliever. Low dose budesonide with formoterol taken as needed is preferred in adults and adolescents where available, because it reduces severe exacerbations compared with a short acting beta 2 agonist alone. Where it is unavailable, salbutamol 100 to 200 mcg as needed is used together with a regular inhaled corticosteroid.

Asthma maintenance. Add a long acting beta 2 agonist to the inhaled corticosteroid when control is incomplete on a low to medium dose, preferably in one inhaler.

COPD. Long acting agents are used alone or with a long acting antimuscarinic. Short acting agents are used for rescue.

Acute severe asthma.

• Salbutamol 4 to 10 puffs of 100 mcg through a spacer, or 5 mg nebulised, repeated every 15 to 20 minutes.
• Continuous nebulisation of 5 to 10 mg/h in life-threatening disease.
• Terbutaline 250 mcg subcutaneously, repeated once after 15 to 30 minutes, when inhalation is not possible.
• Add magnesium sulphate 2 g intravenously over 20 minutes in severe or life-threatening disease.

Hyperkalaemia. Salbutamol 10 to 20 mg nebulised over 10 minutes lowers potassium by about 0.5 to 1 mmol/L within 30 minutes, lasting 2 to 4 hours. Give it with insulin and glucose, never alone, because a minority of patients do not respond.

Tocolysis. Prolonged terbutaline tocolysis is not advised because of maternal cardiac events and pulmonary oedema.

Adverse effects. Tremor, palpitations, tachycardia, headache and muscle cramps are common. High or repeated doses cause hypokalaemia, hyperglycaemia, hyperlactataemia, QT prolongation and arrhythmia. Paradoxical bronchospasm needs the product stopped and changed.

Hypokalaemia. Potassium shifts into cells, and the effect adds to loop and thiazide diuretics, corticosteroids, theophylline and hypoxia. Check potassium after repeated high dose treatment.

Lactic acidosis. High dose salbutamol, nebulised or intravenous, can cause lactic acidosis with tachypnoea that is mistaken for worsening asthma. Check lactate when breathlessness persists despite improving airflow.

Boxed-warning level risk. Long acting beta 2 agonist monotherapy in asthma raises the risk of asthma-related death, so these drugs are always combined with an inhaled corticosteroid.

Cautions. Ischaemic heart disease, arrhythmia, hypertension, thyrotoxicosis, diabetes (ketoacidosis risk at high dose) and hypokalaemia.

Interactions. Non-selective beta blockers antagonise beta 2 agonists and are contraindicated in asthma. Strong CYP3A4 inhibitors with salmeterol are not advised. Macrolides, antipsychotics and ondansetron add QT risk, and monoamine oxidase inhibitors and tricyclic antidepressants add cardiovascular risk.

Monitoring. Reliever use frequency, heart rate, potassium after high dose, glucose in diabetes, and lactate for unexplained tachypnoea.

Special groups. Pregnancy: salbutamol and long acting agents may be continued when needed. Breastfeeding: compatible at usual doses. Children: use a spacer, with a face mask in children under 4 years. Older adults: tremor and arrhythmia are more likely; start at the lower dose.

Referral and escalation. Need for salbutamol more often than every 4 hours, or peak flow under 50 percent of best or predicted, needs admission. Peak flow under 33 percent, silent chest, cyanosis, exhaustion or oxygen saturation under 92 percent needs senior and intensive care review.