Beta Adrenergic Agonists

Beta adrenergic agonists activate beta receptors and increase intracellular cyclic AMP. They relax airway and uterine smooth muscle, increase cardiac contractility and rate, and relax the detrusor. They treat bronchospasm, heart failure and shock, bradycardia, hyperkalaemia, overactive bladder and, rarely, preterm labour.

Classification. Non-selective beta: isoprenaline. Beta-1 selective: dobutamine. Beta-2 selective short acting: salbutamol, terbutaline. Beta-2 selective long acting: formoterol, salmeterol. Ultra-long acting: indacaterol, olodaterol, vilanterol. Beta-3 agonists: mirabegron and vibegron.

Mechanism. Receptors couple to Gs, raising cyclic AMP and protein kinase A activity. In airway smooth muscle this causes relaxation. In the heart it raises rate, contractility and conduction speed. Beta-2 stimulation in skeletal muscle drives sodium-potassium ATPase and moves potassium into cells.

Selectivity. Selectivity is dose dependent and lost at high doses, so tremor, tachycardia and hypokalaemia appear with large inhaled or intravenous doses.

Onset and duration. Salbutamol acts within minutes for 4 to 6 hours. Formoterol acts within 1 to 3 minutes for 12 hours. Salmeterol acts within 15 to 30 minutes for 12 hours. Ultra-long agents act for 24 hours.

Pharmacokinetics. Salbutamol and terbutaline undergo extensive first pass sulphation after oral dosing. Inhaled doses act locally with some systemic absorption. Mirabegron is a CYP2D6 inhibitor.

• Salbutamol, terbutaline: rescue bronchodilators; terbutaline also given subcutaneously.
• Formoterol: rapid and long acting, so usable for maintenance and reliever therapy with an inhaled corticosteroid.
• Salmeterol: slow onset, not for rescue.
• Indacaterol, olodaterol, vilanterol: once-daily maintenance, mainly for COPD.
• Dobutamine: intravenous inotrope with vasodilation.
• Isoprenaline: intravenous chronotrope for bradycardia.
• Mirabegron, vibegron: overactive bladder without antimuscarinic effects.

• Acute asthma: salbutamol 2.5 to 5 mg by nebuliser repeated every 20 to 30 minutes, or 4 to 10 puffs of a 100 microgram inhaler through a spacer. Add ipratropium and systemic corticosteroid in moderate to severe attacks.
• Maintenance: a long-acting beta-2 agonist is never used alone in asthma because it raises the risk of severe attacks and death. Combine with an inhaled corticosteroid. In COPD, long-acting agents are used alone or with a muscarinic antagonist.
• Hyperkalaemia: salbutamol 10 to 20 mg nebulised over 10 minutes lowers potassium by about 0.5 to 1 mmol/L within 30 minutes, together with insulin and glucose and membrane stabilisation.
• Low output heart failure and cardiogenic shock: dobutamine 2.5 to 20 micrograms/kg/minute.
• Bradycardia: isoprenaline 2 to 10 micrograms/minute as a bridge to pacing, and for torsades de pointes with bradycardia.
• Overactive bladder: mirabegron 25 mg daily, increased to 50 mg after 4 to 8 weeks; vibegron 75 mg daily.
• Preterm labour: terbutaline is not advised for prolonged tocolysis beyond 48 to 72 hours because of maternal cardiac risk.
• Selection: prefer inhaled over oral or intravenous routes because adverse effects are fewer.

Contraindications and cautions. Tachyarrhythmias, thyrotoxicosis, hypertrophic obstructive cardiomyopathy, ischaemic heart disease, hypokalaemia, and uncontrolled hypertension (mirabegron, BP 180/110 mmHg or more).

Adverse effects. Fine tremor, palpitations, tachycardia, headache, hypokalaemia, hyperglycaemia, lactic acidosis with high-dose salbutamol, QT prolongation, arrhythmia, muscle cramps, and paradoxical bronchospasm. Tolerance develops to bronchodilator and tremor effects.

Interactions. Non-selective beta blockers antagonise bronchodilation. Hypokalaemia is amplified by corticosteroids, loop and thiazide diuretics and theophylline. Monoamine oxidase inhibitors and tricyclic antidepressants increase cardiovascular effects. Mirabegron raises metoprolol and desipramine levels.

Monitoring. Heart rate, rhythm and potassium with high or repeated doses, lactate if breathlessness persists despite treatment, blood pressure with mirabegron, and peak flow or symptom response.

Referral and escalation. Need for salbutamol more often than every 4 hours, or no response to nebulised therapy, is a marker of severe airway obstruction and needs admission.

Special groups. Pregnancy: inhaled salbutamol is safe. Children: weight-based or age-based inhaler dosing. Older adults: arrhythmia and tremor are more troublesome. Severe renal or hepatic impairment: mirabegron maximum 25 mg daily.