beta-2 agonist

MECHANISM: β2 receptors are Gs-protein coupled. Agonist binding activates adenylyl cyclase, which raises cAMP and activates PKA. PKA phosphorylates and inhibits myosin light-chain kinase and lowers intracellular Ca2+. The result is smooth muscle relaxation. In the airway this causes bronchodilation. Beta-2 agonists also increase mucociliary clearance and inhibit mast cell mediator release.

OTHER β2 EFFECTS (high-yield physiology): - Uterine smooth muscle relaxation (tocolysis): terbutaline, ritodrine. - Vasodilation of skeletal muscle arterioles. - Increased glycogenolysis and gluconeogenesis (hepatic) and lipolysis, which can cause hyperglycemia. - Increased renin release (β1 predominantly). - Shift of K+ into cells via Na+/K+-ATPase, causing hypokalemia. This is the basis for using albuterol to treat acute hyperkalemia. - Increased aqueous humor production (β2) and tremor (skeletal muscle β2).

DRUG CLASSES: - Short-acting (SABA): albuterol (salbutamol), levalbuterol (R-enantiomer), terbutaline, metaproterenol. Onset in minutes, duration 4-6 h. Used for acute asthma/COPD symptoms (rescue). - Long-acting (LABA): salmeterol (slow onset), formoterol (rapid onset, can be used in SMART/MART therapy with budesonide), vilanterol, indacaterol, olodaterol, arformoterol. Duration 12-24 h. Used for maintenance in persistent asthma (always with an ICS) and in COPD. - Isoproterenol is a nonselective β1/β2 agonist (not used for asthma because of cardiac effects).

ADVERSE EFFECTS: Tremor, tachycardia and palpitations (β1 spillover at high doses or reflex tachycardia from vasodilation), arrhythmias, hypokalemia, hyperglycemia, hypomagnesemia, headache, nervousness, and lactic acidosis (with high-dose or IV use). Tachyphylaxis or tolerance can occur from receptor downregulation. LABA monotherapy in asthma was associated with increased asthma-related death (boxed warning historically), so LABAs must be paired with an inhaled corticosteroid. LABAs are not for acute exacerbations.

CLINICAL USES: - Asthma: SABA for rescue; ICS plus LABA (or ICS-formoterol) for persistent disease. - COPD: SABA for symptoms; LABA ± LAMA (tiotropium, umeclidinium) for maintenance. LABA+LAMA is preferred in many symptomatic patients. - Acute hyperkalemia: nebulized albuterol (adjunct). - Preterm labor: terbutaline (limited use; FDA warns against prolonged use due to maternal cardiac risk). - Anaphylaxis: epinephrine is first line; β2 agonists are adjunct for bronchospasm only.

KEY ASSOCIATIONS/BOARD PEARLS: - Beta-blockers (especially nonselective ones) can precipitate bronchospasm in asthmatics. They also blunt SABA response. - Compare with antimuscarinics (ipratropium, tiotropium), which block M3 receptors to cause bronchodilation. Ipratropium is helpful in COPD and added in severe asthma exacerbations. - Theophylline (PDE inhibitor) also raises cAMP but has a narrow therapeutic index. - Cromolyn and nedocromil are mast cell stabilizers. Montelukast and zafirlukast are leukotriene receptor antagonists. Zileuton is a 5-lipoxygenase inhibitor. - Receptor selectivity is dose-dependent. Higher doses lose β2 selectivity and cause β1 cardiac effects. - Second-generation mnemonic: "-terol" suffix typically denotes a β2 agonist.