Epinephrine is an effective, rapidly acting bronchodilator when injected subcutaneously (0.4 mL of 1:1000 solution) or inhaled as a microaerosol from a pressurized canister (320 mcg per puff). Maximal bronchodilation is achieved within 15 minutes after inhalation and lasts 60–90 minutes. Because epinephrine stimulates α and β1 as well as β2 receptors, tachycardia, arrhythmias, and worsening of angina pectoris are potentially serious adverse effects. Its current use is thus largely for treatment of the acute vasodilation and bronchospasm of anaphylaxis. Aerosol delivery of other, more β-selective agents has largely displaced its use in asthma (see below).
Ephedrine was used in China for more than 2000 years before its introduction into Western medicine in 1924. Compared with epinephrine, ephedrine has a longer duration, oral activity, more pronounced central effects, and much lower potency. Because of the development of more efficacious and
FIGURE 20–4 Structures of isoproterenol and several β2-selective analogs.
β2-selective agonists, ephedrine is now used infrequently in treating asthma.
Isoproterenol is a potent nonselective β1 and β2 bronchodilator. When inhaled as a microaerosol from a pressurized canister, 80–120 mcg isoproterenol causes maximal bronchodilation within 5 minutes and has a 60to 90-minute duration of action. An increase in asthma mortality in the United Kingdom in the mid-1960s was attributed to cardiac arrhythmias resulting from the use of high doses of inhaled isoproterenol. As a result of the availability and efficacy of β2-selective agonists, these have displaced the use of isoproterenol for asthma.
The β2-selective adrenoceptor agonist drugs, particularly albuterol, are now the most widely used sympathomimetics for the treatment of acute bronchoconstriction (Figure 20–4). These agents differ structurally from epinephrine in having a larger substitution on the amino group and in the position of the hydroxyl groups on the aromatic ring. They are effective after inhaled or oral administration and have a longer duration of action than epinephrine or isoproterenol.
Albuterol, terbutaline, metaproterenol, and pirbuterol are available as metered-dose inhalers. Given by inhalation, these agents cause bronchodilation equivalent to that produced by isoproterenol. Bronchodilation is maximal within 15 minutes and persists for 3–4 hours. All can be diluted in saline for administration from a hand-held nebulizer. Because the particles generated by a nebulizer are much larger than those from a metered-dose inhaler, much higher doses must be given (2.5–5.0 mg vs 100– 400 mcg) but are no more effective. Nebulized therapy should thus be reserved for patients unable to coordinate inhalation from a metered-dose inhaler.
Most preparations of β2-selective drugs are a mixture of R (levo) and S (dextro) isomers. Only the R isomer activates the β-agonist receptor. Reasoning that the S isomer may promote inflammation, a purified preparation of the R isomer of albuterol has been developed (levalbuterol). Although this purified isomer is often used in children with asthma, meta-analyses of clinical trials have not shown it to have greater efficacy or lower toxicity than the standard and less expensive racemic mixture of Rand S-albuterol in treating exacerbations of asthma or chronic obstructive pulmonary disease (COPD).