In treating asthma, preferential activation of b2receptors without stimulation of b1receptors in the heart is desirable. Drugs with preferential affinity for b2receptors over b1receptors have been
developed, but selectivity is not absolute and is lost at high concentrations. Administration by inhalation of small doses of a b2agonist in aerosol form leads to effective activation of b2 recep-tors in the bronchi but very low systemic drug concentrations. Consequently, there is less poten-tial to activate cardiac b1receptors or to stimulate b2receptors in skeletal muscle (which can cause tremor). The use of b agonists for the treatment of asthma is discussed in Chapter 27.
METAPROTERENOL Metaproterenol (called orciprenaline in Europe), terbutaline, and fenoterolbelong to the structural class of resorcinol bronchodilators that have hydroxyl groups at positions 3 and 5 of the phenyl ring (rather than at positions 3 and 4 as in catechols; see Table 10–1).
Consequently, these agents are resistant to methylation by COMT, and a substantial fraction (40%) is absorbed in active form after oral administration. Metaproterenol is excreted primarily as glu-curonic acid conjugates. Metaproterenol is b2 selective, although probably less selective than albuterol or terbutaline; thus, metaproterenol is more prone to cause cardiac stimulation.
Effects occur within minutes of inhalation and persist for several hours. After oral administration, onset of action is slower, but effects last 3 to 4 hours. Metaproterenol (ALUPENT, others) is used for the long-term treatment of obstructive airway diseases, asthma, and for treatment of acute bron-chospasm (see Chapter 27). Side effects are similar to the short- and intermediate-acting sympa-thomimetic bronchodilators.
TERBUTALINE
Terbutaline is a b2-selective bronchodilator that contains a resorcinol ring and thus is not a sub-strate for COMT. It is effective when taken orally, subcutaneously, or by inhalation. Effects are observed rapidly after inhalation or parenteral administration; after inhalation, its action may persist for 3–6 hours. With oral administration, the onset of effect may be delayed for 1–2 hours.
Terbutaline (BRETHINE, others) is used for the long-term treatment of obstructive airway diseases and acute bronchospasm; a parenteral formulation is used for the emergency treatment of status asthmaticus (see Chapter 27).
ALBUTEROL
Albuterol (VENTOLIN,PROVENTIL, others) is a selective b2agonist with pharmacological properties and therapeutic indications similar to those of terbutaline. It is administered by inhalation or orally for the symptomatic relief of bronchospasm. When administered by inhalation, terbutaline produces significant bronchodilation within 15 minutes; effects persist for 3–4 hours. Cardiovas-cular effects of albuterol are considerably weaker than those of isoproterenol that produce com-parable bronchodilation when administered by inhalation. Oral albuterol may delay preterm labor. Rare CNS and respiratory side effects are sometimes observed.
ISOETHARINE
The selectivity of isoetharine for b2receptors may not approach that of other agents. Although resistant to metabolism by MAO, it is a catecholamine and thus is a good substrate for COMT (Table 10–1). It is used only by inhalation for acute episodes of bronchoconstriction.
PIRBUTEROL
Pirbuterol is a relatively selective b2agonist structurally related to albuterol. Pirbuterol acetate (MAXAIR) is available for inhalation therapy; dosing is typically every 4–6 hours.
BITOLTEROL
Bitolterol (TORNALATE) is a novel b2agonist prodrug in which the OH groups in the catechol moiety are protected by esterification. Esterase activities thought to be higher in lung than heart hydrolyze the prodrug to the active form, colterol, or terbutylne (Table 10–1). The duration of bitolterol’s effect after inhalation is 3–6 hours.
FENOTEROL
Fenoterol (BEROTEC) is a b2-selective agonist administered by inhalation. Fenoterol has a prompt onset of action, and a sustained effect (4–6 hours). Possible association of fenoterol use with increased deaths from asthma in New Zealand is controversial. Fenoterol is under investigation for use in the U.S.
FORMOTEROL
Formoterol (FORADIL) is a long-acting, lipophilic, high-affinity b2-selective agonist. Significant bronchodilation occurs within minutes of inhalation and may persist for up to 12 hours, an advantage over many b2-selective agonists in settings such as nocturnal asthma. Formoterol is
CHAPTER 10 Adrenergic Agonists and Antagonists
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FDA-approved for treatment of asthma, bronchospasm, prophylaxis of exercise-induced bron-chospasm, and COPD.
PROCATEROL
Procaterol (MASCACIN, others; not available in U.S.), a b2-selective agonist, is administered by inhalation and has a prompt onset of action that is sustained for ∼5 hours.
SALMETEROL
Salmeterol (SEREVENT) is a lipophilic b2-selective receptor agonist with prolonged action (>12 hours) and relatively high selectivity (50× that of albuterol) for b2receptors. Since the onset of action of inhaled salmeterol is relatively slow, it is not suitable monotherapy for acute breakthrough attacks of bronchospasm. Salmeterol or formoterol are the agents of choice for nocturnal asthma in patients who remain symptomatic despite anti-inflammatory agents and other standard manage-ment. Salmeterol provides symptomatic relief and improved lung function in patients with COPD.
Salmeterol should not be used more than twice daily (morning and evening) and should not be used to treat acute asthma symptoms, which should be treated with a short-acting b2agonist when breakthrough symptoms occur. Salmeterol is metabolized by CYP3A4 to a-hydroxy-salmeterol, which is eliminated primarily in the feces.
RITODRINE
Ritodrine is a selective b2agonist originally developed as a uterine relaxant. Ritodrine is rapidly but incompletely (30%) absorbed following oral administration; 90% of the drug is excreted in the urine as inactive conjugates; ∼50% of ritodrine is excreted unchanged after intravenous administration. The pharmacokinetic properties of ritodrine are complex and incompletely defined, especially in pregnant women. Administered intravenously to selected patients, ritodrine can arrest premature labor and prolong pregnancy; however, b2-selective agonists may not have clinically significant benefits on perinatal mortality and may actually increase maternal morbid-ity. In one trial comparing nifedipine with ritodrine in managing preterm labor, nifedipine was associated with a longer postponement of delivery, fewer maternal side effects, and fewer admis-sions to the neonatal intensive care unit.
ADVERSE EFFECTS OF B2-SELECTIVE AGONISTS
The major adverse effects of b-receptor agonists occur as a result of excessive activation of breceptors: tremor, to which tolerance develops and which can be minimized by starting oral therapy with a low dose of drug and progressively increasing the dose as tolerance to the tremor develops; feelings of restlessness, apprehension, and anxiety, which may limit therapy; and tachy-cardia, primarily via b1receptors but also possibly via cardiac b2receptors, or to reflex effects that stem from b2receptor–mediated peripheral vasodilation. During a severe asthma attack, heart rate actually may decrease during therapy with a b agonist, presumably because of improvement in pulmonary function with consequent reduction in endogenous cardiac sympa-thetic stimulation. In patients without cardiac disease, b agonists rarely cause significant arrhyth-mias or myocardial ischemia; however, patients with underlying coronary artery disease or preexisting arrhythmias are at greater risk. The risk of adverse cardiovascular effects is increased in patients receiving MAO inhibitors; 2 weeks should elapse between use of MAO inhibitors and administration of b2agonists or other sympathomimetics. Severe pulmonary edema has been reported in women receiving ritodrine or terbutaline for premature labor.
Epidemiologic studies suggest a connection between prolonged use of b receptor agonists and death or near-death from asthma, raising questions about the role of b agonists in the treatment of chronic asthma. Tolerance to the pulmonary effects of these drugs is not a major clinical prob-lem for the majority of asthmatics. Regular use of b2-selective agonists may cause increased bronchial hyperreactivity and deterioration in disease control; whether this potential adverse association may be more unfavorable for long-acting b agonists or excess doses is not yet known.
For patients requiring regular use of b agonists over prolonged periods, strong consideration should be given to additional or alternative therapy (e.g., inhaled glucocorticoids). In some dia-betic patients, b agonists may worsen hyperglycemia, and higher doses of insulin may be required.
All these adverse effects are far less likely with inhalation therapy than with parenteral or oral therapy.
A1-SELECTIVE ADRENERGIC RECEPTOR AGONISTS
Activation of a adrenergic receptors in vascular smooth muscle results in contraction, causing increases in peripheral vascular resistance and blood pressure. Although the clinical utility of aagonists is limited, they may be useful in the treatment of hypotension and shock. Some of the properties of the drugs listed below may be inferred from their structures (Table 10–1).