β-adrenergic receptor agonists

Selective β₂-receptor agonists relax bronchioles and uterine smooth muscle without affecting the heart via β₁-receptor stimulation. These drugs activate adenyl cyclase, which converts adenosine triphosphate (ATP) to cyclic adenosine 3´-5´-monophosphate (cAMP), which in turn causes relaxation of smooth muscle, resulting in bronchodilation. Nonselective β-receptor agonists used for bronchodilation include epinephrine, isoproterenol, and isoetharine. Selective β₂-receptor agonists include albuterol, terbutaline, metaproterenol, and others (Table 94-1). Side effects associated with the use of nonselective medications include increased heart rate, contractility, and myocardial O₂ consumption. Selective β₂-receptor agonists may also produce some cardiac effects, especially if administered subcutaneously or intravenously. Hypokalemia and hyperglycemia may also occur. Chronic use can be associated with tachyphylaxis.

Therapeutic aerosols may be administered, preferably, by a metered-dose inhaler (MDI) or as a wet aerosol from a nebulizer containing the medication. Only particles with a diameter of 1 to 5 μm are efficiently deposited in the lower respiratory tract, which is one of the primary reasons that 13% of the output from MDIs, compared with only 1% to 5% of the output from nebulizers, reaches the lower respiratory tract. Propellants used in MDIs are blends of liquefied gas chlorofluorocarbons (CFCs) that can damage the earth’s ozone layer; in addition, some patients are sensitive to these propellants, resulting in bronchospasm. Because of these concerns, some MDIs use hydrofluoroalkanes (HFAs) as the propellant. The HFA formulations of albuterol and ipratropium bromide have been shown to be equivalent to their respective CFC formulations. However, the delivered dose of HFA-formulated beclomethasone dipropionate is five times greater than the dose delivered with the original CFC formulation.

A breath-activated nebulizer, a new type of jet nebulizer, has a low dead-space volume and nebulizes only on inspiration. With this type of nebulizer, waste during exhalation should be completely eliminated. The delivered dose can be more than three times greater than the dose delivered with continuous nebulization.

The use of continuous bronchodilator therapy is sometimes necessary for the treatment of severe bronchospasm, such as for status asthmaticus. In such situations, a low dose of a bronchodilator (e.g., albuterol, 10-15 mg/h) should be used, and the patient should be continuously monitored for side effects (e.g., tachycardia, arrhythmias, hypokalemia) and worsening of symptoms.

Dry-powder inhalers (DPIs) deliver drugs in powder form to the lung. When using this type of inhaler, patients must generate sufficient inspiratory flow rate (≥50 L/min). Generating this level of inspiratory flow rate may be difficult for patients to achieve if they are in acute respiratory distress, especially during severe asthmatic attack.

Methylxanthines

Theophylline is a poorly soluble methylxanthine found in high concentrations in tea leaves. Methylxanthines inhibit the breakdown of cAMP by phosphodiesterase. Aminophylline is the water-soluble salt of theophylline that can be administered orally (3-6 mg/kg) or intravenously (loading dose of 5 mg/kg, followed by 0.5-1.0 mg·kg⁻¹·h⁻¹). Therapeutic plasma concentrations of theophylline are between 5 and 15 μg/mL, although levels as low as 5 μg/mL have been shown to be clinically effective.

Aminophylline works in vitro by inhibiting phosphodiesterase and, thereby, cAMP breakdown. The in vivo mechanism of aminophylline is less clear. Antiinflammatory actions on neutrophils, sympathetic stimulation, and adenosine antagonism are possible mechanisms. The narrow therapeutic range of aminophylline and the potential for arrhythmias developing in patients with the use of this drug have made its use in the perioperative setting controversial. Theophylline is principally metabolized by the liver, and 10% is excreted unchanged in urine. Smokers metabolize the drug faster than do nonsmokers. Heart failure, liver disease, and severe respiratory obstruction all slow the metabolism of theophylline and increase the likelihood of toxicity. Metabolism is slowed by cimetidine and β-adrenergic receptor antagonists.

Theophylline improves pulmonary function and resolves obstruction, in a dose-dependent manner, in patients with reactive airway disease. The drug decreases pulmonary vascular resistance and increases cardiac output. The cardiac-stimulating effects of theophylline are still seen in the presence of β blockade because xanthines are not receptor dependent. Theophylline and caffeine have been shown to decrease the number and duration of apneic episodes in preterm infants.

Side effects with the use of theophylline are often seen when plasma levels exceed 20 μg/mL. The most frequent side effects are nausea and vomiting. Seizures may result from toxic levels and are likely to occur when plasma concentrations exceed 40 μg/mL. Tachycardia and other arrhythmias may also occur with high plasma levels. Theophylline facilitates neuromuscular transmission; thus, patients receiving theophylline may require higher than normal doses of nondepolarizing neuromuscular blocking agents.

Anticholinergic agents

Cholinergic mechanisms play a major role in mediating reflex bronchoconstriction, and anticholinergic drugs may be used to reduce these responses. These medications have been found to be somewhat more effective than β-adrenergic receptor agonists in some patients with chronic bronchitis and emphysema. In the management of asthma, anticholinergic agents are generally less effective than are β-adrenergic receptor agonists, but in acute asthma, a combination of the two types of agents may produce a greater response. Atropine sulfate, a parasympatholytic that can relax airway smooth muscle, can also be given by nebulizer. Because atropine reduces mucociliary clearance and causes other central nervous system and cardiovascular side effects, even at low doses, this medication is not commonly used as a bronchodilator.

Ipratropium bromide, a quaternary amine delivered by nebulizer or MDI, has little systemic absorption. Its bronchodilator effects begin within minutes, with a peak effect in 1 to 2 h. Ipratropium has little or no effect on mucociliary clearance from the lung and little or no effect on heart rate, blood pressure, and gastrointestinal tract. Ipratropium is also available in combination with albuterol.

Antiinflammatory agents

Antiinflammatory agents, such as cromolyn sodium, which stabilize mast cell membranes and thereby intervene in the inflammatory process, are frequently used to treat bronchospastic diseases. Corticosteroids block both the initial immune response and the subsequent inflammatory process. Corticosteroids do not have direct effects on bronchial smooth muscle relaxation but do facilitate the effects of β₂-adrenergic receptor agonists. Even though the cellular and biochemical effects are immediate, the full clinical effects take longer; the increase in β-adrenergic receptor agonist response occurs within 2 h, and β-adrenergic receptor agonist density increases within 4 h. Systemically administered steroids, such as hydrocortisone or methylprednisolone, may be required in patients with poor responses to β₂-adrenergic receptor agonists over 1 to 2 h. Inhaled corticosteroids, such as beclomethasone, flunisolide, and triamcinolone, which are available as MDIs, DPIs, and nebulizer solutions, are then used to minimize systemic side effects. Symptoms usually improve in 1 to 2 weeks, with maximal response most often occurring in 4 to 8 weeks.

Adjunctive medication

Although the exact mechanism by which MgSO₄ relaxes airway smooth muscle is not completely understood, it is thought that it does so through blockade of voltage-dependent calcium channels, thereby inhibiting Ca²⁺ influx. Intravenously administered MgSO₄ (2 g) is a safe and effective adjunct for the treatment of acute asthma and bronchospasm in both adults and children. Nebulized MgSO₄ has been used, but this treatment is controversial and warrants further studies.

Inhalation anesthetic agents, such as isoflurane, in subanesthetic doses have been used to relieve bronchospasm after extubation and in patients with status asthmaticus. They have also occasionally been used long term (i.e., 2-3 days) in the intensive care unit in patients with status asthmaticus.