Chapter 20. Drugs Used in Asthma & Chronic Obstructive Pulmonary Disease

Asthma is a disease characterized by airway inflammation and episodic, reversible bronchospasm. Drugs useful in asthma include bronchodilators (smooth muscle relaxants) and anti-inflammatory drugs. Bronchodilators include sympathomimetics, especially β2-selective agonists, muscarinic antagonists, methylxanthines, and leukotriene receptor blockers. Anti-inflammatory drugs used in asthma include corticosteroids, mast cell stabilizers, and an anti-IgE antibody. Leukotriene antagonists play a dual role. Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation that is less reversible than in asthma and by a progressive course. However, many of the same drugs are used.

The immediate cause of asthmatic bronchoconstriction is the release of several mediators from IgE-sensitized mast cells and other cells involved in immunologic responses (Figure 20–1). These mediators include the leukotrienes LTC4 and LTD4. In addition, chemotactic mediators such as LTB4 attract inflammatory cells to the airways. Finally, several cytokines and some enzymes are released, leading to chronic inflammation. Chronic inflammation leads to marked bronchial hyperreactivity to various inhaled substances, including antigens, histamine, muscarinic agonists, and irritants such as sulfur dioxide (SO2) and cold air. This reactivity is partially mediated by vagal reflexes. COPD is often triggered by upper respiratory infection (like asthma) but occurs in older patients (usually long-term smokers) and is poorly reversible with bronchodilators.

Acute bronchospasm must be treated promptly and effectively with bronchodilators ("reliever" drugs). Beta2 agonists, muscarinic antagonists, and theophylline and its derivatives are available for this indication. Long-term preventive treatment requires control of the inflammatory process in the airways ("controller" drugs). The most important anti-inflammatory drugs in the treatment of chronic asthma are the corticosteroids. Long-acting β2 agonists can improve the response to corticosteroids. Anti-IgE antibodies also appear promising for chronic therapy. The leukotriene antagonists have effects on both bronchoconstriction and inflammation but are used only for prophylaxis.

Prototypes and Pharmacokinetics

The most important sympathomimetics used to reverse asthmatic bronchoconstriction are the direct-acting β2-selective agonists (see Chapter 9). Of the indirect-acting sympathomimetics, ephedrine was once used, but it is now obsolete for this application. Of the selective agents, albuterol, terbutaline, and metaproterenol* are short-acting and are the most important in the United States. Salmeterol, formoterol, and indacaterol are long-acting β2-selective agonists, but indacaterol is currently approved only for COPD. Beta agonists are given almost exclusively by inhalation, usually from pressurized aerosol canisters but occasionally by nebulizer. The inhalational route decreases the systemic dose (and adverse effects) while delivering an effective dose locally to the airway smooth muscle. The older drugs have durations of action of 6 h or less; salmeterol, formoterol, and indacaterol act for 12–24 h.

Mechanism and Effects

Beta-adrenoceptor agonists stimulate adenylyl cyclase (via the β2-adrenoceptor–Gs-coupling protein-adenylyl cyclase pathway) and increase cyclic adenosine monophosphate (cAMP) in smooth muscle cells (Figure 20–2). The increase in cAMP results in a powerful bronchodilator response.

Clinical Use and Toxicity

Sympathomimetics are first-line therapy in acute asthma. Shorter acting sympathomimetics (albuterol, metaproterenol, terbutaline) are the drugs of choice for acute episodes of bronchospasm. Their effects last for 4 h or less, and they are not effective for prophylaxis. The long-acting agents (salmeterol, formoterol) should be used for prophylaxis, in which their 12-h duration of action is useful. They should not be used for acute episodes because their onset of action is too slow. Furthermore, used alone, they increase asthma mortality, whereas in combination with corticosteroids, they improve control. In almost all patients, the shorter-acting β agonists are the most effective bronchodilators available and are life-saving for acute asthma. Many patients with chronic obstructive pulmonary disease (COPD) also benefit, although the risk of toxicity is increased in this condition.

Skeletal muscle tremor is a common adverse β2 effect. Beta2 selectivity is relative. At high clinical dosage, these agents have significant β1 effects. Even when they are given by inhalation, some cardiac effect (tachycardia) is common. Other adverse effects are rare. When the agents are used excessively, arrhythmias may occur. Loss of responsiveness (tolerance, tachyphylaxis) is an unwanted effect of excessive use of the short-acting sympathomimetics. Patients with COPD often have concurrent cardiac disease and may have arrhythmias even at normal dosage.

*Do not confuse metaproterenol, a β2 agonist, with metoprolol, a β-blocker.

(See Chapter 9)

The sympathomimetic bronchodilators are drugs of choice in acute asthma. Compare the properties of direct- and indirect-acting sympathomimetics relative to the therapeutic goals in asthma. Which type is superior and why? The Skill Keeper Answer appears at the end of the chapter.

Prototypes and Pharmacokinetics

The methylxanthines are purine derivatives. Three major methylxanthines are found in plants and provide the stimulant effects of 3 common beverages: caffeine (in coffee), theophylline (tea), and theobromine (cocoa). Theophylline is the only member of this group that is important in the treatment of asthma. This drug and several analogs are orally active and available as various salts and as the base. Theophylline is available in both prompt-release and slow-release forms. Theophylline is eliminated by P450 drug-metabolizing enzymes in the liver. Clearance varies with age (highest in young adolescents), smoking status (higher in smokers), and concurrent use of other drugs that inhibit or induce hepatic enzymes.

Mechanism of Action and Effects

The methylxanthines inhibit phosphodiesterase (PDE), the enzyme that degrades cAMP to AMP (Figure 20–2), and thus increase cAMP. This anti-PDE effect, however, requires high concentrations of the drug. Methylxanthines also block adenosine receptors in the central nervous system (CNS) and elsewhere, but a relation between this action and the bronchodilating effect has not been clearly established. It is possible that bronchodilation is caused by a third as yet unrecognized action.

In asthma, bronchodilation is the most important therapeutic action of theophylline. Increased strength of contraction of the diaphragm has been demonstrated in some patients, an effect particularly useful in COPD. Other effects of therapeutic doses include CNS stimulation, cardiac stimulation, vasodilation, a slight increase in blood pressure (probably caused by the release of norepinephrine from adrenergic nerves), diuresis, and increased gastrointestinal motility.

Clinical Use and Toxicity

The major clinical use of methylxanthines is asthma and COPD. Slow-release theophylline (for control of nocturnal asthma) is the most commonly used methylxanthine. Aminophylline is a salt of theophylline that is sometimes prescribed. Another methylxanthine derivative, pentoxifylline, is promoted as a remedy for intermittent claudication; this effect is said to result from decreased viscosity of the blood. Of course, the nonmedical use of the methylxanthines in coffee, tea, and cocoa is far greater, in total quantities consumed, than the medical uses of the drugs.

The common adverse effects of methylxanthines include gastrointestinal distress, tremor, and insomnia. Severe nausea and vomiting, hypotension, cardiac arrhythmias, and seizures may result from overdosage. Very large overdoses (eg, in suicide attempts) are potentially lethal because of arrhythmias and seizures. Beta blockers are useful in reversing severe cardiovascular toxicity from theophylline.

Prototypes and Pharmacokinetics

Atropine and other naturally occurring belladonna alkaloids were used for many years in the treatment of asthma but have been replaced by ipratropium, a quaternary antimuscarinic agent designed for aerosol use. This drug is delivered to the airways by pressurized aerosol and has little systemic action. Tiotropium is a longer-acting analog.

Mechanism of Action and Effects

When given by aerosol, ipratropium and tiotropium competitively block muscarinic receptors in the airways and effectively prevent bronchoconstriction mediated by vagal discharge. If given systemically (not an approved use), these drugs are indistinguishable from other short-acting muscarinic blockers.

Muscarinic antagonists reverse bronchoconstriction in some asthma patients (especially children) and in many patients with COPD. They have no effect on the chronic inflammatory aspects of asthma.

Clinical Use and Toxicity

Ipratropium and tiotropium are useful in one third to two thirds of asthmatic patients; β2 agonists are effective in almost all. For acute bronchospasm, therefore, the β agonists are usually preferred. However, in COPD, which is often associated with acute episodes of bronchospasm, the antimuscarinic agents may be more effective and less toxic than β agonists.

Because these agents are delivered directly to the airway and are minimally absorbed, systemic effects are small. When given in excessive dosage, minor atropine-like toxic effects may occur (see Chapter 8). In contrast to the β2 agonists, muscarinic antagonists do not cause tremor or arrhythmias.

Prototypes and Pharmacokinetics

Cromolyn (disodium cromoglycate) and nedocromil are unusually insoluble chemicals, so that even massive doses given orally or by aerosol result in minimal systemic blood levels. They are given by aerosol for asthma but are now rarely used in the United States. Cromolyn is the prototype of this group.

Mechanism of Action and Effects

The mechanism of action of these drugs is poorly understood but may involve a decrease in the release of mediators (such as leukotrienes and histamine). The drugs have no bronchodilator action but can prevent bronchoconstriction caused by a challenge with antigen to which the patient is allergic. Cromolyn and nedocromil are capable of preventing both early and late responses to challenge (Figure 20–3).

Because they are not absorbed from the site of administration, cromolyn and nedocromil have only local effects. When administered orally, cromolyn has some efficacy in preventing food allergy. Similar actions have been demonstrated after local application in the conjunctiva and the nasopharynx for allergic IgE-mediated reactions in these tissues.

Clinical Uses and Toxicity

Asthma (especially in children) was the most important use for cromolyn and nedocromil. Nasal and eyedrop formulations of cromolyn are available for hay fever, and an oral formulation is used for food allergy.

Cromolyn and nedocromil may cause cough and irritation of the airway when given by aerosol. Rare instances of drug allergy have been reported.

Prototypes and Pharmacokinetics

All the corticosteroids are potentially beneficial in severe asthma (see Chapter 39). However, because of their toxicity, systemic (oral) corticosteroids (usually prednisone) are used chronically only when other therapies are unsuccessful. In contrast, local aerosol administration of surface-active corticosteroids (eg, beclomethasone, budesonide, dexamethasone, flunisolide, fluticasone, mometasone) is relatively safe, and inhaled corticosteroids have become common first-line therapy for individuals with moderate to severe asthma. Important intravenous corticosteroids for status asthmaticus include prednisolone (the active metabolite of prednisone) and hydrocortisone.

Mechanism of Action and Effects

Corticosteroids reduce the synthesis of arachidonic acid by phospholipase A2 and inhibit the expression of COX-2, the inducible form of cyclooxygenase (see Chapter 18). It has also been suggested that corticosteroids increase the responsiveness of β adrenoceptors in the airway and they probably act by other mechanisms as well.

Glucocorticoids bind to intracellular receptors and activate glucocorticoid response elements (GREs) in the nucleus, resulting in synthesis of substances that prevent the full expression of inflammation and allergy. See Chapter 39 for details. Reduced activity of phospholipase A2 is thought to be particularly important in asthma because the leukotrienes that result from eicosanoid synthesis are extremely potent bronchoconstrictors and may also participate in the late inflammatory response (Figure 20–3).

Clinical Use and Toxicity

Inhaled glucocorticoids are now considered appropriate (even for children) in most cases of moderate asthma that are not fully responsive to aerosol β agonists. It is believed that such early use may prevent the severe, progressive inflammatory changes characteristic of long-standing asthma. This is a shift from earlier beliefs that steroids should be used only in severe refractory asthma. In such cases of severe asthma, patients are usually hospitalized and stabilized on daily systemic prednisone and then switched to inhaled or alternate-day oral therapy before discharge. In status asthmaticus, parenteral steroids are lifesaving and apparently act more promptly than in ordinary asthma. Patients with COPD tend to be more resistant to the beneficial effects of steroids. Their mechanism of action in these conditions is not fully understood. (See Chapter 39 for other uses.)

Frequent aerosol administration of glucocorticoids can occasionally result in a very small degree of adrenal suppression, but this is rarely significant. More commonly, changes in oropharyngeal flora result in candidiasis. If oral therapy is required, adrenal suppression can be reduced by using alternate-day therapy (ie, giving the drug in slightly higher dosage every other day rather than smaller doses every day). The major systemic toxicities of the glucocorticoids described in Chapter 39 are much more likely to occur when systemic treatment is required for more than 2 weeks, as in severe refractory asthma. Regular use of inhaled steroids does cause mild growth retardation in children, but these children eventually reach full predicted adult stature.

These drugs interfere with the synthesis or the action of the leukotrienes (see also Chapter 18). Although their value has been established, they are not as effective as corticosteroids in severe asthma.

Leukotriene Receptor Blockers

Zafirlukast and montelukast are antagonists at the LTD4 leukotriene receptor (see Table 18–1). The LTE4 receptor is also blocked. These drugs are orally active and have been shown to be effective in preventing exercise-, antigen-, and aspirin-induced bronchospasm. They are not recommended for acute episodes of asthma. Toxicity is generally low. Rare reports of Churg-Strauss syndrome, allergic granulomatous angiitis, have appeared, but an association with these drugs has not been established.

Lipoxygenase Inhibitor

Zileuton is an orally active drug that selectively inhibits 5-lipoxygenase, a key enzyme in the conversion of arachidonic acid to leukotrienes. The drug is effective in preventing both exercise- and antigen-induced bronchospasm. It is also effective against "aspirin allergy," the bronchospasm that results from ingestion of aspirin by individuals who apparently divert all eicosanoid production to leukotrienes when the cyclooxygenase pathway is blocked (Chapter 18). The toxicity of zileuton includes occasional elevation of liver enzymes, and this drug is therefore less popular than the receptor blockers.

Omalizumab is a humanized murine monoclonal antibody to human IgE. It binds to the IgE on sensitized mast cells and prevents activation by asthma triggers and subsequent release of inflammatory mediators. Although approved in 2003 for the prophylactic management of asthma, experience with this drug is limited because it is very expensive and must be administered parenterally.

(See Chapter 9)

Direct-acting sympathomimetics are usually rapid in onset and short acting (eg, epinephrine, albuterol; exceptions: salmeterol, formoterol, indacaterol). Most direct-acting sympathomimetics have poor oral bioavailability. Indirect-acting sympathomimetics (eg, ephedrine) are usually longer acting and have good bioavailability. An important disadvantage of the indirect-acting group is their CNS activity: Most enter the CNS and produce undesirable stimulation. Even more important in asthma is the lack of receptor selectivity of the indirect-acting group. Because they release norepinephrine and epinephrine from stores, they produce all the α- and β1-adrenoceptor-mediated effects of these catecholamines, most of which are undesirable in asthma. In contrast, the direct-acting agents can be tailored for selective β2 activity. Furthermore, local application by aerosol administration is convenient and greatly reduces the systemic toxicity associated with oral or other systemic routes.

When you complete this chapter, you should be able to:

• □ Describe the strategies of drug treatment of asthma and COPD.
• □ List the major classes of drugs used in asthma and COPD.
• □ Describe the mechanisms of action of these drug groups.
• □ List the major adverse effects of the prototype drugs used in airways disease.