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

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 characterized by some degree of permanent structural damage to the airways and parenchyma; exacerbation of symptoms (wheezing, shortness of breath, cough) 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. Nasal oxygen is basic therapy for acute bronchospasm of any cause.

A. Prototypes and Pharmacokinetics

The most important sympathomimetics used to reverse asthmatic bronchoconstriction are the direct-acting β₂-selective agonists (see Chapter 9). Indirect-acting sympathomimetics, eg, ephedrine, were once used, but they are now obsolete for this application. Of the selective direct-acting agents, albuterol, terbutaline, and metaproterenol^* are short-acting and are the most important in the United States. Salmeterol, formoterol, indacaterol, and vilanterol are long-acting β₂ agonists (LABA), but indacaterol and vilanterol are 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, indacaterol, and vilanterol act for 12–24 h.

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

B. Mechanism and Effects

Beta-adrenoceptor agonists stimulate adenylyl cyclase (via the β₂-adrenoceptor–G_s-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.

C. 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 and tremor 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.

The sympathomimetic bronchodilators are drugs of choice in acute asthma (See Chapters 8 and 9). Some patients benefit from muscarinic antagonists. Compare the properties of sympathomimetics and antimuscarinics relative to the therapeutic goals in asthma. Under what conditions might an antimuscarinic drug be preferable? The Skill Keeper Answers appear at the end of the chapter.

A. 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.

B. 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. Several isoforms of PDE have been identified; PDE3 appears to be the primary form responsible for methylxanthine-induced bronchodilation, while PDE4 may be responsible for inhibition of inflammatory cells. 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.

C. 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. Roflumilast, an oral, nonpurine, more selective PDE4 inhibitor, has been approved for use in COPD. 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. Two cups of strong coffee are said to contain enough methylxanthine drug to produce measurable bronchodilation.

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.

A. 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 (see Chapter 8). This drug is delivered to the airways by pressurized aerosol and has little systemic action. Tiotropium and aclidinium are longer-acting analogs approved for use in COPD.

B. Mechanism of Action and Effects

When given by aerosol, these drugs 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.

C. Clinical Use and Toxicity

Inhaled antimuscarinic agents 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.

A. 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 (cortisol).

B. 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). Concentrations of prostaglandins and leukotrienes are reduced. It has also been suggested that the glucocorticoid 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 phospholipase-stimulated eicosanoid synthesis are extremely potent bronchoconstrictors and may also participate in the late inflammatory response (Figure 20–3).

C. 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 the earlier belief 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 small degree of adrenal suppression, but this is rarely significant. More commonly, deposition of inhaled drug droplets in the pharynx causes changes in oropharyngeal flora that 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.

A. Leukotriene Receptor Blockers

Montelukast and zafirlukast 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.

B. 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.

A. Prototypes and Pharmacokinetics

Cromolyn (disodium cromoglycate) and nedocromil are unusually insoluble chemicals, so 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.

B. 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) from mast cells. 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.

C. 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.

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

1. One effect that theophylline, nitroglycerin, isoproterenol, and histamine have in common is

   • (A) Direct stimulation of cardiac contractile force

   • (B) Tachycardia

   • (C) Bronchodilation

   • (D) Postural hypotension

   • (E) Throbbing headache

2. A 23-year-old woman is using an albuterol inhaler for frequent acute episodes of asthma and complains of symptoms that she ascribes to the albuterol. Which of the following is not a recognized action of albuterol?

   • (A) Diuretic effect

   • (B) Positive inotropic effect

   • (C) Skeletal muscle tremor

   • (D) Smooth muscle relaxation

   • (E) Tachycardia

3. A 10-year-old child has severe asthma and was hospitalized 5 times between the ages of 7 and 9. He is now receiving outpatient medications that have greatly reduced the frequency of severe attacks. Which of the following is most likely to have adverse effects when used daily over long periods for severe asthma?

   • (A) Albuterol by aerosol

   • (B) Beclomethasone by aerosol

   • (C) Ipratropium by inhaler

   • (D) Prednisone by mouth

   • (E) Theophylline in long-acting oral form

   4–5. A 16-year-old patient is in the emergency department receiving nasal oxygen. She has a heart rate of 125 bpm, a respiratory rate of 40 breaths/min, and a peak expiratory flow <50% of the predicted value. Wheezing and rales are audible without a stethoscope.

4. Which of the following drugs does not have a direct bronchodilator effect?

   • (A) Epinephrine

   • (B) Terbutaline

   • (C) Prednisone

   • (D) Theophylline

   • (E) Ipratropium

5. After successful treatment of the acute attack, the patient was referred to the outpatient clinic for follow-up treatment for asthma. Which of the following is not an established prophylactic strategy for asthma?

   • (A) Avoidance of antigen exposure

   • (B) Blockade of histamine receptors

   • (C) Blockade of leukotriene receptors

   • (D) IgE antibody blockade

   • (E) Inhibition of phospholipase A₂

6. Mr Green is a 60-year-old former smoker with cardiac disease and severe chronic obstructive pulmonary disease (COPD) associated with frequent episodes of bronchospasm. Which of the following is a bronchodilator useful in COPD and least likely to cause cardiac arrhythmia?

   • (A) Aminophylline

   • (B) Cromolyn

   • (C) Epinephrine

   • (D) Ipratropium

   • (E) Metaproterenol

   • (F) Metoprolol

   • (G) Prednisone

   • (H) Salmeterol

   • (I) Zafirlukast

   • (J) Zileuton

7. A 22-year-old man is brought to the emergency department after suffering seizures resulting from an overdose of a drug he has been taking. His friends state that he took the drug orally and sometimes had insomnia after taking it. Which of the following is a direct bronchodilator that is most often used in asthma by the oral route and is capable of causing insomnia and seizures?

   • (A) Cromolyn

   • (B) Epinephrine

   • (C) Ipratropium

   • (D) Metaproterenol

   • (E) Metoprolol

   • (F) Prednisone

   • (G) Salmeterol

   • (H) Theophylline

   • (I) Zileuton

8. Which of the following in its parenteral form is life-saving in severe status asthmaticus and acts, at least in part, by inhibiting phospholipase A₂?

   • (A) Aminophylline

   • (B) Cromolyn

   • (C) Epinephrine

   • (D) Ipratropium

   • (E) Metaproterenol

   • (F) Metoprolol

   • (G) Prednisone

   • (H) Salmeterol

   • (I) Zafirlukast

   • (J) Zileuton

9. Which of the following has a slow onset but long duration of action and is always used in combination with a corticosteroid by inhalation?

   • (A) Aminophylline

   • (B) Cromolyn

   • (C) Epinephrine

   • (D) Ipratropium

   • (E) Metaproterenol

   • (F) Metoprolol

   • (G) Prednisone/prednisolone

   • (H) Salmeterol

   • (I) Zafirlukast

   • (J) Zileuton

10. Oral medications are popular for the treatment of asthma in children because young children may have difficulty with the proper use of aerosol inhalers. Which of the following is an orally active inhibitor of leukotriene receptors?

    • (A) Albuterol

    • (B) Aminophylline

    • (C) Ipratropium

    • (D) Montelukast

    • (E) Zileuton

1. Theophylline does not ordinarily cause headache or postural hypotension. Nitroglycerin does not cause direct cardiac stimulation but does evoke a compensatory sympathetic reflex. Histamine does not cause bronchodilation. The answer is B.

2. Albuterol is a β₂-selective receptor agonist, but in moderate to high doses it produces β₁ cardiac effects as well as β₂-mediated smooth and skeletal muscle effects. It does not cause diuresis. The answer is A.

3. Chronic systemic corticosteroids have important toxicities (see Chapter 39). If oral corticosteroids must be used, alternate-day therapy is preferred because it interferes less with normal growth and metabolism in children. The answer is D.

4. Although extremely important in severe chronic asthma and status asthmaticus, corticosteroids do not have a demonstrable direct bronchodilator action. The answer is C.

5. Histamine does not appear to play a significant role in asthma, and antihistaminic drugs, even in high doses, are of little or no value. Antigen avoidance is well established. Blockade of leukotriene receptors with montelukast; inhibition of phospholipase with corticosteroids; and inhibition of mediator release with the IgE antibody are also useful. The answer is B.

6. Ipratropium or a similar antimuscarinic agent is the bronchodilator that is most likely to be useful in COPD without causing arrhythmias. The answer is D.

7. Theophylline is a bronchodilator that is active by the oral route. It causes insomnia in therapeutic doses and seizures in overdosage. The answer is H.

8. Parenteral corticosteroids such as prednisolone (the active metabolite of prednisone) are lifesaving in status asthmaticus. They probably act by reducing production of leukotrienes (see Chapter 18). The answer is G.

9. Salmeterol is a β₂-selective agonist that has a slow onset and long duration of action. Used alone, it increases asthma mortality, but in combination with inhaled corticosteroids prophylactic use improves asthma control. The answer is H.

10. Zileuton is an inhibitor of the lipoxygenase enzyme involved in the synthesis of leukotrienes. Montelukast and zafirlukast are leukotriene antagonists at the leukotriene receptor. The answer is D.

Direct-acting sympathomimetics are usually rapid in onset and short acting (eg, epinephrine, albuterol; exceptions: salmeterol, formoterol, indacaterol, vilanterol) (See Chapters 8 and 9). They are extremely efficacious and actively relax the bronchioles. Antimuscarinic drugs are somewhat slower in onset of action and are therefore used more often as “controller” therapy in COPD rather than “reliever” therapy in asthma. Not all asthma patients have vagal reflex output to the bronchi as a major contributor to the bronchospasm, and these patients will not respond well to an antimuscarinic. On the other hand, a patient with severe cardiac disease may be very sensitive to the arrhythmogenic effects of β agonists and therefore tolerate these agents poorly, while antimuscarinic agents rarely cause arrhythmias.

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.