Katzung & Trevor's Pharmacology Examination and Board Review, 9th Edition

Chapter 20. Bronchodilators & Other Drugs Used in Asthma

Bronchodilators & Other Drugs Used in Asthma: Introduction

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 2-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.

High-Yield Terms to Learn

Bronchial hyperreactivity Pathologic increase in the bronchoconstrictor response to antigens and irritants; caused by bronchial inflammation IgE-mediated disease Disease caused by excessive or misdirected immune response mediated by IgE antibodies. Example: asthma Mast cell degranulation Exocytosis of granules from mast cells with release of mediators of inflammation and bronchoconstriction Phosphodiesterase (PDE) Family of enzymes that degrade cyclic nucleotides to nucleotides, for example, cAMP (active) to AMP (inactive); various isoforms, some degrade cGMP to GMP Tachyphylaxis Rapid loss of responsiveness to a stimulus (eg, a drug)

Pathophysiology of Asthma

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.

FIGURE 20-1

Immunologic model for the pathogenesis of asthma. Exposure to antigen causes synthesis of IgE, which binds to and sensitizes mast cells and other inflammatory cells. When such sensitized cells are challenged with antigen, a variety of mediators are released that can account for most of the signs of the early bronchoconstrictor response in asthma. LTC4, D4, leukotrienes C4 and D4; ECF-A, eosinophil chemotactic factor-A; PGD2, prostaglandin D2.

(Modified and reproduced, with permission, from Gold WW: Cholinergic pharmacology in asthma. In: Asthma Physiology, Immunopharmacology, and Treatment. Austen KF, Lichtenstein LM, editors. Academic Press, 1974.)

Strategies of Asthma Therapy

Acute asthmatic bronchospasm must be treated promptly and effectively with bronchodilators ("reliever" drugs). Beta 2 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 and drugs (such as cromolyn and nedocromil ) that inhibit release of mediators from mast cells and other inflammatory cells. Long-acting 2 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.

Beta-Adrenoceptor Agonists

Prototypes and Pharmacokinetics

The most important sympathomimetics used to reverse asthmatic bronchoconstriction are the 2-selective agonists, although epinephrine and isoproterenol are still available and used occasionally (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 and formoterol are long-acting 2-selective agonists. 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 and formoterol act for 12 h or more.

*Do not confuse metaproterenol, a 2 agonist, with metoprolol, a -blocker.

Mechanism and Effects

Beta-adrenoceptor agonists stimulate adenylyl cyclase (via the 2-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.

FIGURE 20-2

Possible mechanisms of  agonists, muscarinic antagonists, theophylline, and leukotriene antagonists in altering bronchial tone in asthma. AC, adenylyl cyclase; PDE, phosphodiesterase.

Clinical Use

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  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.

Toxicity

Skeletal muscle tremor is a common adverse 2 effect. Beta2 selectivity is relative. At high clinical dosage, these agents have significant 1 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.

Methylxanthines

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. The 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

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.

Effects

In asthma, bronchodilation is the most important therapeutic action of theophylline. Increased strength of contraction of the diaphragm has been demonstrated in some patients. 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), and increased gastrointestinal motility.

Clinical Use

The major clinical indication for the use of methylxanthines is asthma, but none of this class of compounds is as safe or effective as the  agonists. Slow-release theophylline (for control of nocturnal asthma) is the most important methylxanthine in clinical use. 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.

Toxicity

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.

Muscarinic Antagonists

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

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.

Effects

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

Ipratropium and tiotropium are useful in one third to two thirds of asthmatic patients; 2 agonists are effective in almost all. For acute bronchospasm, therefore, the  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  agonists.

Toxicity

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 2 agonists, muscarinic antagonists do not cause tremor or arrhythmias.

Cromolyn & Nedocromil

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. Cromolyn is the prototype of this group.

Mechanism of Action

The mechanism of action of these drugs is poorly understood but appears to 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).

FIGURE 20-3

Summary of treatment strategies in asthma.

(Modified and redrawn from Cockcroft DW: The bronchial late response in the pathogenesis of asthma and its modulation by therapy. Allergy Asthma Immunol 1985;55:857.)

Effects

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

Asthma (especially in children) is 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.

Toxicity

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

Corticosteroids

Prototypes and Pharmacokinetics

All the corticosteroids are potentially beneficial in severe asthma (see Chapter 39). However, because of their toxicity, systemic (oral) corticosteroids 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

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  adrenoceptors in the airway.

Effects

See Chapter 39 for details. 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. 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

Inhaled glucocorticoids are now considered appropriate (even for children) in most cases of moderate asthma that are not fully responsive to aerosol  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. Their mechanism of action in this condition is not fully understood. (See Chapter 39 for other uses.)

Toxicity

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.

Leukotriene Antagonists

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.

Skill Keeper: Sympathomimetics in Asthma

(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.

Anti-IgE Antibody

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. It was approved in 2003 for the prophylactic management of asthma, and initial reports have been positive. It is very expensive and must be administered parenterally.

Skill Keeper Answer: Sympathomimetics in Asthma

(See Chapter 9)

Direct-acting sympathomimetics are usually rapid in onset and short acting (eg, epinephrine, albuterol; exceptions: salmeterol, formoterol). 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 - and 1 -adrenoceptor-mediated effects of these catecholamines, most of which are undesirable in asthma. In contrast, the direct-acting agents can be tailored for selective 2activity. Furthermore, local application by aerosol administration is convenient and greatly reduces the systemic toxicity associated with oral or other systemic routes.

Checklist

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

 Describe the strategies of drug treatment of asthma.

 List the major classes of drugs used in asthma.

 Describe the mechanisms of action of these drug groups.

 List the major adverse effects of the prototype asthma drugs.

Drug Summary Table: Bronchodilators & Other Drugs Used in Asthma

Subclass Mechanism of Action Clinical Applications Pharmacokinetics Toxicities, Interactions Short-acting  agonists Albuterol Beta2-selective agonist; bronchodilation

Asthma acute attack relief drug of choice (not for prophylaxis) Inhalation (aerosol) Duration: 2-4 h Tremor, tachycardia Metaproterenol, terbutaline: Similar to albuterol. Terbutaline also available as oral and parenteral formulations Long-acting  agonists Salmeterol, formoterol Beta2-selective agonist; bronchodilation; potentiation of corticosteroid action

Asthma prophylaxis (not for acute relief) Inhalation (aerosol) Duration: 12 h Tremor, tachycardia, cardiovascular events Nonselective sympathomimetics Epinephrine, isoproterenol Nonselective  activation; epinephrine also an  agonist Asthma (obsolete) Inhalation (aerosol, nebulizer) Duration: 1-2 h Excess sympathomimetic effect (Chapter 9) Indirect-acting sympathomimetic Ephedrine Releases norepinephrine; causes nonselective sympathetic effects Asthma (obsolete) Oral Duration: 6-8 h Insomnia, tremor, anorexia, arrhythmias Methylxanthines Theophylline Phosphodiesterase inhibition, adenosine receptor antagonist; other effects poorly understood Asthma, especially prophylactic against nocturnal attacks Oral slow-release Duration: 12 h Insomnia, tremor, anorexia, seizures, arrhythmias Caffeine: Similar to theophylline with increased CNS effect Theobromine: Similar to theophylline with increased cardiac effect Antimuscarinic agents Ipratropium, tiotropium Competitive pharmacologic muscarinic antagonists Bronchodilator in asthma and chronic obstructive pulmonary disease Inhalation (aerosol) Duration: several hours Dry mouth, cough Mast cell stabilizers Cromolyn, nedocromil Reduce release of inflammatory and bronchoconstrictor mediators from sensitized mast cells Prophylaxis of asthma; cromolyn also used for ophthalmic, nasopharyngeal, and gastrointestinal allergy Inhaled aerosol for asthma; cromolyn local application for other applications Duration: 3-6 h Cough Leukotriene antagonists Montelukast, zafirlukast Pharmacologic antagonists at LTD4 receptors

Prophylaxis of asthma Oral Duration: 12-24 h Minimal Zileuton Inhibitor of lipoxygenase; reduces synthesis of leukotrienes Prophylaxis of asthma Oral Duration: 12 h Elevation of liver enzymes Corticosteroids InhaledBeclomethasone, others Inhibitor of phospholipase A2; reduces expression of cyclooxygenase

Prophylaxis of asthma: drugs of choice Inhalation Duration: 10-12 h Pharyngeal candidiasis; minimal systemic steroid toxicity (eg, adrenal suppression) Systemic Prednisone Like inhaled corticosteroids Treatment of severe refractory chronic asthma Oral Duration: 12-24 h See Chapter 39 Prednisolone: Parenteral for status asthmaticus; similar to prednisone Antibodies Omalizumab Binds IgE antibodies on mast cells; reduces reaction to inhaled antigen Prophylaxis of severe, refractory asthma not responsive to all other drugs Parenteral; administered as several courses of injections Extremely expensive; long-term toxicity not yet well documented



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