Nonsteroidal antiasthma agents
After reading this chapter, the reader will be able to:
1. Discuss the indications for nonsteroidal antiasthma agents.
2. List available nonsteroidal antiasthma agents used in respiratory therapy.
3. Differentiate between the specific nonsteroidal antiasthma agents.
4. Describe routes of administration available for various nonsteroidal antiasthma agents.
5. Describe the mode of action for various nonsteroidal antiasthma agents.
6. Discuss the use of nonsteroidal antiasthma agents in the treatment of asthma.
In Chapter 11, to present the antiinflammatory actions of glucocorticoids, the concept of airway inflammation was introduced, and some of the numerous cells and chemicals involved in an inflammatory response were described. Chapter 12 presents drug groups that also have an antiinflammatory effect through mechanisms different from those of the corticosteroids. Three subgroups of agents are included in the nonsteroidal antiasthma group: cromolyn-like drugs (mast cell stabilizers), antileukotrienes, and monoclonal antibodies. A brief summary of the immune mechanisms involved in allergic responses is given as an introduction to the specific mechanisms of action for the drug groups discussed in this chapter.
Clinical indications for nonsteroidal antiasthma agents
The general indication for clinical use of nonsteroidal antiasthma agents described in this chapter is prophylactic management (control) of mild persistent asthma (asthma requiring step 2 care, according to the classification presented in the 2007 National Asthma Education and Prevention Program [NAEPP] guidelines1).
The following are qualifications to the general indication for use of these agents:
• Cromolyn and antileukotrienes are typically recommended as alternatives to low-dose inhaled corticosteroids in asthma requiring step 2 care.1
• Cromolyn is often used with infants and young children as alternatives to inhaled corticosteroids in asthma requiring step 2 care because of the safety profiles of inhaled corticosteroids.1
• Antileukotrienes can be useful in combination with inhaled corticosteroids to reduce the dose of steroid.
All of the nonsteroidal antiasthma drugs described in this chapter are controllers, not relievers, and are used in asthma requiring antiinflammatory drug therapy. Box 12-1 summarizes reliever and controller agents used in drug therapy for asthma, listing cromolyn-like agents, antileukotrienes, and monoclonal antibodies as controllers. Use of rescue β2-agonist agents more than twice a week (i.e., asthma requiring step 2 care) is an indicator of the need to initiate controller drug therapy.
Identification of nonsteroidal antiasthma agents
Individual agents in the cromolyn-like agent group, antileukotriene group, and monoclonal antibody group are presented in Table 12-1 with generic and brand names, formulations and strengths, and usual recommended dosages.
TABLE 12-1
Nonsteroidal Antiasthma Medications: Generic and Brand Names, Formulations, and Usual Recommended Dosages*
| GENERIC DRUG | BRAND NAME | FORMULATION AND DOSAGE |
| Cromolyn-Like Agents (Mast Cell Stabilizers) | ||
| Cromolyn sodium | NasalCrom, Gastrocrom | SVN: 20 mg/ampoule or 20 mg/2 mL |
| Adults and children ≥2 yr: 20 mg inhaled 4 times daily | ||
| Spray: 40 mg/mL (5.2 mg per actuation) | ||
| Adults and children ≥2 yr: 1 spray each nostril, 3-6 times daily every 4-6 hr | ||
| Oral concentrate: 100 mg/5 mL | ||
| Adults and children ≥13 yr: 2 ampoules 4 times daily, 30 min before meals and at bedtime | ||
| Children 2-12 yr: 1 ampoule 4 times daily, 30 min before meals and at bedtime | ||
| Antileukotrienes | ||
| Zafirlukast | Accolate | Tablets: 10 mg and 20 mg |
| Adults and children ≥12 yr: 20 mg twice daily, without food | ||
| Children 5-11 yr: 10 mg twice daily | ||
| Montelukast | Singulair | Tablets: 10 mg and 4-mg and 5-mg cherry-flavored chewable; 4-mg packet of granules |
| Adults and children ≥15 yr: 1 10-mg tablet daily | ||
| Children 6-14 yr: 1 5-mg chewable tablet daily | ||
| Children 2-5 yr: 1 4-mg chewable tablet or 1 4-mg packet of granules daily | ||
| Children 6-23 mo: 1 4-mg packet of granules daily | ||
| Zileuton | Zyflo; Zyflo CR | Tablets: 600 mg |
| Adults and children ≥12 yr: 1 600-mg tablet 4 times per day; CR, 2 tablets twice daily, within 1 hr of morning and evening meals | ||
| Monoclonal Antibody | ||
| Omalizumab | Xolair | Adults and children ≥12 yr: Subcutaneous injection every 4 wk; dose dependent on weight and serum IgE level |
*Detailed prescribing information should be obtained from manufacturer’s package insert.
Mechanisms of inflammation in asthma
Asthma is a chronic inflammatory disorder of the airways.1 Asthma has been divided into extrinsic and intrinsic forms on the basis of the triggers for asthma. Extrinsic asthma is dependent on allergy, or atopy, whereas intrinsic asthma shows no evidence of sensitization to common inhaled allergens.2 The allergic form of asthma, which is immunoglobulin E (IgE)–mediated, is associated with younger subjects, and the intrinsic, or nonallergic, form is associated with later onset in adults in whom childhood asthma may not have been present. Holgate3 described asthma as an “evolving” disease in early childhood, when viruses are an important trigger, whereas in school and teen years, allergens stimulate an immune response. As asthma progresses and in adults, the disease becomes intrinsic and may be driven by T cells (lymphocytes) that release various cytokines, as described in Chapter 11. Asthma is chronic and persistent, with continuous inflammation and episodes of acute obstruction. Drazen and Turino4 described three components of asthma:
1. Acute asthma attack, which resolves spontaneously or with treatment
In both forms of asthma, allergic and nonallergic mediators and enzymes are released to act on target tissues in the airway, and cells involved in inflammation are recruited and activated in the airway. Airway inflammation is manifested in the responses of bronchoconstriction, airway swelling, mucus secretion and obstruction, and subsequent airway wall remodeling that furthers the responsiveness of the airway.5
Immunologic (allergic) response
Most instances of asthma are primarily an allergic response, which involves mast cells and IgE.1 The immunologic response is outlined in Box 12-2. An understanding of the immune response is fundamental to discussing asthma and the mediator antagonists presented in this chapter because allergy is essentially a mistaken immune response.
Generation of an immune response and specifically an allergic asthmatic response is considered to be initiated by the interaction of T lymphocytes with an antigen presented by other cells, such as macrophages or B lymphocytes.4 Activation of T lymphocytes results in production of IgE by B lymphocytes. Antigen-specific IgE binds to effector cells such as mast cells and is termed a cytophilic antibody because of this. When activated by subsequent exposure to an antigen or allergen, mast cells release physiologically active mediators of inflammation, such as prostaglandins, leukotrienes, proteases, histamine, platelet-activating factor (PAF), and certain cytokines.4 The cytokines released, which include tumor necrosis factor-α (TNF-α) and interleukin-4 (IL-4), can upregulate endothelial adhesion molecules.3
This cascade of mediators causes an inflammatory response manifested by vascular leakage, bronchoconstriction, mucus secretion, and mucosal swelling, all of which obstruct airflow in the bronchioles. T lymphocytes also release cytokines (e.g., interleukins), causing accumulation and activation of eosinophils, which also release chemicals to damage the airway. The process of initiating the inflammatory response and continuing it through amplification, as discussed next, is illustrated in Figure 12-1.
After being initiated by exposure to antigen, the inflammatory response in the airway is amplified by chemoattraction of more lymphocytes, eosinophils, basophils, and neutrophils and by an increase in mast cells. Adhesion molecules increase after stimulation of lymphocytes and mast cells by antigen or allergen. These molecules, found in epithelial cells (intercellular adhesion molecule-1 [ICAM-1]) and vascular endothelial cells (vascular cell adhesion molecule-1 [VCAM-1]) in the airway, are responsible for eosinophil, neutrophil, and lymphocyte recruitment from the microvascular circulation into the airways. The adhesion molecules enable leukocytes to marginate, cross the blood vessel wall, and migrate to the airway mucosa, continuing and further amplifying the inflammation begun.6 The increase and activation of eosinophils are associated with increased inflammation and severity in asthma.3
Nonspecific stimuli, such as fog, sulfur dioxide, dust, and cold air, can stimulate sensory receptors and cause reflex bronchoconstriction (see Chapter 7).5 Asthmatic patients are more sensitive to such stimuli, which reflects altered neural control or chronic inflammation sensitizing the airway, or both. Nerve fibers of the noncholinergic, nonadrenergic excitatory system, containing potent peptide mediators, contribute to local effects on smooth muscle and mucous glands and reflexively stimulate cholinergic activity. Some of these peptides include substance P (SP), neurokinin A (NKA), and neurokinin B (NKB); they are released from sensory C-fiber nerve endings. These neuropeptides can also contribute to inflammation and the features of asthma previously described, such as mucus hypersecretion, smooth muscle contraction, plasma leakage, inflammatory cell activation, and adhesion. Neutral endopeptidase (NEP) is an enzyme that inactivates neuropeptides to limit their activity; NEP is found on the surface of cells that contain receptors for neuropeptides (smooth muscle, airway epithelium, and vascular endothelium). An increased release of excitatory neuropeptides may be involved in asthma.5
Nitric oxide is formed in airway tissue through the action of the enzyme nitric oxide synthase (NOS). There is evidence that in asthma NOS is upregulated in airway epithelium.5 Nitric oxide, a potent vasodilator and bronchodilator, may be the neurotransmitter for the nonadrenergic, noncholinergic inhibitory nervous system (see Chapter 5). Nitric oxide, which can damage cells, possibly is induced by proinflammatory cytokines in asthma and contributes to the observed epithelial damage seen in Figure 12-1.6,7
Cromolyn (mast cell–stabilizing) agents
Cromolyn sodium, also termed disodium cromoglycate, is used as an inhaled prophylactic aerosol drug to prevent the inflammatory response in asthma. These drugs differ in structure and activity from the drug groups considered in previous chapters. Their chemical structures are illustrated in Figure 12-2. The basic catecholamine xanthine and steroid structures are given for comparison. Cromolyn is not related to the β agonists, xanthines, theophylline, or antiinflammatory glucocorticoids. Cromolyn has no intrinsic bronchodilating capability.
Cromolyn sodium (disodium cromoglycate)
Cromolyn sodium is used as a prophylactic agent in the treatment of asthma. Although it may not be used as often in clinical practice today as it was previously, this agent is an alternative in mild persistent asthma.1 The antiinflammatory, mast cell–stabilizing effect of cromolyn has led to uses other than asthma prophylaxis, including the following:
• Allergic rhinitis (nasal solution)
• Mastocytosis—to improve diarrhea, abdominal pain, headaches, nausea, and itching (oral)
Mode of action
Cromolyn sodium is considered an antiasthmatic, an antiallergic, and a mast cell stabilizer. Pretreatment with inhaled cromolyn sodium results in inhibition of mast cell degranulation, blocking release of the chemical mediators of inflammation (Figure 12-3). By its action, cromolyn is effective in blocking the late phase reaction in asthma. (The late phase reaction in asthma is discussed in the review of corticosteroids in Chapter 11.)
• The mode of action of cromolyn sodium is prophylactic; pretreatment is necessary for inhibition of mast cell degranulation.
• Cromolyn sodium may inhibit mediator release by preventing calcium influx necessary for microfilament contraction and extrusion of mast cell granules.8,9
• Cromolyn sodium does not have an antagonist effect on any of the chemical mediators themselves.
• Cromolyn sodium does not operate through the cyclic adenosine 3’,5’-monophosphate (cAMP) system and does not affect α or β receptors.
• Antibody formation, attachment of antibody (IgE) to the mast cell, and antigen-antibody union are not prevented by cromolyn; cromolyn does prevent release of mediators.
• Cromolyn sodium can prevent or attenuate the late phase response in an asthmatic episode, which can otherwise cause more severe airway obstruction 6 to 8 hours after initial bronchoconstriction.10,11
The protective effect of cromolyn in inhibiting mast cell degranulation has been captured by scanning electron microscopy and is shown in the sequence in Figure 12-4. Initial understanding of the activity of cromolyn focused on allergy-triggered mast cell release of mediators, and the drug came to be considered useful primarily in allergic asthma. There is evidence that the activity of cromolyn is not limited to preventing allergen-stimulated asthma. Cromolyn inhibits mast cell mediator release caused by nonallergic stimuli and may reduce reflex-induced asthma. The latter requires about twice the usual dose of cromolyn. Understanding of the broader protection given by cromolyn has supported its successful use in allergic and nonallergic asthma and specifically in exercise-induced asthma.12,13
