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Millions of people in the United States have asthma, and billions of dollars are spent annually on their care. Asthma is a condition of the respiratory system involving narrowing (bronchoconstriction) and inflammation of the small air passages of the lower respiratory system. Not only is asthma a serious condition affecting the general health of people, but it also affects their ability to be physically active and participate in sports at maximal levels.
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Technically, asthma, exercise-induced asthma (EIA), and exercise-induced bronchoconstriction (EIB) are separate conditions and are treated differently. True asthma is characterized by both bronchoconstriction and inflammation in the respiratory tract. Triggers that irritate the airways cause an asthma attack, now referred to as an exacerbation. Some athletes may have triggers such as chemicals or air pollutants that, when breathed into the lower respiratory system, start the inflammatory cascade of events. When asthma is triggered by exercise, it is classified as EIA. Unfortunately, exercise triggers symptoms in some people. The increased airflow into the lungs from the physiologic demands of exercise irritates the airway, initiating an inflammatory process in the airways. Exercise is a trigger for approximately 80 to 90 percent of individuals with asthma.3 Those with EIA must have excellent control of their underlying asthma to be able to prevent asthma exacerbations during physical activity.
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EIB without active inflammation is technically not exercise- induced asthma because the bronchoconstriction and inflammatory components are not both present, and therefore it is classified as EIB. It occurs in approximately 11 percent of individuals who do not have asthma,3 and its occurrence may be as high as 50 percent in elite athletes.11
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As mentioned earlier, acute asthma attacks involve both an inflammatory and a bronchoconstriction component. The inflammatory process initiates increased mucus production along the airway lining and bronchoconstriction results from contraction of the smooth muscles of the airways.
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In an asthmatic reaction, the most significant event that occurs as a result of the inflammatory response is the increase in mucus production by the body. This is a protective mechanism used by the body to coat the airway and protect it from exposure to the incoming irritant. Under normal circumstances, this is a good protective approach adopted by the body, which produces a thick, sticky substance and spreads it over the sensitive tissues of the lower respiratory system to limit tissue damage from the irritant.
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Obviously, however, this can become problematic if the source of irritation is not decreased or removed and mucus production continues in individuals who are sensitive to that particular irritant. For example, some people can be exposed to a smoke-filled environment for an extended period of time and never have an asthma exacerbation. On the other hand, for some people, a brief exposure to the same environment may be significant enough to start the cascade of events that is an asthma exacerbation. In these individuals, if the system continues to be irritated, the airways become excessively coated with mucus, resulting in airflow resistance.
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Another mechanism used by the body to protect the airway from exposure to an irritant is to simply constrict the size of the airway. Like mucus coating the airway, this is also an effective protective mechanism by the body. However, excessive bronchoconstriction can also be problematic to the athlete because of the dramatic decrease in the volume of air that can be exchanged between the lungs and the outside environment. Both of these protective mechanisms result in increased respiratory effort.
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The classic signs associated with an acute asthma exacerbation are shortness of breath and wheezing after exercise. However, care must be exercised not to overemphasize the presence or absence of wheezing in determining if a person is having an acute asthma exacerbation. Other signs and symptoms, such as a cough, headache, stomach cramps, pain or tightness in the chest, and nausea can also indicate a potential asthma exacerbation. These signs and symptoms typically start 6 to 8 minutes after the onset of strenuous exercise, but they may not reach maximum severity until up to 15 minutes after the cessation of exercise. Typically, spontaneous return to baseline respiratory function occurs within 20 to 60 minutes after onset of symptoms.
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Asthma Treatment Options
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Athletic trainers often interact with athletes who use an inhaler, more formally known as a metered-dose inhaler (MDI). These athletes are able to maintain adequate control of their asthma symptoms. Unfortunately, athletic trainers may also come into contact with athletes who do not have their asthma under control or who, in many cases, have not yet been given a diagnosis of asthma. For athletic trainers to be ready to deal with the undiagnosed asthmatic athlete, they need to have a basic understanding of asthma from physiological, pharmacological, and management perspectives.
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Most true asthma exacerbations have both inflammatory and bronchoconstriction components. Therefore the use of medications to control and treat asthma may address either or both of these problems. Currently, the most widely accepted approach to asthma treatment is to initially control the inflammatory process associated with the trigger and thus prevent bronchoconstriction onset. This approach is reflected in the switch from heavy dependence on "rescue" inhalers to the increased use of controlling agents. With respect to EIA, the athlete typically experiences little or no active inflammatory process and the primary complication is the bronchoconstriction associated with the exercise trigger. Thus, the treatments for asthma and EIA are different. Asthma exacerbations are categorized according to the severity and the frequency of the symptoms. In general, asthma is broken down into four categories: mild intermittent, mild persistent, moderate persistent, and severe persistent (Table 7–1).
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Commonly Used Drugs for Asthma Control
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Numerous pharmacological approaches are used to treat asthma. Some of the factors that influence the chosen approach are the severity and frequency of the exacerbations and the convenience of using the drug. The drugs used to treat asthma can be classified into two groups: bronchodilators and anti-inflammatory agents. Anti-inflammatory agents can be further divided into steroidal and nonsteroidal types.
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As their name implies, bronchodilators are used to dilate the bronchioles of the respiratory tract after the onset of bronchoconstriction. A bronchodilating MDI delivers a measured (metered) dose of medication each time it is activated. Historically, bronchodilating MDIs were used to rescue the user from an asthma attack, and therefore are commonly referred to as "rescue inhalers." It should be mentioned that some bronchodilators result in a relaxation of the smooth muscles in the airways, but they have not been demonstrated to be effective as "rescue" inhalers because they may take 1 to 2 hours to reach their maximum effectiveness.
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It is generally accepted that anyone with persistent asthma should use a controlling agent for the inflammatory component in conjunction with a "rescue" inhaler for the bronchoconstriction. Individuals with mild intermittent asthma are typically treated with a bronchodilator as needed, based on symptoms and activity level.
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The role of corticosteroids in asthma and respiratory care in general is to combat inflammation of the airways associated with certain respiratory conditions. Thus, they indirectly prevent inflammation-mediated bronchoconstriction through the inhibition of prostaglandins and leukotrienes. In addition, corticosteroids reverse vascular permeability associated with the inflammation process. Too many times, athletes rely on a corticosteroid MDI to resolve an initial anti-inflammatory asthma exacerbation during practice or competition. As we will discuss, the athlete should focus more on prevention of the exacerbation with the use of controlling drugs.
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Oral medications are an attractive alternative to the use of inhaled steroids in the control of asthma. Typically, they are administered orally once or twice a day. In addition, there is no fluctuation in delivery of the medication, which may result from improper use of the MDI. These drugs are used for the control of mild persistent asthma requiring anti-inflammatory treatment and are not effective as a rescuing agent because they do not have a rapid bronchodilating effect. It is important to note that all individuals who use either steroids or nonsteroidal anti-inflammatory medications still need access to a "rescue" inhaler in the event of an asthma exacerbation (Table 7–2).
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How Asthma Drugs Work
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Understanding the mechanism by which bronchodilators work requires a thorough understanding of the receptors associated with the autonomic nervous system's neurotransmitters and how their action is altered to achieve relaxation of the smooth muscles of the airways. As pointed out earlier in this chapter, the neurotransmitter receptors involved in the autonomic nervous system's respiratory control are adrenergic and cholinergic. The corresponding drug classes used to regulate the function of the respiratory system are adrenergic agonists and anticholinergic drugs. The mechanism of action of these two drug types is different. The adrenergic agonists (as their name implies) actually activate and promote the action of the specific receptor, causing muscle relaxation of the smooth muscle and resulting in bronchodilation. The adrenergic agents currently used for respiratory conditions target the beta-adrenergic receptors and, more specifically in most cases of asthma, the beta-2 receptors.
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The anticholinergic drugs work by a different mechanism from that of the adrenergic agonists in that they bind to the receptor site with the intent of blocking the receptor from being activated by impulses transmitted through the autonomic nervous system. The blocking of the receptor reduces bronchoconstriction by preventing the smooth muscle contraction that is generally induced by normal cholinergic receptor activation. Although, to some extent, these drugs do affect the respiratory system, their use in asthma treatment is typically limited. As will be discussed later in this chapter, anticholinergic drugs play a greater role in the mechanism by which some of the antihistamines work in the reduction of cold symptoms.
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Beta-Adrenergic Bronchodilators
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Beta-adrenergic bronchodilators ideally target specifically the beta-2 adrenergic receptors. When these agents are administered, they bind to the beta-2 adrenergic receptors of the smooth muscles in the lower respiratory system. When they attach to the beta-2 receptors, they cause relaxation of the bronchial muscles and, in turn, the bronchioles dilate, allowing increased air flow. These drugs are agonists in their actions and therefore cause dilation of the bronchioles, even though they do not affect the inflammatory process that is occurring.
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In general, beta-2 agonists can be classified according to the length of time they are effective after administration. Their classification is based on a continuum from short acting to long acting. The chemical structure of the beta-2 agonist is the primary factor that determines the length of time it will work. Specifically, the longer the length of the chemical side chain on the base molecule, the longer the effects will last. A molecule with a relatively long side chain will become embedded in the cell membrane adjacent to the receptor and remain attached to the receptor site for a longer period of time than will a molecule with a short chemical side chain. The beta-2 agonists are specifically targeted to the bronchial smooth muscle and do not affect the cardiac muscle, which contains both beta-1 and beta-2 receptors. Over-the-counter (OTC) asthma preparations are generally nonselective agonists that can affect the cardiac muscle, resulting in an increase in heart function. They are disallowed for use during competition by many organizations.
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Historically, beta-2 agonists have been used as rescue and prophylactic drugs to control asthma and treat bronchitis and emphysema by means of their long duration of action. Therefore, the short-lasting beta-2 agonists such as albuterol (Proventil, Ventolin) are used for two specific reasons in the management of asthma symptoms: as "rescue" drugs for rapid bronchodilation when an asthma attack has started, and as a prophylactic treatment to prevent respiratory complications caused by exercise.12 The long-acting bronchodilators (e.g., Serevent) are more commonly used as controlling drugs because of their longer-lasting effects on airway relaxation.
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Specificity of Bronchodilators
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Historically, the progression of bronchodilator use has evolved from agents that stimulate both the beta-1 and beta-2 adrenergic receptors to the specific drug that activates only the beta-2 receptors of the respiratory system. This transition has encouraged the prescription of beta-2 agonists by physicians because the negative cardiac effects, such as tachycardia, are eliminated with the use of the beta-2 agonists. The longer-acting beta-2 agonist agents such as salmeterol (Serevent) are particularly useful because these sustained- release formulations can be effective up to 12 hours. These long-lasting agents are not typically the first line of treatment and are often added to the treatment plan in individuals who are already using inhaled steroids.6 One common reason for adding these to the treatment plan is to assist in the control of nighttime symptoms. In addition, the long-acting beta-2 agonists may be used in people who need additional asthma control, but it is not desirable to increase their steroid dose. These long-acting agents are not without drawbacks. They should not be used as rescue agents because of their extended onset of action.
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Implications for Activity
It is important for the athlete and the athletic trainer to understand the athlete's specific "triggers" so that the athlete can continue participating in activity. If the athlete knows what is likely to trigger an asthmatic exacerbation, he or she can try to avoid that trigger. This will add to the effectiveness of the management of the disorder.
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Some short-acting bronchodilators include albuterol (the most common), levalbuterol, and pirbuterol. These drugs are classified as short-acting agents and are most commonly prescribed and used as "rescue" medications. In athletics these drugs can also be used as "preventive" agents if administered before exposure to the asthma trigger. In individuals for whom exercise is a trigger for their symptoms, administration of a short-acting beta-2 agonist before activity may prevent the onset of symptoms (Box 7–1). This preventive approach is typically used in people who either do not have underlying chronic asthma or who have good control over their underlying asthma.
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BOX 7–1 Suggested Protocol for Medication and Warm-up Before Activity
30 minutes before exercise: Beta-2 agonist
20 minutes before exercise: Mast cell stabilizer
15 minutes before exercise: Warm up
These are suggested timelines that should be fine-tuned by the athlete according to individual need.
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Anticholinergic Bronchodilators
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Anticholinergic bronchodilators reduce airway constriction and inhibit cholinergic stimulation by blocking the acetylcholine activation of the receptor. Because the anticholinergic drugs attach to receptors on the parasympathetic system, they create adverse effects such as sedation through the central nervous system.7 The anticholinergic agents are classified according to the receptors they block: either muscarinic or nicotinic. In general, anticholinergic bronchodilators are more commonly used for chronic respiratory conditions such as chronic obstructive pulmonary disease (COPD) or chronic bronchitis, but some athletes may have these medications prescribed to treat their asthma. Anticholinergic medications do not have labeled indications for use in asthma in the United States because they have more potential adverse effects (mainly as a result of muscarinic receptor activation) and are clearly not superior to beta-2 agonists.10
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Anti-inflammatory Asthma Medications
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Most physicians view asthma as a chronic disease that produces an inflammatory response in the tracheobronchial tree. Therefore, an anti-inflammatory medication is warranted for proper treatment. Anti-inflammatory drugs are effective in controlling the inflammatory response stimulated by the trigger and prevent exacerbations. The inflammatory response is discussed in detail in Chapter 3. The use of both steroidal and nonsteroidal medications for asthma control is discussed here.
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Corticosteroids, which are secreted naturally by the adrenal cortex, are classified as glucocorticoids, mineralocorticoids, and sex hormones (androgens and estrogens). Mineralocorticoids assist in the regulation of fluid reabsorption and will not be discussed here. The sex hormones play little, if any, role in the regulation of respiratory function and thus will not be included in the following discussion. The focus will be on the glucocorticoids, the most important of which is cortisol, commonly known as hydrocortisone. These drugs retard inflammation by inhibiting the formation of some of the proteins associated with the inflammatory process.
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Corticosteroid synthesis is regulated by the complex interaction among the adrenal cortex, pituitary gland, and the hypothalamus. The body is unable to differentiate between naturally occurring corticosteroids and those administered as medications. Oral administration of exogenous steroids may result in suppression of the body's own cortisone production because the body perceives no need to produce cortisone. Oral corticosteroids are typically administered in a tapering dose that prevents suppression of natural cortisol production. This issue of cortisone production suppression is not a serious complication of inhaled administration because the drugs are delivered directly to the respiratory tissue and have little or no effect on the three structures responsible for corticosteroid synthesis.
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Nonsteroidal Asthma Medications
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The mechanism by which nonsteroidal asthma medications work differs from that of corticosteroids. Specifically, the nonsteroidal asthma medications either stabilize mast cells (inhaled drugs) or modify leukotriene productions (oral drugs). Like the steroid drugs used for asthma, the nonsteroidal drugs are not effective as rescue medications.
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Mast cell stabilizers prevent mast cells from releasing inflammatory mediators. Specifically, the stabilizing agent prevents the antibody and antigen complex from causing the mast cell to rupture and release inflammatory mediators. The blocking of this cascade of events results in the prevention of bronchoconstriction. Cromolyn sodium is a commonly used mast cell stabilizer and is available in an MDI.
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Leukotriene modifiers (antileukotrienes), as the name implies, modify the activity of leukotrienes in the inflammatory process. Specifically, arachidonic acid is converted to leukotrienes, which causes increased airway reactivity and vascular permeability. Leukotriene modifiers, like mast cell stabilizers, indirectly prevent bronchodilation and are available under common brand names such as Accolate and Singulair.
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Exercise-induced Asthma
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As discussed earlier in this chapter, EIA is a result of an underlying asthma condition that is triggered by exercise. There are numerous theories regarding the cause of EIA. Water loss, heat exchange cooling the airways, and, most recently, increased sodium intake have all been implicated in EIA exacerbations.8,9 The athlete must first have a formal diagnosis by a physician. Treatment usually follows the same preventive path as that outlined for other asthmatic conditions. It is suggested that an athlete experiencing EIA closely follow a pre-exercise routine that includes both medication and proper warm-up before engaging in practice or competition8 (See Box 7–1).
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There is also a phenomenon known as the refractory period that affects some athletes who experience EIA on a regular basis. This phenomenon is poorly understood, and not all people with EIA experience this refractory period. Little science is available to explain why some people experience it and others do not. Much of the understanding of the refractory period comes from subjective patient observations. Each athlete needs to determine if he or she is able to use this period to his or her benefit.
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Approximately 50 percent of athletes with EIA have found that they experience a symptom-free refractory period shortly after an asthma exacerbation. After the attack is over and all symptoms have resolved, they can return to activity with little or no restrictions for 1 to 2 hours.
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Individuals who are capable of taking advantage of this refractory period follow a very specific routine. Before using their beta-2 agonist inhaler, they warm up and bring their system close to the threshold where symptoms would begin. At this point, they stop activity and use their inhaler. Within a few minutes of the use of the inhaler, they are able to return to activity, and many times remain symptom free.
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As mentioned previously, the difficulty with this approach is that not all individuals who have EIA experience a refractory period, and not everyone who experiences it has consistent results with its use. For these reasons, it is highly recommended that, if someone is going to use this refractory period approach, he or she should experiment extensively with its personal implications before relying on it for use during competition.
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Adverse Effects of Asthma Medications
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The range of adverse effects of asthma medications varies greatly, depending mainly on the class of medication. Asthma medications delivered via MDI generally have less serious adverse effects than oral medications because of the localized delivery of the medication via MDI in comparison to the systemic effects of oral asthma medications.
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The adverse effects of beta-2 agonists are relatively minor because of the specificity of receptors in the respiratory system. Common adverse effects include nervousness, restlessness, trembling, throat irritation, and potential airway hypersensitivity. There is some evidence that the use of beta-2 agonists for the daily treatment of asthma may cause airway hypersensitivity and decrease their effects as a rescue drug.6
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Inhaled steroids, like other inhaled medications, have relatively minor adverse effects, none of which are systematic. The localized adverse effects are throat irritation and hoarseness. The inhaled steroid residue that remains in the mouth alters its bacterial environment, allowing opportunistic yeast infections to develop in the mouth. To limit this problem, users are encouraged to rinse the mouth and brush the teeth after each use of an inhaler.
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The use of oral steroids in the treatment of respiratory conditions has the potential for both short-term and long-term adverse effects. In the short term, the patient may experience increased appetite, acne, poor wound healing, fluid retention, and insomnia. More severe are the known potential adverse effects of long-term use, such as avascular necrosis, osteoporosis, glaucoma, and decreased muscle mass. As mentioned previously, most inhaled medications have fewer adverse effects than oral preparations because of their localized delivery and receptor specificity.
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Adverse effects of the inhaled nonsteroidal asthma medications are a bitter taste in the mouth after administration, throat irritation, and dry mouth. For some athletes, the bitter taste can be so significant that they refuse to use the drug. Additionally, oral nonsteroidal asthma medications produce some of the same adverse effects as the inhaled preparations, such as dry mouth and sore throat. The oral nonsteroidal asthma medications may also cause the athlete to experience headache and skin rash.