Chapter 35. Drugs Affecting the Respiratory System

The respiratory tract may be divided into upper and lower portions. The upper portion consists of the nose, sinuses, oropharynx, and larynx. The lower portion comprises the trachea and lungs with their associated airways. Disorders and drug therapy of the upper respiratory system differ from those of the lower respiratory tract.

Disorders of the upper respiratory tract are those associated with infections (most commonly uncomplicated viral rhinotracheitis) and seasonal allergies (allergic rhinoconjunctivitis and rhinotracheitis). For the most part, these dysfunctions are self-limiting, and the drug classes used to treat them may be obtained without a prescription (over-the-counter, OTC). Disorders of the lower respiratory tract may be broadly classified as parenchymal infections (e.g., pneumonia) and obstructive airway (bronchial) conditions. In general, the latter disorders limit expiratory airflow. They are divided into bronchial asthma, which is characterized by acute episodes, and chronic obstructive airway disorders. Chronic obstructive airway disorders are further subdivided into chronic bronchitis, emphysema, bronchiectasis, and cystic fibrosis. The treatment of infections in all parts of the respiratory tract is discussed in Chapter 27.

Manifestations of upper respiratory tract dysfunctions include mucous and watery discharges and vasodilation, mediated in part through histamine and other substances released from mast cells. Mast cells are important “gate-keeper” cells that are concentrated in the skin and other tissues near external body surfaces.

Histamine is produced from the amino acid histidine and is stored in vesicles. The four histamine receptor subtypes characterized to date are designated H1 to H4. H1 receptors mediate mucous discharge and vasodilation, H2 receptors are important in gastric acid secretion (Chapter 36), H3 receptors are found in the central nervous system (CNS), and H4 receptors may modulate inflammatory reactions by chemotactic effects on eosinophils and mast cells. Secretion of histamine and other mast cell mediators causes vasodilation of the nasal vasculature, leading to the nasal congestion and “runny nose” commonly associated with seasonal allergies and viral infections. Drugs used to decrease these manifestations include H1 receptor antagonists (antihistamines) to decrease mucus production and vasodilation, nasal decongestants to decrease vasodilation, and mast cell stabilizers.

Bronchial congestion with cough and excessive mucus production are also associated with viral infections. These manifestations may be relieved with drugs that suppress coughing (antitussives) or assist in clearance of mucus from larger airways in the lungs (expectorants). The various drug classes used in therapy of the upper respiratory tract are outlined in Figure 35–1. Many of the OTC drugs are presented in Table 35–1. Mast cell stabilizers are discussed in connection with lower respiratory tract conditions.

H1-Blocking Antihistamines

Classification and Prototypes

A wide variety of H1 blockers are available (Table 35–1). Two major subgroups or “generations” have been developed. The older members of the first-generation agents, typified by diphenhydramine and doxylamine, are highly sedating agents with significant autonomic receptor-blocking effects. A newer subgroup of first-generation agents is less sedating and has fewer autonomic effects. Chlorpheniramine and cyclizine may be considered prototypes of this newer subgroup. The second-generation H1 blockers, typified by fexofenadine, loratadine, and cetirizine, are far less lipid soluble than first-generation agents, and are largely free of sedative and autonomic effects. Because they have been developed for use in chronic conditions, all H1 blockers are active by the oral route. Most are metabolized extensively in the liver. Half-lives of the older H1 blockers vary from 4 to 12 hours. Most newer agents (e.g., fexofenadine, cetirizine, loratadine) have half-lives of 12 to 24 hours.

Mechanisms and Physiologic Effects

H1 blockers are competitive antagonists at the H1 receptor. Therefore, these drugs have no effect on histamine release from storage sites and are more effective if given before histamine release occurs. Because their structure closely resembles that of muscarinic blockers and alpha (α)-adrenoceptor blockers, many of the first-generation agents are potent pharmacologic antagonists at these autonomic receptors. A few agents also block serotonin receptors. Most of the older first-generation agents are sedating, and some first-generation agents have antimotion sickness effects. Many H1 blockers are potent local anesthetics. H1-blocking drugs have negligible effects at H2 receptors (Chapter 36).

Clinical Uses

H1 blockers have major applications in type 1 allergic responses as well as additional clinical uses. Immediate allergic responses, which include hay fever and urticaria, are caused by antigens acting on immunoglobulin E (IgE) antibody-sensitized mast cells. H1 blockers are often formulated into OTC combination preparations, and are listed in Table 35–1 under “Allergy and Cold Preparations.” An additional clinical use of diphenhydramine, dimenhydrinate, cyclizine, meclizine, and promethazine is as antimotion sickness drugs. Diphenhydramine is also used for management of chemotherapy-induced vomiting.

Adverse Effects

Sedation and antimuscarinic effects such as dry mouth and blurred vision occur with some first-generation drugs, especially with diphenhydramine, doxylamine, and promethazine. Sedation is much less common with second-generation agents, which do not readily enter the CNS (Table 35–2). Drugs with α-adrenoceptor–blocking actions may cause orthostatic hypotension.

Interactions occur between older antihistamines and other drugs with sedative effects (e.g., benzodiazepines and alcohol). Drugs that inhibit hepatic metabolism may result in dangerously high levels of certain antihistamines if they are taken concurrently. For example, azole antifungal drugs and certain other P450 inhibitors interfere with the metabolism of astemizole and terfenadine, second-generation antihistamines that were withdrawn from the US market because high plasma concentrations of either can precipitate lethal arrhythmias. Some adverse effects can be exploited therapeutically (e.g., they are often used as hypnotics in institutions and in OTC sleep aids).

Decongestants

Classification and Prototypes

Nasal decongestants are agonists at α adrenoceptors and may be classified as systemic or topical (Figure 35–1). Several available OTC formulations are listed in Table 35–1. Despite its long history of use, ephedrinehas not been extensively studied in humans. Ephedrine is one of the active components of “ma-huang,” a popular herbal supplement taken for appetite suppression and weight reduction. Significant safety concerns have been associated with ingestion of ephedrine contained in ma-huang, including hypertension, arrhythmias, myocardial infarction, and stroke. Pseudoephedrine is one of four ephedrine enantiomers, and is used in orally administered nasal decongestants. The convenience of oral administration and longer duration of action come at the cost of lower local concentrations of the drug in the nasal mucosa and greater potential for cardiac and nervous system adverse effects. Xylometazoline and oxymetazolineare classified as long-acting topical decongestants. Phenylephrine is formulated in both in topical and systemic decongestant nasal sprays. All of these mucous membrane decongestants are available as OTC products.

Physiologic Effects

The classification of α receptors, mechanisms of action of drugs stimulating α receptors, and general physiologic effects of α receptor stimulation were discussed in Chapters 4 and 6. Blood vessels of the upper respiratory tract mucosa contain α1 and α2 receptors. Stimulation of these receptors decreases blood flow and thus volume of the nasal mucosa. Ephedrine, phenylephrine, pseudoephedrine, xylometazoline, and oxymetazoline are all direct-acting α agonists and ephedrine and pseudoephedrine also have indirect sympathomimetic effects. Ephedrine also activates β receptors, which probably accounts for its earlier use in asthma. Because ephedrine gains access to the central nervous system (CNS), it is a mild stimulant. The duration of action of these drugs is dependent on the individual compound and the route of administration. These sympathomimetics are not inactivated by catechol-O-methyltransferase; as such they have durations of action of 30 minutes to several hours.

Clinical Use

Mucous membrane decongestants are α agonists that reduce the discomfort of hay fever and, to a lesser extent, the common cold.

Adverse Effects

The adverse effects of adrenoceptor agonists are primarily extensions of their pharmacologic effects in the cardiovascular system and CNS (Chapter 6). Rebound hyperemia—an increase in blood flow to the mucous membranes—may follow the use of these agents. Repeated topical use of high drug concentrations may result in ischemic changes in the mucous membranes, probably as a result of vasoconstriction of nutrient arteries. Cardiovascular effects include an elevation in blood pressure and increased cardiac workload. The latter may evoke manifestations of cardiac ischemia such as angina pectoris. Stimulatory CNS effects may present as insomnia, nervousness, tremor, and anxiety. When taken in large doses, oxymetazoline may cause hypotension.

Antitussives and Expectorants

Classification and Prototypes

Codeine and hydrocodone are opioids that may be included in antitussive formulations. Dextromethorphan is an opioid derivative that lacks analgesic and addictive properties. This drug has recently received attention as a drug of abuse among adolescents because of its hallucinogenic effects. Guaifenesin is the most commonly formulated expectorant in both OTC and prescription medications.

Physiologic Effects and Clinical Use

Natural opioids and their derivatives, such as dextromethorphan, suppress the cough center in the medulla oblongata. This suppression increases the stimulatory threshold required to initiate the cough reflex. Guaifenesin assists in expectoration of respiratory mucus by stimulating respiratory tract secretions, resulting in increased airway fluid volumes and decreased mucus viscosity.

These drugs may be formulated alone, with each other, or in combinations with decongestants or antihistamines (Table 35–1). Except for the opioid drugs, many are available OTC.

Adverse Effects

Opioids can decrease respiratory drive by inhibiting brainstem respiratory mechanisms. This may result in hypercapnia, which may not be tolerated in patients with obstructive airway disorders. For additional adverse effects of opioids on other systems, see Chapter 20. Dextromethorphan can also cause gastrointestinal (GI) distress. When taken in massive overdosage (e.g., when used as a drug of abuse), hallucinogenic effects may result from noncompetitive inhibition of central N-methyl-D-aspartate receptors. These are the receptors antagonized by phencyclidine (PCP, Chapter 21). Additional toxic manifestations include tachycardia, hypertension, lethargy, psychomotor delay, and seizures. Dextromethorphan has weak serotonergie effects and may interact with MAO inhibitors (Chapter 19). Guaifenesin may cause GI distress, dizziness, and drowsiness.

Pathogenesis

Bronchial asthma is a chronic episodic bronchospastic disorder characterized by an early-phase response beginning immediately following exposure to a trigger stimulus and a late-phase response which begins 6 to 8 hours later. In the classic immunologic model, the early phase is initiated by the stimulus (often an allergen) binding to IgE bound to mast cells in the airway mucosa (Figure 35–2). Subsequent release of eicosanoids and other mediators result in the initial bronchospasm and influx of additional inflammatory cells. Bronchospasm decreases the airway diameter and limits expiratory airflow. The hallmark of the late-phase response is airway inflammation with interstitial airway edema, invasion of white blood cells, epithelial injury with decreased mucociliary function, and sustained bronchoconstriction. This combination of factors during the late-phase response also decreases airway diameter and limits expiratory airflow. Both the early and late phases are associated with increased airway responsiveness to subsequent allergen challenges. Examples of allergen triggers that initiate the immunologic response include house dust mites and cockroach detritus, animal dander, pollens, and molds. Nonallergen triggers that provoke asthmatic responses include viral respiratory tract infections, inhaled irritants (e.g., smoke), strong emotions, exercise, and cold air.

Chronic obstructive airway disease (or chronic obstructive pulmonary disease, COPD) includes chronic bronchitis, emphysema, and bronchiectasis. Common characteristics of COPD include chronic and repeated airway obstruction and inflammation. The most common cause of COPD is smoking. Emphysema is a loss of elasticity of the parenchyma (alveoli and interstitial tissue) and breakdown of the alveolar walls. The former inhibits expiratory airflow and the latter results in a loss of surface area available for gas diffusion. In contrast, chronic bronchitis is caused by inflammation that results in submucosal hyperplasia and edema, along with excessive mucous secretion. Airway narrowing and mucous plugs inhibit expiratory airflow. Bronchiectasis is a form of COPD that results from cycles of bacterial infection and subsequent inflammation. This process destroys the elastic support of the airways and forms mucous plugs that decrease expiratory airflow. Cystic fibrosis is a genetic disorder that affects many organs. In the pulmonary system, it results in production of abnormally viscous mucus and blockage of airways with inhibition of expiratory airflow and repeated bacterial infections.

Therapeutic Strategies for Obstructive Lung Diseases

The drug classes used in the treatment of asthma and other obstructive airway disorders are presented in Figure 35–3. Therapeutic interventions may be divided into two categories: “short-term relievers” and “long-term controllers.” The former drugs relieve acute bronchospasm associated with obstructive airway diseases, and the latter drugs minimize the associated inflammation or prevent subsequent acute bronchospastic attacks.

Acute bronchospasm can usually be treated promptly and effectively with bronchodilators. Beta2 (β2)–selective agonists, muscarinic antagonists, and theophylline and its derivatives are available for this indication. Late response inflammation and bronchial hyperreactivity can be treated with corticosteroids, cromolyn or nedocromil, and leukotriene antagonists. These drugs inhibit release of mediators from mast cells and other inflammatory cells or block their effects. The leukotriene antagonists may have inhibitory effects on both bronchoconstriction and inflammation. Anti-IgE antibodies also appear promising for chronic therapy in some cases. A review of these drug classes and their clinical use in asthma is presented in Figure 35–4. Many of these drug classes are used clinically for other obstructive airway disorders.

Bronchodilator Drugs

β-Adrenoceptor Agonists

Prototypes and Pharmacokinetics

The β2-selective agonists are the most important drugs used to reverse asthmatic bronchoconstriction. Epinephrine and isoproterenol are still used occasionally even though they are not selective for β2 receptors. Albuterol, terbutaline, and metaproterenolare the most important short-acting β2 agonists in the United States. Salmeterol and formoterolare long-acting β2 agonists. Beta-receptor 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 hours or less; salmeterol and formoterol act for 12 hours or more.

Mechanism and Physiologic Effects

The classification of β receptors, mechanisms of action of drugs stimulating these receptors, and general physiologic effects of β receptor stimulation are discussed in Chapters 4 and 6. Activation of β receptors stimulates adenylyl cyclase, and increases intracellular cyclic adenosine monophosphate (cAMP) in smooth muscle cells. This causes a decrease in smooth muscle tone and a powerful bronchodilator response (Figure 35–5).

Clinical Use

These drugs are used extensively in asthma. Shorter-acting β2 agonists (albuterol, metaproterenol, terbutaline) should be used only for acute episodes of bronchospasm (not for prophylaxis). The long-acting agents (salmeterol, formoterol) should be used for prophylaxis, not for acute episodes, because they are effective in improving asthmatic control when taken regularly but have a slow onset of action. In almost all patients, the shorter-acting β agonists are the most effective bronchodilators available and therefore the drugs of choice for acute asthma. Some patients with chronic COPD also benefit, although the incidence of adverse effects is increased in this condition.

Adverse Effects

Skeletal muscle tremor is a common adverse β2 effect of these drugs. The β2 selectivity of these drugs is not complete. At high dosage, these agents have significant β1 cardiac effects. Even when they are given by inhalation, tachycardia is common. When the agents are used excessively, arrhythmias may occur. Loss of responsiveness (tolerance, tachyphylaxis) can occur with excessive use of short-acting β2 agonists. 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 three common beverages: caffeine (in coffee), theophylline (in tea), and theobromine (in cocoa). Theophylline is the only member of this group important in the treatment of asthma.

Theophylline and several analogs are orally active and available as a base and as various salts. The drug is available in both prompt-release and slow-release forms, and 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 and Physiologic Effects

The methylxanthines inhibit phosphodiesterase (PDE), the enzyme that degrades cAMP to adenosine monophosphate (AMP) (Figure 35–5), and thus increase cAMP levels. This anti-PDE effect, however, requires high concentrations of the drug. Methylxanthines also block adenosine receptors in the CNS and elsewhere, but a relationship between this action and the bronchodilating effect has not been clearly established. Finally, the possibility exists that bronchodilation is caused by an unrecognized action.

In asthma, bronchodilation is the most important therapeutic action. Increased diaphragm contraction strength has also 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 release of norepinephrine from adrenergic nerve endings), and increased GI motility.

Clinical Use

The major clinical indication for the use of methylxanthines is asthma, but none of these drugs are as safe or effective as the β2 agonists. Slow-release theophylline (for control of nocturnal asthma) is the most important methylxanthine in clinical use. Another methylxanthine derivative, pentoxifylline, is promoted as a remedy for intermittent claudication; this effect is said to result from decreased blood viscosity. Nonmedical use of methylxanthines in coffee, tea, and cocoa is far greater, in total quantities consumed, than their medical uses.

Adverse Effects

These drugs have a narrow therapeutic window. Therapeutic plasma concentrations range from 5 to 20 mg/L, whereas adverse effects begin to occur in some patients when plasma concentrations reach 15 to 20 mg/L. Common adverse effects include GI distress, tremor, and insomnia. Severe nausea and vomiting, hypotension, cardiac arrhythmias, and convulsions may result from overdosage. Very large overdoses (e.g., in suicide attempts) are potentially lethal because of arrhythmias and convulsions. Beta-receptor antagonists are useful antidotes for 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. Ipratropium is delivered to the airways by pressurized aerosol and has little systemic action. Tiotropium is a newer, longer-acting analog.

Mechanism and Physiologic Effect

When given as an aerosol, ipratropium competitively blocks muscarinic receptors in the airways and effectively prevents bronchoconstriction mediated by vagal discharge (Figure 35–5). If given systemically (not an approved use), the drug is indistinguishable from other short-acting muscarinic blockers. Ipratropium reverses bronchoconstriction in some asthma patients (especially children) and in many patients with COPD. The drug has no effect on the inflammatory aspects of asthma.

Clinical Use

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

Adverse Effects

Because ipratropium is delivered directly to the airway and minimally absorbed, there are few systemic effects. When given in excessive dosage, minor atropine-like toxic effects may occur (Chapter 5). In contrast to β2 agonists, ipratropium does not cause tremors or arrhythmias.

Anti-Inflammatory Drugs

Corticosteroids

Prototypes and Pharmacokinetics

For an expanded discussion of the mechanisms of action, clinical uses, and adverse effects of corticosteroids (glucocorticoids), see Chapter 23. All of the corticosteroids are potentially beneficial in severe asthma. However, because of their toxicity, systemic (oral) corticosteroids are used chronically only if other drug delivery options are unsuccessful. In contrast, local aerosol administration of surface-active corticosteroids (e.g., beclomethasone, budesonide, dexamethasone, flunisolide, fluticasone, mometasone) is relatively safe. Inhaled corticosteroids have become common first-line therapy for individuals with moderate to severe asthma. Important intravenous corticosteroids for status asthmaticus (acute severe bronchospasm unresponsive to usual bronchodilator medications) include prednisolone (the active metabolite of prednisone) and hydrocortisone.

Mechanism and Physiologic Effects

Corticosteroids inhibit phospholipase A2 and reduce eicosanoid synthesis. Excessive 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 also participate in the late inflammatory response (Figure 35–6). Corticosteroids reduce the release of arachidonic acid by phospholipase A2 and inhibit the expression of type 2 cyclooxygenase (COX-2, Chapter 34), the inducible form of cyclooxygenase. Corticosteroids may also increase the responsiveness of β2 adrenoceptors in the airway. Corticosteroids bind intracellular receptors and activate glucocorticoid response elements in the nucleus, resulting in synthesis of substances that prevent the full expression of inflammation and allergy (Chapter 23).

Clinical Use

Inhaled corticosteroids are now considered appropriate (even for children) in most cases of moderate asthma that are not fully responsive to aerosol β2 agonists. Early use of corticosteroids 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.

Adverse Effects

Local aerosol administration 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. This adverse effect can be minimized by gargling with water following drug administration. If oral (systemic) therapy is required, adrenal suppression can be reduced by using alternate-day therapy (i.e., giving the drug in slightly higher dosage every other day rather than smaller doses every day). The major systemic toxicities of these drugs (Chapter 23) are much more likely to occur if systemic treatment is required for more than 2 weeks, as in severe refractory asthma. Regular use of inhaled steroids causes mild growth retardation in children, but these children eventually reach predicted adult stature.

Leukotriene Antagonists

These drugs interfere with leukotriene synthesis or their receptor interactions. They reduce the frequency of exacerbations but are not as effective as corticosteroids in severe asthma and are not useful in acute episodes.

Lipoxygenase Inhibitors

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. Zileuton 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 (Figure 35–6). The toxicity of zileuton includes occasional elevation of liver enzymes. Therefore, this drug is less popular than the leukotriene receptor blockers.

Leukotriene Receptor Blockers

Zafirlukast and montelukastare antagonists at the LTD4 leukotriene receptor (Figure 35–6). The LTE4 receptor is also blocked. These drugs are orally active and are used for prophylaxis. They have been shown to be effective in preventing exercise-, antigen-, and aspirin-induced bronchospastic attacks. They are not recommended for acute episodes of asthma. Toxicity is generally low, but rare reports of Churg-Strauss syndrome (allergic granulomatous angiitis) have appeared. Evidence of a causal association is lacking.

Anti-IgE Antibody

Omalizumab is a humanized murinemonoclonal antibody to human IgE. The antibody binds to the IgE antibody on sensitized mast cells and prevents mast cell activation and subsequent release of inflammatory mediators by asthma triggers. This very expensive therapy is approved for prophylaxis in asthma and it must be administered parenterally.

Cromolyn and Nedocromil

Prototypes and Pharmacokinetics

Cromolyn (disodium cromoglycate) and nedocromil are unusual chemicals. They are extremely insoluble, so that even massive doses given orally or by aerosol result in minimal systemic blood levels. 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 conjunctivae and the nasopharyngeal tract. When used in the nasopharyngeal tract (for hay fever) or in the bronchi (for asthma), these drugs are delivered by aerosol.

Mechanism and Effects

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. Although these drugs have no bronchodilator action, they 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.

Clinical Uses

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

Adverse Effects

These drugs may cause cough and airway irritation when given by aerosol. Rare instances of drug allergy have been reported.

Patients may be taking OTC drugs for respiratory disorders without consulting health-care professionals, and some of these drugs can have significant interactions with rehabilitation therapy. Decongestants can increase blood pressure and cardiac workload. Cardiac effects may be manifested as exertional angina or tachycardia during aerobic activities or painful procedures during wound care. Orthostatic hypotension may also occur when a patient is taking oxymetazoline, but is more common with opioid antitussives and antihistamines. Antitussives can also depress respiratory drive, resulting in hypercapnia during aerobic activities. Finally, antihistamines and antitussives can cause sedation.

Patients with obstructive airway disorders will often be in rehabilitation. Some of these patients will be in rehabilitation for nonpulmonary therapy, but their pulmonary disorders and the drugs used to treat these disorders can have significant effects on rehabilitation outcomes. Other patients will be in pulmonary rehabilitation for these same obstructive airway disorders. Exercise therapy has proven beneficial in patients with COPD and cystic fibrosis. There is less clear evidence for the benefits of exercise therapy in patients with asthma and bronchiectasis. In some asthmatics, bronchospasm is precipitated by exercise. These patients may also benefit from resistive exercises to improve aerobic conditioning.

Patients should be educated regarding the benefits of maintaining their respiratory prescription regimens for rehabilitation activities. Drugs used to treat obstructive airway disorders will reduce the effort of respiration and improve aerobic capacity during the treatment sessions.

Optimal pulmonary rehabilitation programs include exercise therapy, patient education, and psychosocial-behavioral training. The same drugs that benefit the patient with obstructive airway disorder may also precipitate adverse effects during the treatment process. Bronchodilators such as β2 agonists and methylxanthines can cause cardiac disturbances, which are exacerbated during aerobic activities in rehabilitation. The corticosteroid drugs, when administered systemically for prolonged periods, can result in osteoporosis and insulin resistance.

Adverse Drug Reactions

Drugs used to treat upper airway dysfunction

• • Antihistamines cause sedation and orthostatic hypotension.
• • Nasal decongestants may increase blood pressure or cause headaches.
• • All antitussives decrease respiratory drive.

Drugs used to treat lower airway dysfunction

• • Beta2 agonists may cause tachycardia with ordinary use, and excessive use is associated with cardiac arrhythmias.
• • Methylxanthines may cause cardiac arrhythmias and convulsions.
• • Antimuscarinic drugs when taken in excessive doses may result in hyperthermia or tachycardia. (See Chapter 5 for more information.)
• • Chronic systemic administration of corticosteroids may result in insulin resistance, hyperglycemia, and osteoporosis. (See Chapter 23 for more information.)

Effects Interfering with Rehabilitation

• • Drugs that cause sedation and orthostatic hypotension may increase the risk of falls.
• • Nasal decongestants that increase blood pressure or heart rate may precipitate angina in patients during rehabilitation as a result of increased cardiac workload.
• • Opioid drugs that decrease respiratory drive may precipitate hypercapnia in patients during aerobic activities.
• • Antimuscarinic drugs that inhibit perspiration may result in hyperthermia in patients during aerobic activities.
• • Patients taking corticosteroids and those with poor glucose control associated with diabetes mellitus may have short-term plasma glucose elevations exacerbated by aerobic activities.

Possible Therapy Solutions

• • Monitor heart rate (may not be elevated if β blockers are present) or relative perceived exertion during rehabilitation activities.
• • Monitor plasma glucose levels prior to rehabilitation.
• • Monitor for signs of hyperthermia during aerobic activities.

Potentiation of Functional Outcomes Secondary to Drug Therapy

• • Patients with obstructive airway diseases may benefit from the use of bronchodilators prior to beginning rehabilitation:
  • • If exercise has been documented to initiate an asthmatic attack in a patient where aerobic activities are a component of the treatment.
  • • If the treatment includes lumbar traction or aquatic therapy, and this activity results in dyspnea.

Brief History: The patient is a 54-year-old male who works in the shipping and receiving department at a state university. His job entails transporting mail and other objects to and from various locations around the university. Two days ago, he hurt his back while moving several boxes. The pain prevents him from walking and from moving objects, thus preventing him from completing his job. He was referred to the university-associated rehabilitation clinic.

Current Medical Status and Drug Therapy: The patient’s medical chart states that he had asthma in childhood, and that he currently smokes and has a 30-plus pack-year history of smoking. He has a prescription for ipratropium and albuterol (Combivent) to take as needed for dyspnea. He also has essential hypertension and takes nadolol combined with bendroflumethiazide (Corzide) as an antihypertensive medication. His current blood pressure and heart rate are 138/82 mm Hg and 79 bpm, respectively.

Rehabilitation Setting: The patient’s diagnosis was documented as severe low back strain. Initial treatment was for pain relief and initiation of pain-free functional movement. The rehabilitation clinic does not have a traction table, but instead uses aquatherapy at the university pool. A small pool to the side of the main pool has a shallow end at 2 to 4 feet and a deeper end at 6 to 10 feet. This pool is kept at 34°C, and is used by both the rehabilitation clinic and athletics programs at the university. The patient is sent from the rehabilitation clinic to the pool. He is observed smoking a cigarette along the way. In the shallow end of the pool, a float is attached to the upper chest of the patient under the axillas; this keeps his head out of the water. Then a 4-kg weight is attached to each ankle. The patient is guided to the deep end of the pool so that his feet do not touch the bottom. The patient is told to relax and see if the pain begins to decrease. After 10 minutes, the patient states that the pain begins to decrease. The patient is then instructed to begin slowly walking in place. Approximately 4 minutes into this part of the therapy, the patient begins to complain of shortness of breath. He is pale and frantically attempts to reach the shallow end of the pool. He is assisted to the side of the pool and out of the water. His blood pressure and heart rate are 154/90 mm Hg and 89 bpm, respectively.

Problem/Clinical Options: During the aerobic part of the aquatherapy to provide analgesia and pain-free function, the patient developed exertional dyspnea as the result of a combination of factors. Although not diagnosed with COPD, the patient currently smokes, has a significant smoking history, had asthma in childhood, and uses prescribed bronchodilators as needed (ipratropium and albuterol). This information strongly suggests a diminished pulmonary reserve. Nadolol in his combination antihypertensive medication (nadolol and bendroflumethiazide) is a nonselective betareceptor antagonist. Therefore, this drug would block both β1 receptors on the heart and β2 receptors in the airways. The latter blockade would cause bronchoconstriction and make breathing more difficult. With the patient in the pool up to his neck, the hydrostatic pressure on the thorax increases. This increased external pressure diminishes ventilation and thus reduces gas exchange. Weights on the lower extremities would also diminish the elevation of the rib cage during inspiration. This combination of factors exceeded the patient’s pulmonary reserve during the aerobic portion of therapy, and he became dyspneic. Finally, smoking a cigarette prior to the therapy session decreased the oxygen-carrying capacity of his red blood cells. Incomplete combustion of organic matter (smoking) results in the formation of carbon monoxide. Carbon monoxide binds to hemoglobin in red blood cells forming carboxyhemoglobin. Carboxyhemoglobin prevents the binding of oxygen to hemoglobin, leading to hypoxemia and peripheral tissue hypoxia. Patients should be strongly advised not to smoke prior to performing aerobic activities because the oxygen-carrying potential of the blood is diminished.

Sympathomimetics Used in Asthma (See Also Chapter 6)

Albuterol (Generic, Proventil, Ventolin, Others)

Inhalant: 90 mcg/puff aerosol; 0.083, 0.5% solution for nebulization

Oral: 2-, 4-mg tablets; 2 mg/5 mL syrup

Oral sustained-release: 4-, 8-mg tablets

Albuterol/Ipratropium (Combivent, DuoNeb)

Inhalant: 103 mcg albuterol + 18 mcg ipratropium/puff; 3 mg albuterol + 0.5 mg ipratropium/3 mL solution for nebulization

Bitolterol (Tornalate)

Inhalant: 0.2% solution for nebulization

Ephedrine (Generic)

Oral: 25-mg capsules

Parenteral: 50 mg/mL for injection

Epinephrine (Generic, Adrenalin, Others)

Inhalant: 1, 10 mg/mL for nebulization; 0.22 mg epinephrine base aerosol

Parenteral: 1:10,000 (0.1 mg/mL), 1:1000 (1 mg/mL)

Formoterol (Foradil)

Inhalant: 12 mcg/puff aerosol; 12 mcg/unit inhalant powder

Isoetharine (Generic)

Inhalant: 1% solution for nebulization

Isoproterenol (Generic, Isuprel, Others)

Inhalant: 0.5, 1% for nebulization; 80, 131 mcg/puff aerosols

Parenteral: 0.02, 0.2 mg/mL for injection

Levalbuterol (Xenopex)

Inhalant: 0.31, 0.63, 1.25 mg/3-mL solution

Metaproterenol (Alupent, Generic)

Inhalant: 0.65 mg/puff aerosol in 7-, 14-g containers; 0.4, 0.6, 5% for nebulization

Pirbuterol (Maxair)

Inhalant: 0.2 mg/puff aerosol in 80- and 300-dose containers

Salmeterol (Serevent)

Inhalant aerosol: 25 mcg salmeterol base/puff in 60- and 120-dose containers

Inhalant powder: 50 mcg/unit

Salmeterol/Fluticasone (Advair Diskus)

Inhalant: 100, 250, 500 mcg fluticasone + 50 mcg salmeterol/unit

Terbutaline (Brethine, Bricanyl)

Inhalant: 0.2 mg/puff aerosol

Oral: 2.5-, 5-mg tablets

Parenteral: 1 mg/mL for injection

Aerosol Corticosteroids (See Also Chapter 23)

Beclomethasone (QVAR, Vanceril)

Aerosol: 40, 80 mcg/puff in 20-dose containers

Budesonide (Pulmicort)

Aerosol powder: 160 mcg/activation

Flunisolide (AeroBid)

Aerosol: 250 mcg/puff in 100-dose container

Fluticasone (Flovent)

Aerosol: 44, 110, and 220 mcg/puff in 120-dose container; powder, 50, 100, 250 mcg/activation

Fluticasone/Salmeterol (Advair Diskus)

Inhalant: 100, 250, 500 mcg fluticasone + 50 mcg salmeterol/unit

Triamcinolone (Azmacort)

Aerosol: 100 mcg/puff in 240-dose container

Leukotriene Antagonists

Montelukast (Singulair)

Oral: 10-mg tablets; 4-, 5-mg chewable tablets; 4 mg/packet granules

Zafirlukast (Accolate)

Oral: 10-, 20-mg tablets

Zileuton (Zyflo)

Oral: 600-mg tablets

Cromolyn Sodium and Nedocromil Sodium

Cromolyn Sodium

Pulmonary aerosol (generic, Intal): 800 mcg/puff in 200-dose container; 20 mg/2 mL for nebulization (for asthma)

Nasal aerosol (Nasalcrom)1: 5.2 mg/puff (for hay fever)

Oral (Gastrocrom): 100 mg/5 mL concentrate (for gastrointestinal allergy)

Nedocromil Sodium (Tilade)

Pulmonary aerosol: 1.75 mg/puff in 112–metered-dose container

Methylxanthines: Theophylline and Derivatives

Aminophylline (Theophylline Ethylenediamine, 79% Theophylline) (Generic, Others)

Oral: 105 mg/5 mL liquid; 100-, 200-mg tablets

Oral sustained-release: 225-mg tablets

Rectal: 250-, 500-mg suppositories

Parenteral: 250 mg/10 mL for injection

Theophylline (Generic, Elixophyllin, Slo-Phyllin, Uniphyl, Theo-Dur, Theo-24, Others)

Oral: 100-, 125-, 200-, 250-, 300-mg tablets; 100-, 200-mg capsules; 26.7, 50 mg/5 mL elixirs, syrups, and solutions

Oral sustained-release, 8–12 hours: 50-, 60-, 75-, 100-, 125-, 130-, 200-, 250-, 260-, 300-mg capsules

Oral sustained-release, 8–24 hours: 100-, 200-, 300-, 450-mg tablets

Oral sustained-release, 12 hours: 100-, 125-, 130-, 200-, 250-, 260-, 300-mg capsules

Oral sustained-release, 12–24 hours: 100-, 200-, 300-tablets

Oral sustained-release, 24 hours: 100-, 200-, 300-mg tablets and capsules; 400-, 600-mg tablets

Parenteral: 200-, 400-, 800-mg/container, theophylline and 5% dextrose for injection

Other Methylxanthines

Dyphylline (Generic, Other)

Oral: 200-, 400-mg tablets; 33.3, 53.3 mg/5 mL elixir

Parenteral: 250 mg/mL for injection

Oxtriphylline (Generic, Choledyl)

Oral: equivalent to 64, 127, 254, 382 mg theophylline tablets; 32, 64 mg/5 mL syrup

Pentoxifylline (Generic, Trental)

Oral: 400-mg tablets and controlled-release tablets

Note: Pentoxifylline is labeled for use in intermittent claudication only.

Antimuscarinic Drugs Used in Asthma

Ipratropium (Generic, Atrovent)

Aerosol: 18 mcg/puff in 200–metered-dose inhaler; 0.02% (500 mcg/vial) for nebulization

Nasal spray: 21, 42 mcg/spray

Antibody

Omalizumab (Xolair)

Powder for SC injection, 202.5 mg

1OTC preparation.