It is important that RCPs and health care workers teach asthma patients to be aware of the compounds and ingredients of drugs that may have serious adverse reactions

Asthma is a serious and growing health problem in the United States. Current estimates are that there are approximately 17 million asthma patients in the United States and more than 480,000 hospitalizations for asthma annually.1 Researchers are engaged in a constant endeavor to bring newer, safer, and more efficacious medications to bear in the treatment of asthma. According to the National Center for Health Statistics,2 an estimated 1.1 billion medications were provided or prescribed at US ambulatory care visits in 1992.

Unfortunately, the administration of any prescription or nonprescription agent has the potential of resulting in undesired side effects. These drug reactions and interactions can lead to a host of adverse outcomes, including the exacerbation of asthma.

Definitions
A drug acts on the human body by combining with a particular cellular receptor. All drug effects are the result of this interaction with cellular receptors.

Drug-drug interactions can be either pharmacokinetic or pharmacodynamic in nature. Pharmacokinetic interactions are related to the absorption, distribution, metabolization, and/or elimination of a particular combination of drugs. Pharmacodynamic interactions occur depending on how a drug or its metabolites interact in terms of their pharmacologic actions or adverse effects. Drug interactions are most often seen either when two drugs are metabolized through the same pharmacokinetic or pharmacodynamic pathways or when their pharmacologic effects are altered by the direct or indirect effects of another drug (such as an effect on cellular absorption or transport).

Adverse drug reactions are any unintended or undesired effects of a drug that occur at doses routinely used for medical diagnosis or treatment. Adverse drug reactions can be divided into two categories: predictable and unpredictable. Predictable adverse drug reactions account for 70% to 80% of all adverse outcomes observed. They are related to the pharmacologic effects of the drug and are generally dose dependent, rather than individual. Unpredictable adverse drug reactions account for 20% to 30% of all adverse reactions. These are unusual reactions (often, and mistakenly, referred to as allergic) that are independent of the dose given and are unique to the individual patient.

Incidence
Adverse drug reactions are the fourth leading cause of death in the United States, resulting in the loss of more than 100,000 lives each year.3 Up to 5% of the general population and 15% to 30% of hospitalized patients will experience adverse drug reactions per year. Between 3% and 11% of hospital admissions may be related to adverse drug reactions.4 Respiratory symptoms have been reported in approximately 0.5% to 1.2% of patients experiencing adverse drug reactions.5

People with underlying sensitivities, such as asthma patients, may be more prone to such problems. This is especially true of elderly asthma patients, who are more likely to be taking multiple medications. This is compounded by physiologic changes associated with aging. As aging progresses, there may be a decline in lung function and decreased immunologic response to antigens. Since there may be age-related changes in absorption, metabolism, and clearance by the renal and hepatic systems, doses need to be adjusted in this population. Some elderly patients may experience a decline in the effectiveness of their asthma rescue medications; however, many asthma medications have a higher incidence of adverse effects (particularly an increase in bronchospasm) in the elderly.6

Drug Interactions and Asthma
Although some drug interactions are pharmacodynamic, stemming from changes in the therapeutic response to a medication, most drug interactions are pharmacokinetic and due to changes in absorption, protein binding, drug metabolism, or elimination.7 Red flags for drugs likely to exhibit pharmacokinetic interactions might be that they are orally ingested, are highly protein bound, have a narrow therapeutic index, are metabolized by the liver, or have a long half-life. Patients who are taking oral medications for their asthma may be affected by such drug interactions.

Theophylline is an older-generation drug that has largely been replaced by newer agents in asthma treatment. Theophylline interacts with a wide variety of drugs, as well as some foods. Theophylline is 40% protein bound and 90% metabolized by the liver. Cytochrome P-450 isoenzymes 1A2, 2EI, and 3A3 play a vital role in theophylline metabolism. Many other drugs also depend on cytochrome P-450 isoenzymes and compete with the theophylline that a patient may be taking.

Because theophylline has a very narrow therapeutic range, these possible drug interactions must be monitored very closely. If a patient is taking a medication that decreases the clearance of theophylline, such as erythromycin or cimetidine, he or she may experience increased side effects (for example, jitteriness or seizures). Conversely, taking a medication that increases the clearance of theophylline, such as rifampin or certain barbiturates, can leave a patient subject to asthma exacerbation.

Patients who are using multiple medications must be evaluated by their physicians to determine the potential risks versus benefits of theophylline therapy. If it appears to be an essential component of a patient’s asthma treatment, frequent checking of serum theophylline levels is indicated.

There have been some reports of drug interactions associated with the use of antileukotriene medications. Smith8 has noted that zileuton is not seen frequently in clinical practice because of questions of liver toxicity and that several drug interactions have been noted with zafirlukast, including a decrease in theophylline effectiveness. One serious problem noted was an increase in Churg-Strauss syndrome, which involves an inflammatory reaction in the lungs that is more pronounced in asthma patients. Smith has stated, however, that most of these cases appear to be related to the concomitant decrease in the dosage of oral corticosteroids. According to Smith, “Physicians must be careful to monitor their patients on these two therapies as they attempt to taper the oral corticosteroid dose; however, the actual risk is quite small: approximately 60 cases per million patients per year observed in the United Kingdom.”8 He has also noted that these drugs are most effective in aspirin-sensitive asthma patients, rather than the asthma population at large, so physicians need to be mindful of whether their patients are adequately protected against asthma exacerbation by antileukotrienes alone.

Since beta-blockers are b-adrenergic antagonists, it follows that they work in opposition to medications that are b-adrenergic agonists (such as albuterol), thereby decreasing their effectiveness. These compounds also decrease the effectiveness of theophylline. Some experts suggest using selected calcium-channel blockers as an alternative in anti-hypertensive therapy, since they may also have some bronchodilating capabilities.9 Many b-blockers can cause exacerbation of asthma in the absence of other medications.

Adverse Reactions and Asthma
It is currently estimated that there are more than 200 drugs known to affect the lungs adversely.10 It is generally acknowledged that patients with known asthma or chronic obstructive pulmonary disease are at the most significant risk for drug-induced bronchospasm.11 Adverse drug reactions can also reveal a previously undiagnosed reactive airway disease in some individuals. Drug-induced bronchospasm and cough may play a significant role in the clinical picture of patients with difficult-to-control asthma. Many beta-blockers can cause exacerbations of asthma, even in the absence of other medications.

Aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) are among the more significant drugs associated with bronchospasm and cough. It is estimated that drugs may contribute to 10% or more of all asthma attacks.12 Approximately 80% of these cases are believed to be related to the use of NSAIDs, and more than half of that number are attributable to aspirin ingestion. This is a significant problem, since more than 200 drugs and remedies contain aspirin, as do many foods. Physician reports indicate that up to 20% of all adults with asthma will experience bronchospasm and exacerbation of asthma after ingesting aspirin or other NSAIDs.12 Indeed, aspirin sensitivity may be the first sign of adult-onset asthma. Many patients start to show symptoms in their 30s or 40s, with no previous history of NSAID sensitivity, allergies, or positive skin tests. The patient may also exhibit problems with sinusitis and nasal polyps. The exacerbations experienced by these patients can be quite severe and refractory to conventional treatment. Suggested management includes the use of antileukotriene medications and the substitution of acetaminophen. There is some indication that the new COX-2 inhibitors, such as celecoxib, may provoke fewer asthma exacerbations than other NSAIDs. The Adverse Drug Reactions Advisory Committee13 of Australia has reported that 3% of the adverse reactions reported in the first 6 months of celecoxib availability were asthma and worsening asthma symptoms. Health caregivers need to provide in-depth education to patients on how to avoid aspirin and NSAID exposure.

Sulfiting agents are used to preserve foods and beverages, as well as to preserve the potency and stability of certain medications. Approximately 5% of asthma patients are believed to be sensitive or allergic to sulfites.14 The reaction of an asthma patient to these compounds can be quite serious. The bronchoconstriction can be severe enough to close the airways completely, leading to hypoxemia, brain and other organ damage, and/or fatal arrhythmias. The US Food and Drug Administration (FDA) recommends that asthma patients use a bronchodilator when eating outside the home, and that people with known sensitivity carry an antihistamine and epinephrine injector with them. In 1986, the FDA banned the use of sulfites on fruits and vegetables served raw; this reduced exposures, but not all restaurant food is covered by the regulations. It is very important for patients to read food labels and to inquire when they are unsure of any food items. Known sources of sulfites are:

• foods, including some baked goods, condiments, molasses, shrimp, gravy and soup mixes, jams, guacamole, canned vegetables, dried and glacĂ©ed fruit, and processed potatoes;
• beverages, including beer, wine, hard cider, fruit/vegetable juices, and tea; and
• medicines, including some nebulizer solutions (such as isoetharine and isoproterenol), injected epinephrine, injected lidocaine, and metoclopramide.

B-blockers can be involved in drug-interactions in asthma patients; however, B-blockers can cause exacerbations in up to 50% of asthma patients when used as single agents.12 An important factor in the severity of exacerbation is the relative cardioselectivity of the b-blocker given. A b-blocker that has higher affinity for b1 receptors may lessen the effect on asthma patients, although this can be dependent on the dose involved. In general, asthma is a contraindication for these medications. If this particular type of therapy is warranted, efforts are made to choose a cardioselective agent and to use the lowest dose possible. In addition, it can be beneficial to prescribe an inhaled anticholinergic medication such as ipratropium to address any potential bronchospasm. It is important to note that b-blockers are also used in topical eye drops for glaucoma. These medications can have the same exacerbating effects on asthma as do oral cardiovascular drugs.

Up to 30% of patients treated with angiotensin-converting enzyme (ACE) inhibitors will exhibit a dry, persistent cough.12 This problem is compounded in patients with asthma. This cough is resistant to treatment with antitussives, b-agonists, and inhaled corticosteroids, and it generally does not diminish until use of the ACE inhibitor is stopped. The mechanism involved appears to be that metabolism of the drug results in a buildup of bradykinin, substance P, and prostaglandins, all of which lead to bronchoconstriction. This appears to be relatively universal for all agents used. The introduction of angiotensin II receptor agonists such as losartan and irbesartan has alleviated the problem somewhat in that these agents do not lead to the accumulation of bradykinin or substance P, but some reaction is still seen. Studies12,15 have found that 97% of asthma patients had cough with lisinopril and 18% with losartan. Using drugs that prevent bradykinin-induced bronchospasm, such as nedocromil sodium, can be helpful in reducing asthma exacerbations in patients who need ACE inhibitors for the treatment of heart failure.

There are several other agents that can exacerbate asthma. Contrast agents, especially those containing iodine, can cause a severe reaction in asthma patients. It is important to discuss the nature of any diagnostic procedures in advance and to be sure that all concerned are aware of a patient’s underlying asthma. Treatment in advance with antihistamines, anti-inflammatories, or bronchodilators may be indicated.

Asthma patients undergoing operative procedures may be at increased risk from some of the anesthetics and other medications related to surgery. Preoperative and postoperative inhaled bronchodilators should be administered. In addition, some patients may be treated preoperatively with corticosteroids to reduce the chance of exacerbation. In general, the agents not recommended for asthma patients are morphine, meperidine, tubocurarine chloride, and ester-type local anesthetics. It is important for patients to discuss their asthma with their physicians and anesthesiologists thoroughly before surgery.

The influenza drug zanamivir has been reported by the manufacturer to cause bronchospasm in some individuals and exacerbation in asthma patients. Any patient should discuss the use of zanamivir thoroughly with his or her physician, covering possible risks and benefits. At the very least, bronchodilator therapy before use of this medication is indicated.

Herbal Remedies
It is estimated that approximately $4 billion per year is spent in the United States on herbal remedies.16 A new study17 conducted in Oregon surveyed 134 patients and found that asthma/allergy was the third most common reason given for taking these supplements.

Another study18 looked at 1,918 patients in Vancouver, British Columbia. The investigators found that 418 of these patients reported having asthma. It is disturbing to note that while only 28 of these asthma patients reported taking regular peak-flow measurements, 112 used herbal supplements. Even more worrisome is the fact that 126 patients reported skipping doses of their prescribed medications, and only 49 discussed their use of alternative therapy with their physicians. The reason given for turning to these supplements was fear of side effects from conventional medications. The failure to communicate their use was related to fear of disapproval by the physicians.

The reason that these studies are so troubling is that herbal products and dietary supplements are mainly unregulated by the FDA or any other US organization. Dietary supplements are also exempted from food-additive requirements. The onus is on the manufacturers to provide a safe product, but they are not regulated as to their manufacturing methods. This allows for many natural and manufacturing variations to occur in herbal products. Factors such as species variation, stage of development, plant parts used, environmental variations, drying methods, storage, product handling, extraction procedure, and solvents used could all lead to problems with a particular compound. In addition, it is important to remember that these are mainly plant products. Asthma patients who are sensitive to grasses, molds, and pollens take these supplements, erroneously believing that because they are not inhaled, they will not exacerbate their asthma.

Kent Christopher, MD, is a pulmonologist practicing in Denver. He says, “Because these compounds are not regulated by the FDA, there is always some concern about the consistency, purity, and quality of the product. Most of these nutraceuticals have not been subjected to the rigorous scientific study that is mandatory for prescription medications. There is not a uniform method to identify and track potential bad effects from these compounds, unlike prescription drugs, and some supplements have adverse interactions with prescription medications.”

On November 6, 2000, the New England Journal of Medicine released a report19 in advance of publication because of links between phenylpropanolamine and ephedra (ma huang) and serious adverse effects. Because of strong FDA concerns, drug stores across the country removed cold remedies, decongestants, and diet aids from their shelves. In addition, some studies20 have shown that St John’s wort decreases the effectiveness of theophylline in asthma treatment. Other researchers21 have discovered adverse drug reactions in users of echinacea; the most common was bronchospasm.

Conclusion
It is imperative that RCPs and all health caregivers elicit information from their patients concerning not only what prescription medications they are taking, but what over-the-counter drugs and alternative supplements they are using. Asthma patients, especially, need to be made aware of the compounds and ingredients of these drugs to which they may have serious adverse reactions. Asthma patients need to be taught to be proactive and to ask about potential interactions and adverse effects. Patients should be instructed
• to keep a record of all current medications and supplements;
• to tell their physicians or pharmacists what over-the-counter medications they take;
• to read labels carefully;
• to understand what to do if they miss a dose;
• to understand the number of refills permitted;
• to understand how to store the drugs, and when the drugs expire;
• to know what side effects to expect and which side effects to report;
• to know what foods and drugs to avoid while taking certain medications; and
• to discuss any proposed supplements with their physicians and health caregivers before taking them, always.

By working as a team, RCPs, physicians, and patients can keep drug-related asthma exacerbations to a minimum.

Peggy Walker, RRT, is the Western Regional Liaison Representative for the Asthma and Allergy Support Center, Los Angeles.

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