Asthma Medicines

Theophylline has been used for treating bronchial asthma for nearly sixty years but is a weaker bronchodilator than the B-adrenergic agonists. Although widely used as a bronchodilator, the mechanism of its action is unclear. The most recent theories suggest an anti-inflammatory effect that is supported by the inhibition of the late phase response. Due to the controversy over its mode of action, theophylline has fallen out of favor and is no longer regarded as a first-line asthma medication comparable to the B2adrenergic agonists. As more data is obtained that firmly establishes theophylline as an anti-inflammatory agent it is likely to be regarded again as a first-line agent.

At this time theophylline may still prove useful as a second-line drug. A recent study has demonstrated that theophylline may allow patients who require high doses of inhaled corticosteroids to reduce their steroid dosages. Patients with intolerance to B-agonist side effects may find they are better able to tolerate theophylline. Its availability as an oral medication in a sustained time release form may be preferred by some patients. Dosing is usually on a twice-a-day basis, with some patients able to achieve satisfactory results from once-a-day administration. This once-a-day dose is best given in the evening and may prove extremely helpful in treating nocturnal asthma.

Sustained-Release Preparations

Large numbers of sustained-release theophylline preparations are available by prescription, but they may vary in their rate of release of medication into the bloodstream. Once a certain preparation is prescribed, adjustment of the dosage will require follow-up and blood testing. After the proper dosage is established it is advisable not to substitute one preparation for another since the substitute may not achieve the same results. There is little use for short-acting theophylline preparations since they must be given several times a day.

Intravenous Form: Aminophylline

An intravenous form of theophylline known as aminophylline is available for emergencies. In view of the faster onset of action of the B2-adrenergic agonists intravenous aminophylline would also not be considered a first-line treatment in an emergency room. Although there is some controversy concerning its effectiveness in emergencies, aminophylline’s use as a second-line agent has been established.

Obtaining a Therapeutic level

One drawback to theophylline is that a certain amount must be present to achieve an effect. This has been termed a therapeutic level (10-20 mg of the drug per liter of blood). Some patients, however, may benefit from lower levels. To achieve the therapeutic level a certain dosage must be administered. Dosing is based on the patient’s body weight and when given by mouth may require several adjustments based on blood test results before the achievement of a patient’s daily maintenance dose. When theophylline is given by mouth an effect may be achieved in approximately one hour but it may require two to three days to achieve the desired maintenance level. With intravenous administration of aminophylline a “loading dose” is usually given over thirty minutes, followed by a constant infusion. Blood levels are again required to adjust the intravenous drip. Compared to the rapidly acting B-agonists, theophylline is both weaker and slower in producing bronchodilatation. Of note, however, when theophylline is given at the same time that the patient is receiving the B-agonist, the effect of the two drugs together may be greater than when given alone.

Adverse Effects of Theophylline

Besides the above considerations, theophylline may have significant side effects, often related to high blood levels, but some patients may experience adverse effects from small dosages, including stomach and bowel upset, rapid or irregular heart beat, insomnia, nervousness, urinary frequency, and headache. Some of these effects may be prevented or reduced by avoiding caffeine, which is structurally similar to theophylline; this explains why coffee has often been noted to relieve asthma. Patients should be advised to avoid or reduce caffeine in their diets while receiving theophylline.

Children and Theophylline

One disturbing but controversial side effect has been noted in children. A possible adverse effect on learning and behavior has been raised by some studies. There are conflicting results with additional studies that have not demonstrated these effects. At this time, theophylline should be used with caution in young children. Careful monitoring for changes in behavior patterns and learning must be performed.

Overdosage

In excessive or toxic dosages, theophylline may cause nausea, vomiting, irregular heart rhythms, and seizures. Theophylline should never be used without direction and supervision from the physician. Fatalities have been reported in asthmatics who have overused over-the-counter asthma medications that contain theophylline. These arc preparations should be withdrawn to avoid toxic reactions.

Drugs That Interact with Theophylline

Another important consideration when patients receive theophylline is the potential for drug interaction. This interaction may result in higher blood levels or toxicity from theophylline. One major group of drugs that can interact with theophylline are certain antibiotics, including erythromycin, clarithromycin, ciprofloxacin, levafloxacin, and olfloxacin. In addition, a widely prescribed stomach medication, cimetadine (Tagamet), may also interact with theophylline. One of the anti-leukotrienes, zileuton (Zyflo) has also been found to interact with theophylline. Fortunately, many other antibiotics and stomach medications, and anti-leukotrienes, are compatible with theophylline. In instances where one of the drugs that may interact with theophylline must be given, a reduction in the theophylline dosage may be made in order to avoid toxicity. A simple rule is to cut in half the total daily dose whenever receiving one of the above medications. It is vital to monitor blood levels in that situation.

Factors That Affect Theophylline Breakdown

Other factors may contribute to slower breakdown or clearance of theophylline, such as age, liver disease, and heart disease. Elderly patients have been found to clear theophylline more slowly. Patients with diseases of the liver as well as those with congestive heart failure have also been found to have slower metabolism of theophylline. In these groups, lower dosages of theophylline should be given.

Some drugs may accelerate clearance of theophylline from the body. Cigarette and marijuana smokers are often found to clear theophylline more rapidly than nonsmokers and may need their dosages increased. TWo medications used for epilepsy, phenytoin (Dilantin) and phenobarbital, may also increase breakdown of theophylline.

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The use of epinephrine by injection for the treatment of asthma dates to as early as 1903. An aerosol form was developed around 1910. For many decades epinephrine was the only available medication for the treatment of bronchial asthma. Its use in the emergency setting has certainly saved countless numbers of lives.

In view of the fact that epinephrine is a nonselective agent that has potent effects on the heart and circulation, its use for treating bronchial asthma has declined. In elderly patients in particular, administration of epinephrine may result in increases in blood pressure and heart rate. These effects may contribute to the development of stroke and heart attack. For these reasons, emergency room treatment of bronchial asthma usually consists of the administration of a selective B-adrenergic agonist by nebulization.

For Anaphylaxis

Epinephrine is still an important medication for treating severe allergic reactions. It is the treatment of choice for a severe reaction known as anaphylaxis, a total body allergic reaction that may lead to collapse or shock. One example is the severe reaction to a bee sting in a sensitive individual. Injectable preparations of epinephrine that automatically inject a premeasured dose are available by prescription for highly allergic patients.

Over-the-Counter Medication

Over-the-counter nonprescription preparations of aerosol epinephrine should be avoided. These preparations are extremely weak and short acting with effects that may last only a few minutes, and therefore are commonly abused. With the far more effective treatment available for bronchial asthma I feel these agents would best be withdrawn since they may actually deter patients from seeking appropriate and necessary medical attention.

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Gold Salts

Gold salts have been adminitered to asthmatic patients based on the benefit of this drug in patients with rheumatoid arthritis. Small numbers of patients have been treated with gold injections or an oral gold compound called auranofin, and individual patients have been reported to reduce their symptoms and steroid requirements. Studies of large numbers of patients are lacking and this approach is not without adverse effects, since gold may also cause pulmonary fibrosis. For these reasons, the use of gold salts in the treatment of asthma must be regarded as investigational.

Troleandomycin

Troleandomycin (TAO) , an antibiotic, has been administered to asthmatic patients who have been steroid dependent. It appears to simply slow the excretion of one of the oral corticosteroids, methylprednisolone. Selected patients receiving methylprednisolone who are given troleandomycin have been able to reduce their steroid dosage. A similar effect of TAO has been noted on theophylline breakdown. For this reason, blood levels of theophylline are required of patients maintained on this medication during TAO administration. TAO has no anti-inflammatory effect of its own and may cause liver damage. It must be concluded that TAO has little place in the routine treatment of bronchial asthma.

Antihistamines

Antihistamines have long been regarded as contraindicated in asthmatics. This prohibition has stemmed from the drying effect antihistamines have on lung secretions and the greater potential for “plugging”of the bronchial tubes in asthmatic attacks. This adverse effect has clearly been documented in many patients. On the other hand, studies of large dosages of antihistamines in asthmatic patients have occasionally demonstrated a beneficial effect. This is not surprising, since histamine is one of the irritating substances involved in provoking an asthmatic attack.

Azelastine

Azelastine is an antihistamine that has undergone trials in Japan and other countries in patients with bronchial asthma. Despite early positive results no significant benefit has been proven in large numbers of patients. One adverse effect is drowsiness. This drug is not available in the United States.

Ketotifen

Another antihistamine, Ketotifen, has been available for use in Europe for bronchial asthma. Tb date, studies do not demonstrate a significant beneficial effect. This agent may also cause drowsiness. Until further studies of additional agents are made available there can be no basis for the routine use of antihistamines for treatment of bronchial asthma. Antihistamines may be carefully administered for nasal or sinus disease if the patient is closely monitored by a physician.

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Inhaled Corticosteroids

With greater emphasis being placed on the inflammatory nature of bronchial asthma, the anti-inflammatory agents have achieved greater importance in treatment. The most effective anti-inflammatory agents are corticosteroids, limited to oral or injectable forms until relatively recently, when an inhalation form became available. The topically active inhaled steroids have radically changed and improved the treatment of bronchial asthma. Patients who would have previously been dependent on oral steroids with serious lifetime consequences have been able to be maintained on the spray with virtually no side effects. Those patients with milder forms of asthma but who overuse bronchodilator drugs have been able to decrease their consumption of these agents, reducing the adverse effects of these drugs and perhaps avoiding fatal attacks.

How They Work

Corticosteroids reduce inflammation in the bronchial tubes. Steroids prevent the late phase response and reduce bronchial hyperresponsiveness. The inhaled corticosteroids (bec1omethasone dipropionate, triamcinolone acetonide, flunisolide, budesonide, fluticasone) are “topically active” and achieve their effect on the surface of the bronchial lining. Many of these same agents are used as creams or ointments for skin conditions. If you visualize the lining of the bronchial tube in asthma to be red and inflamed, then the application of the steroid spray is not unlike applying a steroid cream to a skin rash. The results may be a dramatic reduction in inflammation and irritability.

It must be emphasized that for corticosteroids to be effective they must be administered regularly. Tho often patients may abandon a steroid inhaler before it has a chance to work. Compared to the B-adrenergic agonists, corticosteroids do not have an immediate effect and cannot rapidly reduce symptoms. For this reason patients may stop this important medication before it has had an adequate trial. Remember that the primary purpose of corticosteroid sprays is prevention. If used correctly these agents may provide long-term control over asthma. Another major benefit of the regular use of inhaled corticosteroid sprays is the reduced need for B2-agonists, which is extremely important in view of the detrimental effects noted from overusing B2-adrenergic agents.

Specific Agents

The inhaled corticosteroids, their brand names, and the forms that are available. Beclomethasone dipropionate, triamcinolone acetonide, budesonide, fluticasone propionate, and flunisolide are available in the United States. Budesonide (Pulmicort Thrbuhaler) and fluticasone propionate (Flovent Rotadisk) are now available in multidose DPI dispensers. These two agents have only recently been introduced into the United States.

Dosage and Administration

Inhaled corticosteroids may be given in varying dosages depending on individual patients. A common starting dose would be between 100 and 400 micrograms (l1g) per day. High doses (600-2000 ug) may be necessary for control of severe asthma. Inhaled corticosteroids are best given on a twice-a-day basis.

Current information suggests that the inhaled corticosteroids are not equivalent on a per puff or microgram (u.g) basis. Fluticasone propionate appears to be the most potent agent in laboratory studies. Although these laboratory studies appear to correlate with increased effectiveness in patients, direct comparison of the five agents is lacking. The delivery systems used to administer inhaled corticosteroid may affect the effectiveness of the specific medication. For example, when budesonide is administered as a DPI (Thrbuhaler), twice the amount of medication is delivered when compared to the MDI. Budesonide is only available in the DPI form in this country. Fluticasone propionate is available in three dosages (44, 110, and 220 u.g per puff) which allows increased flexibility in adjusting the appropriate dosage for the individual patient.

“High-Dose” Sprays

In view of the large number of sprays needed on a daily basis, “high-dose” sprays have been made available with up to 250 u.g per puff of corticosteroid. These inhalers allow patients with stable asthma to be maintained on as little as two puffs twice a day.

Adverse Effects and How to Prevent Them

The primary side effect of inhaled corticosteroids is development of a yeast infection known as candidiasis in the mouth or throat. With large numbers of puffs from the “low-dose” inhaler or the use of the “high-dose” preparation, there is a greater risk of this infection. This is a local infection and the rare instances of its spreading outside the mouth have typically occurred in patients with lowered immunity who took no precautionary steps. Several preventive steps can be taken to avoid the infection, including rinsing the mouth and spitting after spraying. If unable to rinse the patient may simply drink, flushing residual medication away from the mouth and throat. Passage through the digestive tract leads to rapid breakdown of the drug but rinsing is still preferred. Another extremely helpful step in administering inhaled steroid aimed at reducing the risk of yeast infection is a spacer. This simple device improves delivery of the steroid to the lung as well as reducing the amount likely to be deposited in the mouth and throat. Triamcinolone acetonide (Azmacort) incorporates a spacer in its MDI.

If candidiasis is discovered, treatment should be given promptly, consisting usually of an antifungal agent (nystatin, clotrimazole) prepared as an oral suspension or as a lozenge. It is rare that development of an oral yeast infection will recur and prompt discontinuation of inhaled steroids. In patients with recurrent yeast infection a switch to another anti-inflammatory agent such as cromolyn sodium or nedocromil is indicated.

Another infrequent side effect of inhaled steroids is an effect on the voice. This uncommon effect is usually noted as hoarseness and may be alleviated with a spacer and by a temporary reduction in dosage. Patients who complain of changes in voice should have a careful examination of the vocal cords to ensure that there is no other explanation for the abnormality.

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Having a Treatment Plan

The drop in peak flow to 50 percent of the patient’s best identifies a serious attack. The patient should repeat the maneuver to determine if it is reproducible. Each patient should have a plan of treatment that has been worked out with the physician. This will typically call for immediate use of rapidly acting bronchodilator medication delivered as an aerosol. The plan should contain instructions on the use of corticosteroids and notification of the patient’s physician.

The physician’s knowledge of the patient’s history will prove invaluable at this time. Patients who have required hospitalization and especially those who have required respirator support for treatment of asthmatic attacks in the past will be advised not to delay treatment decisions. This patient group may require emergency room treatment as will patients with severe attacks who do not rapidly increase their peak flows with bronchodilator medication administered as directed (and not overused).

In treatment of bronchial asthma it is necessary to be aggressive early in treatment of severe attacks, including the possible use of an emergency room. With early recognition of a severe attack and aggressive treatment at its onset, fatal or near-fatal episodes can be avoided.

In the patient group with severe attacks who respond promptly to treatment, the patient’s treatment plan may often be continued in the home. With severe attacks this will most certainly require corticosteroids. Communication with the physician is essential and will be more accurate with serial peak flow measurements. Increasing airflows will confirm the effectiveness of treatment and can be used to adjust medication dosage and frequency of administration.

Following a severe attack that has been successfully treated it is important for the physician and patient to reassess maintenance medication and the treatment plan. The diary of peak flows will be extremely helpful since it may identify a downward trend that began before a severe attack was recognized. Emphasis on earlier recognition may prove helpful in avoiding future attacks.

With each significant attack the physician will look for a “trigger” mechanism that might be prevented in the future. An example would be raking moldy leaves or dusting without a face mask. Avoiding allergens will be stressed in sensitive patients who suffer serious attacks on exposure to these substances. Often the trigger for an asthmatic attack is the common cold. Although this infection cannot be prevented, the patient should be alerted to the possible adverse effects that might result and be prepared to institute the treatment plan.

In many instances the trigger for a severe asthmatic attack cannot be identified. If attacks are frequent, a review of the medical evaluation should be made. Additional allergy tests may be indicated and another careful examination of the home and work environment made. The patient’s administration of medication should also be examined and the maintenance medication program reviewed.

What If Avoidance Doesn’t Work?

Despite measures to avoid asthma triggers, the patient may still experience asthmatic attacks. These attacks may be frequent and severe and at times require hospitalization. In a small number of patients these attacks may prove fatal.

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Assessing enrichment of the blood with oxygen by the lung can be made by a noninvasive technique called oximetry, in which a sensor placed on the fingertip or earlobe can accurately measure oxygen saturation. Such a sensor is often immediately placed on an asthmatic patient who has been admitted to an emergency room. Oxygen saturation testing measures how much oxygen the blood has acquired in the air sacs of the lungs.

The oximeter transmits different wavelengths of light through small blood vessels called capillaries. The fingernail and earlobe are used since these small vessels are close to the surface of the skin. In these small blood vessels oxygen is carried by a protein called hemoglobin. As oxygen is used by the body, the hemoglobin undergoes a change that can be detected by a different absorption of light from the oximeter. This determine is made during each pulse beat and from the relative amounts of hemoglobin with and without oxygen, the saturation is determined. The patient’s pulse is also recorded.

This technique can be extremely helpful in evaluating bronchial asthma since oxygen levels will typically fall with significant degrees of airway obstruction. An asthma attack that reduces oxygen levels signifies a more severe episode and calls for aggressive medical treatment. Oximetry is painless and does not require blood sampling.

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As a rule, all patients with bronchial asthma should have an allergy evaluation. In children, allergy clearly plays a significant role in the severity of the disease and the frequency of attacks. In adults, the role of allergy is less important although most patients, when tested, are found to be allergic.

Allergy Skin Tests

Although useful as a screening test, the IgE level by itself is not sufficient to determine the presence of allergy (also called atopy). Additional evaluation may include allergy skin testing for specific substances known as allergens that may trigger asthma attacks. This method has been used for more than 100 years and represents an extremely reliable way of determining the presence of allergy to a specific substance. Skin testing is performed by pricking, scratching, or injecting the skin with a small amount of allergen. Positive reactions, which resemble hives, are noted in twenty to thirty minutes. But skin testing is time consuming and may cause total body reactions in highly sensitive individuals.

Allergy Blood Tests

Evidence for allergy may also be obtained through blood testing that detects the presence of specific antibodies to various allergens. One technique is known as RAST (Radioallergosorbent test). This test utilizes radioactive material and detects the presence of a specific IgE antibody that has been produced against a certain allergen. This method is thought to be less accurate than skin testing, however, although it may prove useful in selected individuals. Other drawbacks include greater cost when compared to skin testing as well as a delay of up to three weeks in obtaining results.

A relatively new technique known as MAST (Multiple Antigen Simultaneous Testing) has been developed for measuring allergen specific IgE antibodies. This technique is faster and less expensive than RAST and provides accurate results when compared to RAST and skin prick tests. Results may be obtained in one week.

Allergic Reaction

A positive allergy test does not always identify a significant allergy, so the patients history becomes an extremely important factor in correlating allergy test results with true triggers of asthma attacks.

Immediate and “Late” Reactions

Allergy reactions are often immediate and severe as in the patient who is allergic to bee venom, but an allergic reaction may not always be immediately apparent. Recently, it has been demonstrated that a “late phase” response may occur several hours after exposure to an offending substance. In the late phase reaction, inflammation plays a significant role, and it is essential that effective therapy be directed at this component as well as to bronchial obstruction. If not treated, this late phase reaction may form the basis of recurrent and increasingly severe asthma attacks.

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Peak Flow Meter

In bronchial asthma it is extremely important to recognize the presence of an attack before it becomes severe and requires emergency measures. Each patient should have a means of assessing the degree of asthma that is present from day to day. In this manner severe episodes and often the use of oral or injectable corticosteroids necessary for such emergencies can be avoided. As an extension of this home monitoring the patient should be instructed how to respond to the presence of increased asthma. In this way a contingency plan can be in place and ready before severe attacks occur and require emergency room care. The cornerstone of this home monitoring is the peak flow meter. In essence it is an “early warning” device for individuals with asthma.

What the Peak Flow Meter Measures

The peak flow meter is a simple and inexpensive device that can be used in and out of the home to monitor bronchial asthma and similar conditions. This compact device determines the maximal expiratory flow rate that the patient is capable of producing. Similar to the office spirometry, the patient inhales fully and then exhales fully and forcefully into the flow meter device. A simple scale registers the peak flow. If done as instructed this flow rate correlates well with other measurement of airflow through the large airways of the lung. With a diary to record readings the patient can maintain an accurate assessment of the degree of asthma from day to day. This is not unlike the diabetic who records blood sugar readings. This information can be invaluable to the physician in managing patients with bronchial asthma since it gives an objective measurement to go by instead of trying to assess asthma by the degree of shortness of breath or wheezing. Communication with the physician can be much more meaningful with a record of the patient’s peak flows, resulting in earlier and better treatment. With earlier recognition of an attack through peak flow measurements, severe and potentially fatal asthma attacks may be avoided.

An electronic peak flow meter is now available in the form of Air-Watch which is made by Enact. This more sophisticated and expensive device is capable of storing several hundred peak flow measurements. Patients may also download their readings by phone to a central computer which then faxes the results to the physician.

Asthma with Normal Peak Flows

Remember that peak flow measurements reflect primarily large airways and therefore do not totally assess the asthmatic condition. Normal peak flows may occur in the presence of significant small airway disease that requires continued and effective treatment. This explains why patients may continue to be symptomatic even with normal peak flow rates.

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Asthma is often divided into either an allergic or “extrinsic” type that commonly has its onset in childhood, and an adult onset or “intrinsic”type. Although there is considerable overlap between these groups, it is helpful to classify patients according to several features that distinguish them.

Extrinsic Asthma

Extrinsic patients are younger and have attacks clearly triggered by exposure to allergens such as pollens, dust, animal dander, foods, and molds. These patients often have strong family histories of relatives with allergies or asthma. Allergy treatment known as desensitization has often been helpful in these patients. For many years it has been thought that the majority of these patients “outgrew” their asthma by age thirty, but recent evidence suggests that 75 percent remain asthmatic for life. These patients may have long symptom free periods.

Intrinsic Asthma

Intrinsic group patients often develop asthma as adults, and at any age. Often the trigger for these attacks is infection with involvement of the lower respiratory tract as in bronchitis or pneumonia. Some of the most severe infections of this type are viral but they may also be bacterial. Patients in the intrinsic group usually do not have histories of allergies and produce negative allergy tests. Once the diagnosis is evident, further attacks are often triggered by less severe infections. There are fewer symptom free periods in this group and these patients usually require medication for life.

Should This Classification Be Used

Many practitioners no longer use this older classification of the types of bronchial asthma. When discussing the future outlook of the disease as well as treatment options, I find it helpful to use these two general classes of asthma to provide simple guidelines that can be followed. In the younger, highly allergic, or extrinsic asthmatic, for example, emphasis on avoidance of allergens will be extremely important.

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