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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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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Cromolyn sodium, a derivative of khellin, an Egyptian herbal remedy, is a useful anti-inflammatory agent that may be used as an alternative to inhaled corticosteroids. In severe patients, cromolyn sodium (Intal) may be used in conjunction with steroids. Like the inhaled corticosteroids, cromolyn is also underused. This underutilization does not result from fear of adverse effects but rather from a misunderstanding of its application. Since its introduction, cromolyn has been the drug of choice for childhood asthmatics. From this early application it has been incorrectly assumed that it was a poor drug for adults, particularly those without allergic characteristics. Many studies, however, have documented that cromolyn may be an effective drug for asthmatics of all ages, even in patients with “intrinsic” asthma. It is also clear that cromolyn does not work for all patients. Like the inhaled corticosteroids, it is slow acting and therefore requires a trial of three to six weeks to assess response. Because of this, many patients abandon this drug before it has had an adequate trial.

How Does Cromolyn Work?

It is not clear how cromolyn sodium reduces inflammation. Some evidence has pointed to an action on inflammatory and allergy cells that prevents release of irritating chemicals that cause inflammation. There may also be an antagonistic action on nervous stimulation that prevents bronchoconstriction and reflex cough. Cromolyn has been demonstrated to prevent both the immediate and late reactions of asthma as well as exercise induced asthma in many patients.

How Cromolyn Is Supplied and Used

Cromolyn sodium was initially made available as a powder for inhalation. Unfortunately, this produced considerable coughing and wheezing. It is currently also available as an aerosol for metered-dose inhalers and in solution for nebulization. When used for nebulization it may be combined with a B2-adrenergic agonist. The recommended dosage is two puffs four times a day from an MDI or 20 mg in solution via a nebulizer, also four times a day.

Cromolyn is not an effective drug for acute asthmatic attacks and, like the inhaled corticosteroids, must be used as a preventive maintenance drug. For this reason cromolyn is best not started during an acute attack. It can be introduced toward the end of an oral steroid taper similar to the way that the inhaled corticosteroids are started. Also, like the inhaled corticosteroids, cromolyn can be used alone and does not necessarily require premedication with a B-adrenergic agonist.

Adverse Effects of Cromolyn

Besides being an effective drug, cromolyn has an extremely low incidence of side effects, which explains its first-line use in children where high-dose inhaled corticosteroids have been shown to slow bone development. In adults the inhaled corticosteroids are considered more effective, making cromolyn a second line agent. In those patients with adverse steroid effects cromolyn is an excellent alternative anti­inflammatory. There are few adverse effects to speak of. Occasionally, cough and wheezing may result from its inhalation. This can often be prevented with the use of a B-adrenergic agonist sprayed five to ten minutes before use or given in solution with cromolyn via nebulization. Rarely have total body effects been noted. An extremely small number of patients have noted joint pains and rash. These effects have resolved completely on discontinuation.

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