Section E. Drug Treatment of Asthma And Other Reversible Airway Problems

HOW IS ASTHMA TREATED?

Although there is usually no cure for asthma, the disease responds remarkably well to treatment. The specifics of treating asthma are highly variable and depend on its severity, prior response to medications, and so forth. Table 1 lists types of therapy commonly used in treating asthma.

Therapies 1 and 2 are usually used to prevent asthma symptoms. Drugs are also used for this purpose, as will be discussed below. Therapies 3 through 7 are used in the active treatment of asthma symptoms: shortness of breath, coughing, and wheezing. Therapy number 7, alternative or natural therapy, is out of the mainstream of medical therapy and will be discussed in Section F.

For practical purposes the medical treatment of asthma symptoms isdrug therapy, the main subject of this chapter. Other therapies will be mentioned insofar as they interact with drug therapy. Though asthma symptoms will sometimes abate when a known stimulus (such as a pet) is removed, the foundation for treating an asthma attack or athtma symptoms is drug therapy.

TABLE 1. THERAPIES USED IN TREATING ASTHMA
P 1. Avoidance of exciting stimuli
P 2. Allergy shots
Rx 3. Chest Physiotherapy
Rx 4. Reassurance
Rx 5. Increased fluid intake
P, Rx 6. Drugs
P, Rx 7. Alternative, or natural therapies
P = prevention of asthma symptoms
Rx = treatment of asthma symptoms

HOW ARE DRUGS USED TO TREAT ASTHMA?

There are many different medications used to treat asthma, but they all fall into 6 basic groups. The fact that there are many more than 6 asthma drugs is due in part to manufacturers' combining several key ingredients in various ways to create a different brand of drug. In other cases a basic drug molecule effective in asthma is altered slightly, and then introduced as a "new" drug, although it is not really much different from the old one.

Two simple classifications of drug therapy are presented. Table 2 groups all asthma drugs according to how they are administered. More than anything else, a patient will always remember how a drug is taken. Table 3 lists asthma drugs according to their general mechanism of action.

TABLE 2. CLASSIFICATION OF DRUGS USED IN TREATING ASTHMA BY ROUTE OF DRUG ADMINISTRATION.
Inhalation Inhalation is usually of a powder or fine mist delivered from a machine hand-held device.
Oral Tablets, capsules, and liquids are swallowed.
Subcutaneous/ Intramuscular Some medications are administered by injection either under the skin (sub-cutaneous) or into the muscle (intra-muscular).
Intravenous Intravenous medications are given through a fine tube placed safely in a vein; this route is reserved for hospitalized patients.

WHAT TYPES OF DRUGS ARE USED IN TREATING ASTHMA?

This is a most important question and I will answer it in two ways: first a narrative answer, then a detailed classification of available drugs in tabular form. In the next question I will provide more information on how these drugs work.

There are many ways to classify drugs for asthma. (With a few exceptions, these are also the same drugs used in treating COPD, or chronic obstructive pulmonary disease. In discussions of COPD later in the book, reference will be made to this list of asthma drugs).

The classification offered here is based on the drugs' mechanism of action in improving the basic problem -- which is airway obstruction -- and by their route of administration (oral or pill form, by inhalation, or by injection).

Our lungs contain many branching airways that deliver fresh air to the blood. The phrase "drugs for asthma" means drugs that help open up the airways when they become narrowed due to disease. Other drugs may be used in people with asthma and COPD, such as antibiotics for infection, but they are not used to directly "open up" the airways.

When it comes to drugs for "opening up" the airways, all available medications can be classified by one of two fundamental mechanisms of action: bronchodilation and anti-inflammatory.

Bronchodilators "dilate" or open up the bronchi, which are the larger airways delivering air inside the lungs. Bronchodilators act on smooth muscle in the walls of the bronchi. Anti-inflammatory drugs, by contrast, act to decrease the inflammation inside the airways; in this case "inflammation" means fluid and cellular debri that tends to clog up the airways of people with asthma and COPD.

There are three different types of bronchodilators and three different types of anti-inflammatory drugs for asthma (and COPD); the distinction among "types" is based on their specific biochemical mechanism of action. Thus, for example, there are three separate biochemical mechanisms by which drugs can lead to bronchodilation and three by which drugs can fight inflammation. This broad classification can be simplified as follows: 

  I.  Bronchodilation
		1.  beta-adrenergic
		2.  methyl xanthines
		3.  anti-cholinergic

  II.  Anti-inflammatory
		1.  corticosteroids
		2.  mediator-release inhibitors
		3.  anti-leukotrienes

So far this seems simple enough, but complexity arises for several reasons. First, within each of the 6 types, drugs can be given by different routes (e.g., orally with a pill; inhalation with a spray; by injection into the tissues or directly into the vein). Second, similar drugs within each type can be used for different purposes.

For example, while most bronchodilators of the "Beta-adrenergic" mechanism are given by the inhalation route, and are used mainly for immediate relief of symptoms, at least one of them (Salmeterol, brand name Serevent) is used to prevent symptoms from occurring; it is not designed to provide quick relief of symptoms.

The situation with anti-inflammatory drugs is even more complicated. Steroids (also known as corticosteroids) are powerful anti-asthma drugs that work by reducing airway inflammation. However, they only provide relief of symptoms when taken in pill form or when injected into the muscle or directly into the vein. When steroids are inhaled, they don't provide sufficient dose to relieve symptoms; instead, the low dose afforded by inhaled steroids is used mainly to prevent a worsening of symptoms, or to improve mild symptoms over the long term (days).

Another class of anti-inflammatory drugs, called mediator-release inhibitors (brand names Cromolyn and Tilade), also doesn't provide quick relief of symptoms; the two drugs in this group are used mainly as preventive medication, i.e., to prevent symptoms from worsening or from occurring in the first place.

To further confuse things, the newest class of drugs, the anti-leukotrienes, has both anti-inflammatory and bronchodilation action; however, their bronchodilation activity isn't quick enough to give relief of symptoms like most of the inhaled beta-adrenergic drugs. These drugs (available under the brand names Accolate and Zyflo), may help to control asthma symptoms over the long term. (Note: the anti-leukotrienes are the first truly new type of asthma drug, based on mechanism of action, to become available in over 25 years.)

How is the patient to sort all this out? It's not easy, particularly since there is far from universal agreement among physicians about how to best use asthma drugs. A patient with asthma symptoms could go to three different physicians and end up with three different regimens, and hence with three different levels of effectiveness.

A rule of thumb is that the sicker the asthmatic or COPD patient, the more likely he or she will need (and benefit by) steroids, either in pill form or by injection. Steroids will usually be prescribed along with a quick-acting inhaled bronchodilator. (In my opinion, the other two classes of anti-inflammatory drugs, as well as all inhaled steroids, should not be relied on to provide quick relief to a suffering asthmatic.)

Of the drugs listed in Table 3, only Primatene mist (a short acting, inhaled bronchdilator) is sold over the counter in the U.S. All others are by prescription only. Primatene is a very short acting drug, and while it can provide some immediate relief, it does not provide any anti- inflammatory activity. Thus it is imperative that any suffering asthmatic (or COPD patient) get under the care of a physician who is knowledgeable about the available medications and how to manage flareups of asthma (and COPD).

Table 3. Drugs for Asthma and COPD

Classified by mechanism of action and route of administration.
Listed are generic names, with brand names in brackets. (This is not an exhaustive list, but it does contain most of the drugs used in the U.S. *Atrovent is not approved for asthma, but only for COPD. The anti-leukotrienes are only approved for asthma, and not COPD.)



I. Bronchodilator Drugs

1. Beta-adrenergics

----> Inhaled. All act within about 15 minutes, except salmeterol.

----> Subcutaneous (epinephrine, terbutaline)

----> Oral (albuterol, terbutaline, ephedrine)

----> BETA-ADRENERGIC AGENTS ARE NOT USED INTRAVENOUSLY IN ADULTS

2. Methyl xanthines

----> Oral (caffeine, theophylline [many brands], oxtriphylline [Choledyl])

----> Intravenous (aminophylline)

----> THEOPHYLLINE AND OTHER TYPES OF METHYL XANTHINES ARE NOT USED BY INHALATION

3. Anti-cholinergics

----> Inhaled form only (atropine, ipratropium bromide [*Atrovent])

----> NOT AVAILABLE IN ORAL OR PILL FORM

II. Anti-inflammatory Drugs

1. Corticosteroids

----> Inhaled; not used for quick relief.

----> Oral (prednisone, prednisolone, methylprednisolone [Medrol, Medrol DosePak], dexamethasone)

----> Intramuscular (methylprednisolone [Depo-Medrol])

----> Intravenous (hydrocortisone [SoluCortef], methylprednisolone [SoluMedrol], dexamethasone)

2. Mediator-release inhibitors

----> Inhaled only (cromolyn sodium [Intal], nedocromil sodium [Tilade])

NOTE: Both drugs are used only for prophylaxis of asthma, not for treatment of the acute attack or for the symptomatic patient.

----> THESE TWO DRUGS DRUGS ARE NOT AVAILABLE IN ORAL FORM

3. *Anti-leukotriene drugs

----> Oral. The first two drugs of this group are zafirlukast, a "leukotriene-receptor-blocking drug" and zileuton, a drug which blocks the formation of leukotriene. Their trade names are, respectively, Accolate(released November 1996) and Zyflo (released January 1997).

----> ANTI-LEUKOTRIENE DRUGS ARE NOT USED BY INHALATION

HOW DO ASTHMA DRUGS WORK?

BRONCHODILATORS

Beta­adrenergic and theophylline drugs are two of the three types of bronchodilators. Both work by relaxing smooth muscle in the airways; during an asthma attack this smooth muscle becomes tightened or shortened, narrowing the airway.

Both types of drugs increase an important body chemical called cyclic AMP. Normally present in small amounts, cyclic AMP is one of the major chemicals responsible for keeping the airways open. Any drug that tends to increase cyclic AMP has a bronchodilating or airway­opening effect.

Interestingly, during an asthma attack the body's own adrenal glands produce adrenergic compoungs; however, the output is not nearly enough to open up the airways. The amount of beta­adrenergic drugs used to treat asthma is far in excess of what the body produces.

2. Theophylline and its derivatives are not naturally occurring in the body. Theophylline is chemically related to caffeine, the stimulant in coffee and tea; many asthmatics report improvement in symptoms after a hot cup of coffee or tea.
Thus the two types of bronchodilators - theophylline and beta-adrenergic -- increase cyclic AMP by different pathways. Beta­adrenergic increase the production of cyclic AMP. Theophylline helps prevent its natural breakdown in the body. The net result for either action is a buildup of cyclic AMP. (An analogy: your bank account can be increased by putting more money in – increased production – or by not taking any out; in the latter case, interest accumulates and your account is not broken down.) Because they operate by two different pathways, the two drug types are sometimes used together; unfortunately, this also tends to increase the side effects, which are additive (such as tremor or heart arrhythmia).

Anti-cholinergic drugs are the third type of bronchodilator used in patients with airflow obstruction. They block nerve impulses that tend to cause broncho-constriction. "Cholinergic" nerves are imbedded within the lungs, and when they fire off (as in an asthma attack) they tend to increase secretions and narrow the airways.

In summary, the three bronchodilator types work by different mechanisms and, in theory, could be used together. As a practical matter, usually no more than two of the three are used in any given patient (but all three could be used).

ANTI-INFLAMMATORY DRUGS

3. Corticosteroids. This group of drugs is produced naturally in the body's adrenal gland, but in a different section than the adrenergic hormones. Like the adrenergics hormones, the body simply cannot produce enough corticosteroids during an asthma attack to help, and the dose physicians give is vastly greater. Steroids are by far the most powerful anti-inflammatory drugs available, and are a mainstay of treatment for most asthma attacks. Unfortunately, we have very little understanding of just how these powerful hormones work to reduce inflammation.

3. Mediator-Release Inhibitors. Cromolyn and Tilade work by helping to prevent the breakup of certain inflammatory cells in the lungs, called mast cells. These cells release certain compounds that cause airway narrowing. The problem is, once these compounds are already released, the drugs are ineffective - sort of like locking the barn door after the horses have escaped. Hence this group of drugs is not useful in patients who already have symptoms. They are used mainly to prevent symptoms, and seem to have their greatest benefit in the stable pediatric population.
3. Anti-leukotrienes. This is a new and exciting group of anti-inflammatory drugs. Leukotrienes are a class of compounds that narrow the airways tremendously; they can cause both bronchoconstriction and inflammation. Researchers have found two main ways to stop them from acting: one, block leukotrienes from being formed (they are a break-down product of another chemical), and second, block them (once formed) from attaching to the lung tissue. Thus there are two broad groups of anti-leukotrines. One group prevents the compound from forming; the other group prevents the luekotriene from reaching the lung tissue. At this writing one drug from each group is available, and no one recommends that both be used. We will hear much more about the anti-leukotrienes in coming months.

The action of corticosteroids (usually abbreviated "steroids") is unknown. These drugs don't act by increasing cyclic AMP. Steroids probably work by decreasing the inflammation and edema (swelling) present in the airways during an asthma attack. How they do so is unclear. Steroids are the most powerful asthma drugs available; the sicker a patient the more likely steroids will be used. Also, since their action is different from bronchodilators, steroids can and should be used in conjunction with them.

WHAT DRUG REGIMENS ARE USEFUL IN ASTHMA?

Ideally, asthmatics should never require treatment. By avoiding whatever excites the hypersensitive airways, an asthmatic should be able to breathe comfortably without medication. Unfortunately, this ideal is seldom realized for many patients, which is why drugs are so commonly used. In any given patient, the need for drugs may arise infrequently (once a year) or may be continuous, even life-long.

The variability of asthma is such that it's difficult to generalize about the type and frequency of drugs. Table 3 lists the types of drugs available and routes they can be given. For a particular patient in an individual situation, intelligent selection from the list is necessary. Some possible drug combinations are shown in Table 4.

For treating a patient with asthma symptoms, the more severe the attack the more likely two types of drugs will be used; this will be one bronchodilator and a steroid. Beta­adrenergic agents or theophylline may be used alone and can be effective in mild cases. Either one, plus steroids, will provide maximum drug treatment in most conditions, including those requiring hospitalization.

For preventing an asthma attack the situation is a little different. Often just one drug on a continuous basis will suffice, preferably an inhaled steroid. Inhaled steroids are not effective once an attack has begun, since the steroid dose is too small to be effective. (Cromolyn sodium is also used to prevent asthma symptoms; it is discussed in a later section).

The 6 types of asthma drugs in Table 3 (five of which are used to treat patients with symptoms) allow for hundreds many different therapeutic regimens. When other factors are considered -- route of administration; dose of drug; brand name of drug -- the possible treatment combinations becomes enormous. Thus it is possible, indeed likely, that patients with similar or identical symptoms can be treated equally well with different regimens.

TABLE 4. SOME POSSIBLE DRUG COMBINATIONS FOR TREATING ASTHMA
1. Beta-adrenergic drug alone
2. Theophylline drug alone
3. Anti-cholinergic drug alone
4. Corticosteroid alone
5. Anti-leukotriene drug alone
6. One or two bronchodilators with a corticosteroid
6. One or two bronchodilators with an anti-leukotriene drug

WHAT OTHER DRUGS ARE USED IN ASTHMA?

The drugs in Table 3 are universally used in treating patients with air flow obstruction. However they are frequently given along with other medications, including:

None of these drugs is specific for treating the symptoms of an asthma attack. The symptoms of asthma — cough, shortness of breath, chest tightness, wheezing - should be treated with one or more of the drug types listed in Table 3.

WHAT ARE THE SIDE EFFECTS OF ASTHMA DRUGS?

Side effects are unwanted effects. All medication has potential for producing side effects. Fortunately, most side effects from asthma drugs are dose­related; by adjusting the dose the side effects will often subside or disappear. Occasionally side effects are so severe that the drug must be stopped completely. Despite being generally dose­related, both the occurrence of side effects and tolerance to them vary greatly among individuals. Principal unwanted effects from the three main drug types are discussed below.

Beta­Adrenergic Drugs

Most side effects from beta­adrenergic are from stimulation of the nervous system; they include nervousness, tremor, headache, palpitations, tachycardia (increased heart rate), sweating, and occasional muscle cramps. In addition some of these medications may cause drowsiness, nausea, and vomiting. The most common problem seems to be flushing and rapid heart rate soon after ingestion or inhalation of an adrenergic drug. Severe side effects are uncommon except in patients with underlying heart disease; such patients should use these drugs cautiously.

Theophylline and Its Derivatives

The most frequent side effect of theophylline is gastrointestinal (GI) upset: nausea, vomiting, abdominal pain, or diarrhea. For unclear reasons, equivalent doses of theophylline are tolerated much better by some patients than others; intolerance does not appear solely related to the blood level of the drug. Stopping the drug will usually relieve GI symptoms.

Another potential problem is heart effects, similar to what can occur with adrenergic agents. Palpitations, tachycardia (fast heartbeat), and flushing may all occur with theophylline, as may a low blood pressure. Taken to excess, or in the presence of underlying heart disease, heart arrhythmias (irregular heartbeats) may occur.

With very high doses seizures may occur; however, this is not a problem if recommended blood levels are maintained. Any patient with headaches, irritability, restlessness, insomnia, or muscle twitching should have a blood level measured if the drug is to be continued.

Generally, severe side effects can be prevented by checking the amount of theophylline in the blood and adjusting the dose accordingly. Drug levels are not available with other drugs. Many things can interfere with theophylline metabolism, including cigarette smoking, certain antibiotics, some anxiety medications some antacids, and the presence of liver or heart disease. Also, theophylline is metabolized faster in younger patients than in older ones.

Because of side effects and because the drug requires a blood test to assure the right dose, theophylline has fallen into general disfavor in the past decade. It is now considered a "second line" drug, behind beta-adrenergic drugs and steroids for treatment of asthma.

Corticosteroids

These drugs rarely cause immediate side effects like the bronchodilators. They are much more likely to cause long-term problems, particularly when maintained at high doses. The two most bothersome side effects are stimulation of appetite leading to weight gain and increased puffiness of the face, referred to as "moon face.". Much more serious over the long term are development of diabetes and weakened bones; these problems don't happen to everyone on long­term steroids, and usually only occur if the dose has been maintained at a high level.

Another major and potentially serious side effect is permanent adrenal suppression. The body's adrenal glands (which sit on top of the kidneys) normally produce several types of steroids necessary for life. When steroids are given as a drug for treating asthma, the adrenal glands sense the high blood levels and shut off their own production. If the steroids are given for less than two weeks, the adrenal glands will start making the hormones again without difficulty. However when the drugs are given for longer periods, especially after several months, the adrenal glands may not respond when the drug is stopped. Abrupt removal of steroid medication in the face of adrenal suppression has been fatal in a number of patients. One way to prevent this is to taper the steroids very slowly over several months, giving the adrenal glands a chance to respond.

Serious effects of corticosteroids are usually avoided if patients take only a short course - two weeks or less. Fortunately, this duration is sufficient to treat most asthma flare­ups. Patients should not be maintained on longer term oral steroids without a clear and compelling reason.

Despite the best intentions of physicians, some asthmatics do end up taking steroids for months or years. In these patients every attempt should be made to minimize the risks. Several strategies can be tried.

1. Substituting an inhaled steroid for oral steroids. There are several inhaled steroids available and all are safer to use long­term than steroid tablets. In recommended doses, the dose of inhaled steroid is not enough to give serious side effects. Substituting inhaled steroid is most feasible in patients needing 10 milligrams or less of daily oral prednisone. Inhaled steroid should only be used during stable asthma, when the patient feels comfortable and the dose of all asthma drugs is constant from day to day. During asthma attacks, the drug can be irritating and should not be used. Also, the dose is too small to treat an asthma attack. Another potential problem is the confusion that sometimes arises between inhaled steroid and inhaled beta­adrenergic medication. Both drugs come in identically­shaped canisters, but only the beta-adrenergic will provide relief during an asthma attack. Unfortunately, some patients who have both drugs mistakenly rely on the inhaled steroid during an attack, to no avail. Despite these limitations, inhaled steroid is an excellent drug, and should be tried in all steroid­dependent asthmatics.

2. Using the lowest oral dose of prednisone compatible with patient comfort and ability to function. Steroids should not be maintained solely to normalize breathing tests, but to allow the patient to be relatively symptom free and comfortable. Regardless of the dose used, frequent and continuing attempts should be made to wean the patient off steroids completely.

3. Using an alternate day schedule, where the dose of oral steroid is taken every other day. This strategy minimizes some of the adrenal suppression and other side effects, although it may also lead to flare-up of symptoms on the day steroids are not taken.

4. Using antacids, such as Tagamet of Pepcid. Steroids can cause an upset stomach, and may aggravate peptic ulcer in patients susceptible to this condition particularly when high doses are used. This effect can be minimized if antacids are taken along with the steroids. Antacids are not routinely needed for most asthmatics taking a short course of steroids.

5. Monitoring the blood periodically for its acid content. Steroids tend to cause an imbalance in blood acidity that can be corrected with potassium chloride or other medication.

WHY IS THERE A VARIABLE RESPONSE TO ASTHMA THERAPY?

It has long been known that asthmatics with similar symptoms may respond differently to identical asthma therapy. There are several possible reasons for this variation.

1. Different causes of asthma attack. As defined earlier the asthma syndrome is one of hypersensitive airways that can be triggered by a variety of stimuli. Although attacks may appear similar in severity, the underlying stimulus may affect the drug response. For example, a patient who is allergic to cats and who remains around them may not respond as well as another patient whose asthma is exacerbated by a common cold that soon runs its course. Similarly, long­term cigarette smokers may develop asthma that doesn't respond as well as asthma in nonsmokers, though examination and breathing tests may be similar before initiating treatment.

2. Type of airway obstruction. Asthmatics whose airway obstruction is mainly from bronchospasm respond better than those whose airways are filled with thick, tenacious mucus (mucus plugs) from inflammation. On initial examination there is no way to know for sure the relative components of each. Generally, the more the inflammation, the more severe the asthma. The lungs of patients who die from asthma are invariably filled with inflammation and mucus plugs.

3. Taking drugs incorrectly. Whenever multiple drugs are prescribed there are many chances for patient error. Lack of expected response can often be traced to improper use of drugs. The common mistakes are:

a. Quitting medication prematurely. After the patient feels a little better he stops the drugs, only to have symptoms flare again in a day or so. Many asthma attacks are not over when a patient begins to feel better; proper treatment may require long term medication. This is best gauged by breathing tests or by the experience of the physician managing the problem.

b. Misunderstanding the difference between medication prescribed to prevent symptoms and medication prescribed to treat symptoms. This misunderstanding commonly occurs with inhaled steroid and inhaled Cromolyn; both are prescribed only to prevent asthma flare­ups, not to treat them. Patients may incorrectly stop these drugs when they feel better or first use them when they have trouble breathing.

c. Improperly using beta­adrenergic inhalers. This is a common error. Some coordination is required to inhale the spray that comes from these devices. Careful observation of some patients shows they don't inhale the medication properly, and hence do not receive the intended dose. Proper technique is discussed in a later question.

To a great extent you – or any patient – can prevent problems by learning about these drugs. This means asking questions, reading package inserts, and going over a new drug with your doctor whenever it is first prescribed.

WHAT ELSE CAN AFFECT A PATIENT'S RESPONSE TO ASTHMA DRUGS?

There are many other possible reasons for variability of patient response. Emotional reaction to illness, disruption of work or lifestyle, patient-physician interaction — all are factors that may affect the outcome of asthma therapy. It is only on follow­up, over days, weeks, or longer that the pattern and degree or response will become evident.

For outpatients the best course is to take the medication recommended, then have it adjusted either at follow­up visits or over the phone. Proper adjustment will depend on side effects, response of the asthma, and, when necessary, measurement of drug levels or theophylline. This method makes drug therapy for asthma a dynamic process and necessitates frequent interaction between the patient and his or her doctor. For mild attacks or chronic asthma, once the patient has been evaluated or is already well known to the doctor, much of this drug manipulation may be handled over the phone. For patients unresponsive to oral therapy, hospitalization and intravenous therapy are usually required.

-END OF SECTION E-