Controller Medications - Medications To Treat Your Asthma: Asthma

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Controller medications

Just as you can prevent tooth decay with daily brushing, you can keep your asthma under control by using your medicine once or twice a day, preventing severe, potentially dangerous asthma attacks.

There are two ways in which controller medications work. Those with anti-inflammatory properties reduce the swelling and inflammation of the bronchial tubes, making the airways less sensitive to asthma triggers. Those that function as long-acting bronchodilators relax the bronchial muscles throughout the day, helping to prevent muscle spasms that narrow the bronchial tubes. Some controller medications achieve both effects. Controller medications also help reduce mucus production.

Some people with asthma need to take a controller medicine only during allergy season or following a respiratory infection. Most people with persistent asthma, however, need to take preventive medicines every day.

Controller medications help you feel better over time. In most cases, within two weeks or less you will have fewer asthma symptoms and find yourself less sensitive to asthma triggers and attacks. You will be pleased at how rarely you need your quick-relief bronchodilator.

Inhaled corticosteroids

Inhaled corticosteroids (see Table 2), usually referred to simply as inhaled steroids, have consistently proved to be the most effective type of controller medication for asthma. Although some forms of steroid medication can have harmful effects because they reach many parts of the body (see "Not all steroids are alike"), inhaled steroids are safe at the usual dosages because only minuscule amounts of medication enter the bloodstream. Like a steroid skin cream rubbed on a rash, for the most part an inhaled steroid medicine exerts its effect only where it's applied — in this case, directly to the airways, where it reduces inflammation.

Inhaled steroids take longer to work than quick-acting bronchodilators. It takes up to one to two weeks of regular use for an inhaled steroid to reduce the swelling and irritation of the bronchial tubes. At that point, you will probably experience fewer symptoms and find that you need to use your bronchodilator less frequently. Another difference between the medications is how often you need them. You use a quick-acting bronchodilator only when your symptoms act up. By contrast, you take your inhaled steroid every day, whether you have symptoms or not.

Regular use of inhaled steroids in asthma is known to improve a person's sense of well-being, reduce asthma symptoms, increase breathing capacity, and reduce the risk for asthma attacks. In fact, one study found that people using inhaled steroids were only half as likely to be hospitalized for a severe asthma attack as those not taking these medications.

For several decades, only three inhaled steroids were available to treat asthma: beclomethasone (Beclovent, Vanceril), triamcinolone (Azmacort), and flunisolide (Aerobid). Since the 1990s, new steroids have been introduced, each with distinctive and potentially advantageous features: fluticasone (Advair, Flovent), budesonide (Pulmicort), beclomethasone with a non-CFC propellant (Qvar), and mometasone (Asmanex).

Your doctor will decide how much inhaled steroid to give you, which in turn determines how many puffs or inhalations you take every day. If your doctor prescribes your inhaled steroid to be taken twice a day, that usually means morning and evening; doses do not need to be spaced 12 hours apart. Budesonide and mometasone have been approved for once-daily dosing in mild, well-controlled asthma.

The most common side effects of inhaled steroids are a dry, irritated throat and a hoarse voice. A minor yeast infection of the mouth and throat called thrush or oral candidiasis can develop, requiring treatment with antifungal mouthwash, lozenges, or tablets. You can avoid thrush by rinsing your mouth after each use of the steroid inhaler and by using a spacer with steroids that are delivered by metered-dose inhaler.

Inhaled steroids can cause more serious long-term side effects if they are absorbed into the bloodstream. This can happen in two ways. You might swallow the medication residue in your mouth, so it gets into your stomach and is then absorbed into the bloodstream. (Again, you can avoid this by rinsing your mouth after each use of the inhaler and using spacers with steroids delivered by metered-dose inhaler.) In addition, some of the medication is absorbed by the blood vessels in the bronchial tubes and transported into the bloodstream. When low doses of the steroids are used, this is not a problem. But if you use high doses of inhaled steroids for a long time, after several months you begin to be at risk, to a slight degree, for side effects more typical of systemic steroids. These include an increased risk for glaucoma and cataracts, skin bruising, and bone loss with increased risk for osteoporosis.

Systemic corticosteroids

When asthma is unusually difficult to control, or during a severe flare-up, you can take steroid medication as tablets or by injection instead of inhaling it. Such systemic steroids are the most powerful medicines available to treat asthma (see Table 3). But systemic steroids are often thought of as a double-edged sword: powerful both in their benefits and, over time, in their undesirable side effects.

Typically, steroid tablets are given for a few days, up to two or three weeks, for an asthmatic crisis, when no other medicine or combination of medicines can relieve symptoms or improve breathing capacity. This is called a "burst." At such times, burst treatment is given in relatively large doses: 40 to 60 milligrams (mg) per day and more.

Often, the initially large doses of a steroid burst are gradually reduced during a one- to two-week course of treatment. For example, the dose may be tapered as follows: 40 mg for two days, 30 mg for two days, 20 mg for two days, 10 mg for two days, then none.

In very rare instances, daily or every-other-day steroid tablets will be necessary to control symptoms in a person with severe persistent asthma. This is known as steroid-dependent asthma. If you have steroid-dependent asthma, ask to see an asthma specialist. It may be possible to find a safer alternative for controlling your asthma.

Long-acting bronchodilators

Like quick-acting bronchodilators (see Table 1), long-acting bronchodilators (see Table 4) help keep the muscles around your bronchial tubes relaxed. Not all begin to work as fast as the quick-acting bronchodilators, but their effects last longer — 12 hours or more. When taken once or twice daily, the long-acting bronchodilators can provide effective asthma control, especially when used together with anti-inflammatory medications.

The first of the long-acting inhaled beta-2 agonist bronchodilators, salmeterol (Serevent), was introduced in 1995. When used together with an anti-inflammatory drug, it proved to be a highly successful controller medication. Several studies have shown that when asthma symptoms are poorly controlled, adding a long-acting inhaled beta-2 agonist (salmeterol or formoterol) to a regimen of inhaled steroids works better than taking higher doses of the inhaled steroids alone. Many people with difficult-to-control asthma find that by combining a long-acting inhaled beta-agonist and an inhaled steroid, they can take lower doses of inhaled steroids than they would otherwise need, thus avoiding the possible side effects of high-dose inhaled steroids.

Salmeterol (Serevent). Doctors usually prescribe salmeterol to be taken twice daily, although occasionally people who have asthma symptoms only during the daytime may take it once a day in the morning, and people whose asthma bothers them exclusively at night may take it once a day in the evening. Salmeterol begins to work about 15 to 20 minutes after you inhale it. The morning dose works to prevent asthma symptoms brought on by exercise at any time throughout the day; the evening dose works as a bronchodilator all night long and may help prevent nighttime awakenings due to asthma. Side effects (jitteriness, tremor, racing heart, muscle cramping) tend to be minimal, and many people do not experience them at all. The medication is available in a dry-powder inhaler device called the Diskus (see "Dry-powder inhalers").

Formoterol (Foradil). Like salmeterol, formoterol is a selective beta-2 agonist that keeps bronchial muscles relaxed for at least 12 hours with minimal side effects. It, too, should be used in combination with an anti-inflammatory medication. Formoterol differs from salmeterol in that it begins to act very rapidly — often within three to five minutes. Another distinguishing feature is its unique dry-powder inhaler device, called an Aerolizer, which delivers the medicine to your bronchial tubes. The Aerolizer is a single-dose device: Each dose of the medicine has to be loaded individually. A long-acting bronchodilator, available as a liquid for nebulization, is a derivative of formoterol called arformoterol (Brovana).

Advair. This medication combines salmeterol with an anti-inflammatory steroid, fluticasone. Advair is available in a single dry-powder inhaler Diskus device and in an HFA inhaler (see "CFC-free inhalers"). It is convenient and highly effective: With one device, you can simultaneously treat airway narrowing caused by bronchial muscle contraction and inflammation. One disadvantage is that the doses of the two medicines are linked in a fixed combination and cannot be adjusted independently. For example, if you want to double your dose of inhaled steroids by taking two inhalations from your Advair Diskus, you will also get twice as much salmeterol, which is more than the recommended dose. To overcome this drawback, Advair has been made available with three different dosage strengths of the fluticasone component.

Symbicort. Symbicort, another drug that combines a long-acting beta-agonist and a corticosteroid, was approved by the FDA in July 2006. Symbicort is a metered-dose inhaler combining the long-acting bronchodilator formoterol with the corticosteroid budesonide.

Safety concerns. In 2006, concerns about safety led the FDA to require a "black box" warning — its strongest — in the package insert of Serevent, Foradil, Advair, and Symbicort. In addition, the FDA issued a Public Health Advisory to caution medical providers about potential risks associated with the use of long-acting beta-agonists.

The concern over long-acting beta-agonists comes from studies suggesting that, in rare cases, severe asthma attacks and deaths may be associated with their use. In the largest of these studies, the Salmeterol Multi-center Asthma Research Trial, or SMART study, involving 26,000 people, more people who were assigned to receive salmeterol died from asthma compared with those assigned to receive a placebo. It must be noted that serious adverse outcomes were rare in both groups (less than 1%).

It is unclear why people using long-acting beta-agonists are at increased risk of death. One theory is that the drugs work so well at relaxing the bronchial tubes that people taking a long-acting bronchodilator without an anti-inflammatory steroid are falsely lulled into a sense of well-being and then expose themselves to asthma triggers. For example, you might spend the day playing with a new kitten or doing yard work while your bronchial tubes swell and fill with mucus — leading to a full-blown asthma attack and difficulty breathing.

Many doctors are continuing to prescribe long-acting beta-agonists in combination with anti-inflammatory medications, because they have proved enormously helpful for many people with moderate and severe persistent asthma. Long-acting beta-agonists are best used as part of a comprehensive program of asthma management, which also includes avoiding asthma triggers, periodically reviewing your treatment with your doctor, monitoring your asthma, and developing and sticking to an asthma action plan (see "Plan for an asthma attack").

Other long-acting bronchodilators. Theophylline and albuterol are available in slow-release preparations that are sometimes used for long-acting bronchodilation. Theophylline is available in generic slow-release preparations and is sold under such brand names as Uniphyl, Theo-24, and Theolair. Some people with asthma have taken slow-release theophylline for many years with good results. If you are comfortable with the medication, you might continue it, but talk with your physician about newer alternatives. Slow-release albuterol (Ventolin, VoSpire, others) is not as effective as the inhaled version at opening bronchial tubes, and it carries a greater risk for side effects.

An ultra-long-acting bronchodilator called tiotropium (Spiriva), which belongs to the same class as ipratropium (see "Other bronchodilators"), is available for the treatment of emphysema and chronic bronchitis. Tiotropium is used once daily, providing bronchodilation for a remarkable 24 hours. The dry-powder inhalation device, called a Handihaler, aerosolizes one capsule of medication at a time. Tiotropium is not as effective as the long-acting inhaled beta-2 agonists at providing bronchodilation in asthma; for that reason, like ipratropium, it is recommended only rarely for use in asthma.

Mast cell stabilizers

Whereas inhaled steroids target various aspects of inflammation, mast cell stabilizers (see Table 5) work specifically on a particular type of allergy cell, the mast cell (see "The allergy connection"). These medications prevent mast cells from breaking open and releasing chemicals like histamine that contribute to inflammation. The mast cell stabilizers cromolyn (Intal) and nedocromil (Tilade) are available to treat asthma. If the medication is in your system, it interrupts the allergic response that would typically result when you encounter an allergen. Cromolyn and nedocromil are purely preventive, however: Taking the drug after you have already begun coughing and wheezing from an exposure will not relieve your symptoms.

The great appeal of the mast cell stabilizers is that they are virtually free of side effects. And one particular use is worth mentioning: Cromolyn and nedocromil effectively block exercise-induced bronchial narrowing when taken as a single dose 15 to 20 minutes before exercise. Although quick-acting bronchodilators may also be used for this purpose, mast cell stabilizers offer an alternative for people who are especially susceptible to the jittery side effects of quick-acting bronchodilators, such as albuterol. They can also be taken in addition to albuterol or other quick-acting bronchodilators if the latter are not enough to prevent exercise-induced asthma attacks.

However, cromolyn and nedocromil have a number of shortcomings. First, they must be administered four times daily to be effective as controller medications. Second, they are only modestly effective, especially when compared with inhaled steroids; they do not provide protection against severe asthma flare-ups as reliably as inhaled steroids. Third, increasing the dose does not help during asthma attacks.

Leukotriene modifiers

A family of controller medications called leukotriene modifiers (see Table 6), which first became available in the mid-1990s, represents a real innovation in asthma medications. Leukotriene modifiers are available as tablets (and as sprinkles for very young children), can be taken once or twice daily, and generally have no side effects. Their safety is demonstrated by the approval for use of one of the leukotriene modifiers in children as young as 12 months.

Leukotrienes are chemicals that contribute both to asthmatic inflammation and bronchial muscle contraction. After years of scientific research into the structure and function of leukotrienes and the importance of their role in asthma, zafirlukast (Accolate) was introduced as the first medication that blocks the action of leukotrienes in the same way that antihistamines block the effects of histamine. Since then, two more leukotriene modifiers have been introduced: montelukast (Singulair) and zileuton (Zyflo). Zafirlukast and montelukast block the action of leukotrienes after the body makes them; zileuton inhibits the formation of leukotrienes in the first place. Zileuton, which needs to be taken four times a day and has a small potential for causing liver inflammation, was briefly withdrawn from the market in late 2003 but is available again.

For some people, leukotriene modifiers work very well — lessening symptoms, improving breathing capacity, and reducing the frequency of asthma attacks. For mild asthma, they may be the only preventive medication needed. They can also be used in combination with other controller medicines for more severe disease. But these medications do not seem to help everyone with asthma; as many as 4 of 10 people derive little or no benefit. One particular indication for using a leukotriene modifier: People with aspirin-sensitive asthma (see "Medication triggers") make relatively large amounts of leukotrienes and are particularly likely to benefit from leukotriene modifiers.

Monoclonoal antibodies

Imagine if you could design a molecule that would bind to the allergy protein IgE (see "The allergy connection") and remove it from the bloodstream so that it would not be available to bind to mast cells and await the arrival of allergens to trigger an allergic response. One asthma medication, omalizumab (Xolair), is just such an anti-IgE monoclonal antibody: This molecule is specifically designed to bind to IgE molecules in the blood without activating an allergic reaction — essentially damping down the allergic apparatus of asthma (and other atopic diseases). Omalizumab is one of the series of biologic molecules revolutionizing treatment not only for asthma and allergy, but also rheumatoid arthritis and cancer.

Omalizumab is administered as an injection once or twice a month (depending on dose). Localized reactions at the injection site are few, but the FDA requires that the label warn of an increased risk of a serious generalized allergic reaction (anaphylaxis) of approximately 1 in 1,000. The cost of the medication is enormous, in the range of $10,000 per year or more, and so the indications for its use have been quite selective. Omalizumab is recommended for people with moderate-to-severe persistent asthma whose symptoms are not well controlled with conventional therapy. In addition, they must have an elevated blood level of IgE protein and demonstrate allergic sensitivity to at least one year-round inhaled allergen. For some (although not all) of the people meeting these criteria, treatment with anti-IgE antibody therapy has helped to improve symptoms, reduce the need for steroids, and prevent asthma attacks.

Last updated:	September 27, 2007