Clinical Pharmacology of Drugs Acting on the Respiratory Organs Function

Sympathomimetics The sympathomimetics, also called beta agonists or adrenergic agents, can be thought of as rescue medications because they provide rapid relief of labored breathing during an asthma episode. Derivatives of adrenaline, or epinephrine, they are chemically altered to maximize this natural compound’s airway muscle relaxing effect while minimizing the heart, muscle, and nervous system side effects of the parent compound. All of the currently available beta agonists are superior to both adrenaline and ephedrine for duration of action and less-pronounced side effects. These potent, when inhaled, provide rapid relief of bronchial obstruction. Duration of action varies from four to six hours. An exception is salmeterol (Serevent®) which works for up to twelve hours but has a slower onset of action of about an hour. These agents are excellent for the prevention of wheezing triggered by exercise or cold air if taken before the activity or exposure. A number of products are available. Individuals may prefer one agent to another for reasons of taste, cost, or personal preference. Generic agents are now available for albuterol. Users of generic substitutes should be aware of the potential problem of dosage variability. Side effects are mild affecting less than 10% of users. They include rapid heart rate, palpitations, restlessness, anxiety, and muscle tremors. Some children may become "revved up" especially when the oral form is given or sometimes after receiving an aerosol treatment from a nebulizer. Maxair® is thought to cause less heart stimulation while metaproterenol may cause a little more. There is considerable individual variation.

Salmeterol is a bronchodilator. It works by relaxing muscles in the airways to improve breathing. Salmeterol inhalation is used to prevent asthma attacks. It will not treat an asthma attack that has already begun. Salmeterol inhalation is also used to treat chronic obstructive pulmonary disease (COPD) including emphysema and chronic bronchitis. Salmeterol inhalation may also be used for conditions other than those listed in this medication guide.

Theophylline This drug is so similar to caffeine that they share the same chemical formula. Their three-dimensional structures are slightly different. As small changes in molecular shape often result in major changes in function, theophylline is 100 times as potent a bronchodilator as caffeine. That means you would have to drink several pots of coffee or several six-packs of cola to get the same beneficial effect of a theophylline tablet. Upset stomach, nausea, rapid or irregular heartbeat, insomnia, hyperactive behavior, and headaches are all adverse effects that caffeine and theophylline share. Theophylline has a narrow therapeutic range meaning that such adverse effects occur commonly The belief that theophylline hinders learning is unfounded. In fact, most tests demonstrate enhanced school performance in children taking theophylline. Like caffeine, theophylline is a diuretic. Many patients taking this agent note increased urine production and may awaken at night to answer nature’s call. No longer the mainstay of therapy as it was a decade ago, theophylline still has a role to play in the treatment of asthma. Once a day dosing makes it useful in treating nocturnal asthma (asthma occurring during sleep). It serves an ancillary role in severe cases of asthma. There are also a few patients who respond better to theophylline than to inhaled corticosteroids. Some studies suggest that theophylline may have a mild anti-inflammatory effect but this is far from established. Both theophylline and caffeine are rapidly absorbed from the gastrointestinal tract. Modern theophylline products use specially-formulated tablets or capsules which delay absorption to produce relatively constant blood levels of theophylline throughout the day and night with once daily (Theo24®, Unidor®, Uniphyll®) or twice daily (Slobid®, Theodur®) use.

Anticholinergic Drugs In the treatment of asthma, anticholinergic drugs are both old and new. One hundred years ago, atropine, the parent drug of this class, was smoked as a cigarette for asthma. Its usefulness was limited by unacceptable side effects of rapid heart rate, hot skin, and dry mucous membranes. Excessive doses could even provoke delusions and irrational behavior. Ipratropium (Atrovent®) preserves the bronchodilator effects while eliminating these adverse effects. Atrovent® is not as potent as the sympathomimetics and is not considered a first choice medication. It has an additive effect when beta agonists are insufficient for symptom relief. It can serve as an acceptable alternate when sympathomimetics aren’t tolerated. Atrovent® should be inhaled four times daily for maximum effectiveness. It's available in multidose inhaler form and in unit dose ampoules for nebulizer use. The only common side effect is dry mouth. Combivent® is a convenient, combination product composed of albuterol and ipratropium.

Anti-inflammatory Agents Asthma medications may be divided into two broad categories, bronchodilators and anti-inflammatory agents. Within each category are several subclasses and variety of products. While bronchodilators relieve the symptoms of coughing and wheezing, the anti- inflammatory agents treat the underlying cause of asthma. The asthmatic state involves fundamental changes in the way the bronchi regulate their internal diameter. When the cells lining the inner surface of the bronchial tubes are injured, forces designed to control airway size become unbalanced. Bronchoconstriction (airway narrowing) becomes predominant.

–Anti-inflammatory agents act at several points in this process. Cromolyn and nedocromil stabilize mast cells and nerve endings preventing initiation of the inflammatory process. Leukotriene antagonists block the production of leukotrienes, a potent mast cell messenger chemical, or block the transmission of their message to receptor cells. Corticosteroids stabilize blood vessels reducing vascular leakiness. They also restore sensitivity of receptor cells to beta-agonists and down-regulate the production and release of inflammatory chemicals. This results in decreased numbers of eosinophils in the airway walls. Corticosteroids have considerably greater anti-inflammatory activity than any of the other drugs. The result is a gradual resolution of the asthmatic condition. –Since these drugs do not relax bronchial muscle, they don’t provide the immediate relief characteristic of bronchodilators. With regular and continued use of anti-inflammatory agents however, the need for bronchodilators is gradually reduced. Inhaled corticosteroids may trigger cough during an acute asthma attack. Oral prednisone may be substituted at such times.

The Cromones: Cromolyn & Nedocromil These agents act primarily to stabilize mast cells. They have an extraordinary safety record but high cost and the need for frequent dosing (four times daily for cromolyn, three times for nedocromil) limit their use. Cromolyn may require administration for up to a month before its protective effect is fully noted. Nedocromil is usually helpful within a few days. Neither drug is as potent as the inhaled corticosteroids. Another limiting factor of nedocromil (Tilade®) is its unpleasant aftertaste. Rinsing the mouth with water helps. Both drugs are good preventers of exercise-induced asthma when taken before activity. Because of their safety record, they are the drugs of first choice for children. Both are available as multidose inhalers. Cromolyn (Intal®) is approved for children as young as two years and is available in unit dose ampoules for nebulizer use.

Leukotriene Antagonists When mast cells become activated, they release a host of preformed chemical mediators which initiate an asthma attack consisting of increasing cough, wheeze, and difficulty breathing. The job of the mast cells is not complete with this act. Mast cells begin to produce a different mixture of chemical messengers even more potent than the first. This mix includes prostaglandins, thromboxanes, and leukotrienes. These biochemical messengers intensify and prolong the asthma episode. Leukotrienes are responsible for the intensification of the asthma episode, called the late phase, which often begins six to twelve hours after the onset of wheezing. A new class of anti-inflammatory drug, the leukotriene antagonists, consists of two subclasses, the leutins and the lukasts. Leutin-type drugs block the creation of leukotrienes. Lukast-type drugs attach to receptors for leukotrienes on cells thus blocking attachment and consequently preventing the effect of these potent asthma accelerators. Available agents in the United States include the leutin, zileutin (Zyflo®), and the lukasts zafirlukast (Accolate®) and montelukast (Singulair®). These agents are about as effective as the cromones and about half as effective as moderate doses of inhaled corticosteroids in controlling the symptoms of asthma. Montelukast may be taken once daily while zafirlukast must be taken twice a day. Moreover, administration of zafirlukast with food may affect its absorption from the gastrointestinal tract. Initially, zileutin must be taken four times a day. This may be decreased to three or even two times a day after a period of demonstrated effectiveness.

For this class of medication, minor side-effects have been reported infrequently; major ones rarely. Both zileutin and zafirlukast may cause mild, reversible injury to the liver. Patients taking these medications should have liver function tests prior to initiating therapy and periodically thereafter. They should not be used in the presence of preexisting liver disease. Churge-Strauss Syndrome has been reported in some patients with severe asthma requiring daily oral corticosteroids whose chronic symptoms initially responded to zafirlukast and, in a few cases, to montelukast. Churge-Strauss Syndrome is a complex of symptoms that occur only in patients with severe asthma. When present, patients experience increasing symptoms of asthma as well as skin rash, bruising, and injury to internal organs that may include the kidney, liver, and heart. Because the treatment of this disorder is oral prednisone and its appearance in patients using lukasts is associated with intentionally reduced dosages of prednisone, it remains unclear whether the leukotriene antagonists cause Churge-Strauss or that the disorder, already present, is "unmasked" by reduction in daily prednisone use. Although the answer remains elusive, the former explanation seems the more plausable given the number of new cases of Churge-Strauss reported with Accolate® use. Prior to the introduction of the lukasts for the treatment of asthma this was a very rare disorder. Of the three agents, montelukast is by far the most convenient to use as it is administered once daily and can be taken with food or on an empty stomach. Zafirlukast taken twice daily should be taken at least one hour before or two hours after meals. Zileutin may be taken without regard to stomach contents but the need to dose four times a day makes compliance difficult. Singulair® is approved for adults and children six years of age or older. Accolate® and Zyflo® are not approved for children under twelve years of age.

Corticosteroids

Corticosteroids Continued use of inhaled corticosteroids reduces bronchial hyperreactivity. This means that for many patients asthma symptoms will disappear as will the need to use additional asthma medications. Use of these medications in children with asthma has been found to restore or preserve normal lung growth. Children with moderate asthma who don’t receive inhaled corticosteroids may reach adulthood with significantly smaller lungs. In adults with asthma, use of inhaled corticosteroids reduces the rate of lung tissue loss over time. Continued use of inhaled corticosteroids reduces bronchial hyperreactivity. This means that for many patients asthma symptoms will disappear as will the need to use additional asthma medications. Use of these medications in children with asthma has been found to restore or preserve normal lung growth. Children with moderate asthma who don’t receive inhaled corticosteroids may reach adulthood with significantly smaller lungs. In adults with asthma, use of inhaled corticosteroids reduces the rate of lung tissue loss over time. A variety of agents are available for use. All are effective on a twice-daily routine. Azmacort® comes with its own built-in spacer but its small volume is not optimal. Aerobid® has a taste that some users find unpleasant. A menthol form, Aerobid-M® tastes better. Budesonide (Pulmicort®) is marketed as a multidose, dry powder inhaler that provides precision dosing without a Freon® propellant. A variety of agents are available for use. All are effective on a twice-daily routine. Azmacort® comes with its own built-in spacer but its small volume is not optimal. Aerobid® has a taste that some users find unpleasant. A menthol form, Aerobid-M® tastes better. Budesonide (Pulmicort®) is marketed as a multidose, dry powder inhaler that provides precision dosing without a Freon® propellant.

Step-wise approach to the treatment of asthma according to recent guidelines. LTRA, leukotriene receptor antagonist; SR, slow release. The dose of inhaled corticosteroids refers to beclomethasone dipropionate