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 antiinflammatory 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.
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