Medical Letter Vol. 42 (Issue 1073)
March 6, 2000
DRUGS FOR ASTHMA

Asthma is a chronic inflammatory disorder of the airways; inflammation caused
by allergens, viral respiratory infections or other stimuli leads to bronchial
hype rresponsiveness and obstruction of airflow. Anti-inflammatory drugs,
particularly inhaled corticasteroids, are central to its management. Treatment
of asthma in the hospital or emergency department is not addressed here.

INHALATION DELIVERY DEVICES - Delivery devices, drug formulation and patient
technique determine the doses of inhaled drugs that reach the lung (HW Kelly,
Respir Care Clin N Am, 5:537, December 1999; AM Wilson et al, Lancet,
353:2128, 1999). Inhaled drugs for asthma have been available in the USA
mainly in pressurized metered-dose inhalers, which require a propellant. The
chlorofluorocarbon (CFC) propellants in these formulations are being changed
for environmental reasons, usually to hydrofluoroalkanes (HFA), which have a
smaller particle size and may deliver more of the drug to the lower airways.
Dry-powder inhalers, which are activated by inspiration, do not require a
propellant, and patients who have difficulty with hand-breath coordination
find them easier to use. Some young children and elderly patients may be
unable to activate a dry-powder inhaler and may need to use a metered-dose
inhaler with a spacer device or a nebulizer.

BETA 2 AGONISTS - Inhaled short-acting beta 2-adrenergic agonists are the most
effective drugs available for treatment of acute bronchospasm and for
prevention of exercise-induced asthma. Regular use of short-acting beta 2
agonists offers no advantage over PRN use. Levalbuterol, the R-isomer of
racemic albuterol, offers no clinically significant advantage over racemic
albuterol (Medical Letter, 41:51, 1999; MJ Asmus and L Hendeles,
Pharmacotherapy, 20:123, 2000).

Salmeterol, a long-acting beta 2 agonist, has a relatively slow onset of
action and a prolonged effect; it is not recommended for treatment of acute
bronchospasm. Patients taking salmeterol regularly should use a short-acting
beta 2 agonist PRN to control acute symptoms. Twice-daily inhalation of
salmeterol has been effective for maintenance treatment in combination with
inhaled corticosteroids and may especially useful in patients with nocturnal
symptoms. In moderate asthma, addition salmetrol to inhaled corticosteroids
may be more effective than raising the dose of the corticosteroid (JJ Condemi
et al, Ann Allergy Asthma Immunol, 82:383, 1999; DS Pearlman et al, Ann
Allergy Asthma Immunol, 82:257, 1999; JA van Noord et al, Thorax, 54:207,
1999). A product that combines both salmeterol and the corticosteroid
fluticasone in a dry powder formulation (Advair Diskus - Glaxo Wellcome) is
vailable in Canada and is expected to be approved soon by the FDA (G Shapiro
et al Respir Crit Care Med, 161:527, 2000; KR Chapman et al, Can Respir J,
6:45, 1999). A long-acting beta 2 agonist, formeterol (Foradil, and others),
is available in Canada and expected to be approved soon by the FDA (G Shapiro
et al, Am J Respir Crit care Med, 161:527, 2000; KR Chapman et al, Can Respir
J, 6:45, 1999).  Another long acting beta2 agonist, formeterol (Foradil, and
others) is available in Canada and Europe.

Oral beta 2 agonists are less effective, produce more adverse effects and have
a onset of action than the same drugs given by inhalation. Extended-release
products q12h may be beneficial in adults unable to use a metered-dose inhaler
correctly and fc turnal asthma. Oral syrup formulations may be useful for some
young children and patients with infrequent mild symptoms who cannot use an
inhaler and spacer device.

Adverse Effects - Albuterol, bitolterol, pirbuterol, terbutaline and
salmeterol are rE ly beta 2-selective in their action and produce more
bronchodilation with fewer cardiov< effects than older adrenergic drugs such
as epinephrine, isoproterenol or metaproterenol.  Nevertheless, tachycardia,
palpitations, tremor and paradoxical bronchospasm can occi high doses can
cause hypokalemia. Overuse of inhaled beta 2 agonists has been ass with an
increase in mortality, but probably reflected worsening of the disease.
adrenergic blockers such as propranolol (Inderal, and others) taken
concurrently decreease bronchodilating effect of beta-adrenergic agonists.

INHALED CORTICOSTEROIDS - Regular use of an inhaled corticosteroid can
suppress inflammation, decrease bronchial hyperresponsiveness and decrease
symptoms in patients with persistent asthma. Inhaled corticosteroids are
recommended for treatment of patients with mild or moderate persistent asthma
as well as those with severe disease. The optimum dosage of inhaled
corticosteroids, the lowest one that controls symptoms, may decrease or
increase over time.

Adverse Effects - Recommended doses of inhaled corticosteroids have generally
been free of serious toxicity. Dose-dependent slowing of linear growth may
occur within six to 12 weeks in some children and adolescents; the effect, if
any, on final adult height is uncertain (M Puruker, J Pediatr, 135:264, 1999;
J Efthimiou and PJ Barnes, Eur Respir J, 11:1167, 1998). Suppression of the
hypothalamic-pituitary-adrenal axis and dermal thinning can occur with high
doses. Decreased bone density, glaucoma and posterior subcapsular cataract
formation have been reported (E Garbe et al, JAMA, 280 539, 1998; RG Cummings
and P Mitchell, Drug Safety, 20:77, 1999; P Mitchell et al, Ophthalmology,
106:2301, 1999). Churg-Strauss vasculitis has been reported rarely in
association with a reduction in the dosage of inhaled and oral
corticosteroids. Dysphonia and oral candidiasis can occur due to local
deposition of the drug. The use of a spacer device and rinsing the mouth after
inhalation decreases the incidence of candidiasis.

LEUKOTRIENE MODIFIERS - Cysteinyl leukotrienes are products of arachidonic
acid metabolism that increase migration of eosinophils, production of mucus
and edema of the airway wall, and cause bronchoconstriction. Montelukast and
zafirlukast are leukotriene receptor antagonists. Zileuton inhibits synthesis
of leukotrienes.

Montelukast (Singulair) - In placebo-controlled clinical trials, montelukast
has been modestly effective for maintenance treatment of adults and children
with intermittent or persistent asthma (Medical Letter, 40:71, 1998). It is
taken once daily in the evening, with or without food. As monotherapy it is
less effective than inhaled corticosteroids, but addition of montelukast may
permit a reduction in corticosteroid dosage (K Malmstrom et al, Ann Intern
Med, 130:487, 1999; C-G Lofdahl et al, BMJ, 319:87, 1999). Montelukast added
to oral or inhaled corticosteroids can improve symptoms in patients with
aspirin-intolerant or chronic asthma (M Laviolette et al, Am J Respir Crit
Care Med, 160:1862, 1999). Churg-Strauss vasculitis has been reported with use
of montelukast, but could have been a consequence of corticosteroid withdrawal
rather than an effect of the leukotriene modifier (ME Wechsler, et al, Drug
Saf, 21:241, October 1999).

Zafirlukast (Accolate) - Zafirlukast has been modestly effective as
monotherapy for maintenance treatment of patients with mild to moderate asthma
(Medical Letter, 38:111, 1996; J Grossman et al, Ann Allergy Asthma Immunol,
82:361, 1999). It is less effective than inhaled corticosteroids (JB Busse et
al, Am J Respir Crit Care Med, 159:A628, 1999). Taking zafirlukast with food
markedly decreases its bioavailability; the manufacturer recommends taking it
twice daily one hour before or two hours after a meal. 

In a single case report, concurrent use of zafirlukast was associated with
toxic serum concentrations of theophylline (RK Katial et al, Arch Intern Med,
158:1713, 1998). Zafirlukast is metabolized by cytochrome P450 2C9.
Theophylline given concurrently can decrease its effect. Zafirlukast increases
serum concentrations of oral anticoagulants and may cause bleeding (DL Vargo
et al, J Clin Pharmacol, 37:858, 1997; A Morkunas and K Graeme, J Toxicol Clin
Toxicol, 35:501, 1997). Infrequent adverse effects include mild headache,
gastrointestinal disturbances and increased serum aminotransferase activity.
Drug-induced lupus has been reported in one patient (TH Finkel et al, J
Allergy Clin Immunol, 103:533, 1999). Churg-Strauss vasculitis has been
reported with use of zafirlukast, but cause and effect have not been
established (RL Green and AG Vayonis, Lancet, 353:725, 1999; M Wechsler and JM
Drazen, Lancet, 353:1970, 1999).

Zileuton (Zyflo) - Zileuton has been effective for maintenance treatment of
asthma, but it is taken four times a day and patients must be monitored for
hepatic toxicity (Medical Letter, 39:18, 1997). One direct comparison with
theophylline suggested that zileuton is equally effective in treating
persistent asthma, but with a slower onset of action (HJ Schwartz et al, Arch
Intern Med, 158:141, 1998). Controlled comparisons with inhaled
corticosteroids are not available. Zileuton, when added to a regimen of medium
to high doses of inhaled or oral corticosteroids, led to greater control of
asthma and nasal symptoms in patients with aspirininduced asthma (B Dahlen et
al, Am J Respir Crit Care Med, 157:1187, 1998). Zileuton is metabolized by the
cytochrome P450 1A2, 2C9 and 3A4 isozymes. Given concurrently, it can decrease
clearance and markedly increase serum concentrations of theophylline, and can
also cause clinically significant increases in serum concentrations of
warfarin (Coumadin, and others) and propranolol.

CROMOLYN SODIUM (Intal) AND NEDOCROMIL SODIUM (Tilade) - Cromolyn sodium, an
inhibitor of mast cell degranulation, can decrease airway hyperresponsiveness
in some patients with asthma. The drug has no bronchodilating activity and is
useful only for prophylaxis. A four-week trial may be necessary to determine
whether it is effective. Pretreatment with cromolyn 15 to 30 minutes prior to
exercise or exposure to allergens or cold air can prevent or diminish
bronchospasm, particularly in children, but less effectively than inhalation
of a beta 2 agonist. Cromolyn has virtually no systemic toxicity. Nedocromil
is a chemically unrelated drug with similar effects (Medical Letter, 35:62,
1993). Some patients have complained about its taste. Both cromolyn and
nedocromil are much less effective than inhaled corticosteroids.

THEOPHYLLINE - Oral theophylline has a slower onset of action than inhaled
beta 2 agonists and has limited usefulness for treatment of acute symptoms. It
can, however, reduce the frequency and severity of. symptoms, especially in
nocturnal asthma, and can decrease inhaled corticosteroid requirements (DJ
Evans et al, N Engl J Med, 337:1412, 1997). Since theophylline absorption and
clearance vary, and the drug has a narrow therapeutic index, measurement of
serum concentrations are needed to determine optimal dosage.

Adverse Effects - When theophylline is used alone, serum concentrations
between 5 and 15 pg/ml are most likely to produce therapeutic results with
minimal adverse effects. At higher serum concentrations, nausea, nervousness,
headache and insomnia may occur. Vomiting, hypokalemia, hyperglycemia,
tachycardia, cardiac arrhythmias, tremor, neuromuscular irritability and
seizures can also occur. Many other drugs used concomitantly can cause either
an increase or decrease in serum theophylline concentrations (The Medical
Letter Handbook of Adverse Drug Interactions, 2000, page 386).

IPRATROPIUM - Ipratropium bromide, an inhaled anticholinergic agent available
both alone (Atrovent) and in combination with albuterol (Combivent), acts as a
bronchodilator and is used to relieve bronchospasm in chronic bronchitis and
chronic obstructive pulmonary disease (COPD). It is not FDA-approved for use
in asthma. Ipratropium has a slower onset of action than short-acting beta 2
agonists, but can be used in patients unable to tolerate beta2 agonists and in
those who have both asthma and COPD. Dry mouth, pharyngeal irritation, urinary
retention and increases in intraocular pressure may occur; the drug should be
used with caution in patients with glaucoma and in those with prostatic
hypertrophy or bladder neck obstruction.

ORAL CORTICOSTEROIDS - Oral corticosteroids are the most effective drugs
available for acute exacerbations of asthma unresponsive to bronchodilators.
Even when an acute exacerbation responds to bronchodilators, many clinicians
treat recovering patients for up to 10 days with oral corticosteroids, which
decrease symptoms and may prevent an early relapse (K Chapman et al, N Engl J
Med, 324:788, 1991). Chronic daily use of oral corticosteroids can cause
glucose intolerance, weight gain, increased blood pressure, bone
demineralization leading to osteoporosis, cataracts, immunosuppression and
decreased linear growth in children. Alternate-day use of corticosteroids can
decrease the incidence of adverse effects, but not of osteoporosis, the most
common major complication of long-term use.

EXERCISE-INDUCED BRONCHOSPASM - Most patients with exercise-induced
bronchospasm inhale a short-acting beta 2 agonist before exercise. The
long-acting beta 2 agonist salmeterol may offer protection for unanticipated
or prolonged physical activity, but regular long-term use may decrease the
duration of the bronchoprotective effect (FER Simons, Pediatrics, 99:655,
1997; JA Nelson et al, N Engl J Med, 339:141, 1998). In some patients,
cromolyn or nedocromil taken before exercise can be effective against
exercise-induced bronchospasm. Leukotriene inhibitors taken regularly may
decrease exercise-induced bronchospasm, but many patients show little or no
response to these drugs. The US Olympic Committee allows athletes to use
cromolyn, nedocromil, ipratropium, theophylline and all the leukotriene
modifiers without prior approval; the inhaled beta 2 agonists (albuterol,
terbutaline, salmeterol) and most inhaled corticosteroids require prior a
pproval. The National Collegiate Athletic Association (NCAA) permits most
asthma medications except for oral beta 2 agonists.

ASTHMA DURING PREGNANCY AND LACTATION - Clinical experience suggests that many
of the drugs used to treat asthma can be used safely during pregnancy and
lactation (AT Luskin, J Allergy Clin Immunol, 103:S350, 1999; M Schatz,
Lancet, 353:1202, 1999). Among the inhaled corticosteroids, the most
experience has been with beclomethasone (B Kallen et al, Obstet Gynecol,
93:392, 1999). Metaproterenol, terbutaline, albuterol, salmeterol,
theophylline, cromolyn, nedocromil and ipratropium also appear to be safe
during pregnancy. Based on animal studies, montelukast and zafirlukast may be
safe to use, but zileuton should be avoided. Taking theophylline during
lactation may produce irritability in the newborn. Oral corticosteroids may
decrease birth-weight and increase the risk of pre-eclampsia, and possibly
increase the risk of oral cleft defects (E Rodriguez-Pinilla and ML
Martinez-Frias, Teratology, 58:2, 1998); in severe asthma, however, their
benefits outweigh the risks.

CHOICE OF DRUGS - Both children and adults with infrequent mild symptoms of
asthma may require only intermittent use, as needed, of a short-acting inhaled
beta 2-adrenergic agonist. Patients with exercise-induced asthma can use a
beta 2 agonist before exercise. Overuse of inhaled short-acting beta 2
agonists (daily use according to some clinicians, or more than twice a week
according to National Institutes of Health guidelines) indicates that an
inhaled corticosteroid should be added to the treatment regimen or, if one is
already being used, that the dosage should be increased. The role of
leukotriene modifiers as possible alternatives to inhaled corticosteroids in
mild asthma remains to be established.

Maintenance treatment with a long-acting inhaled beta 2 agonist such as
salmeterol in addition to an inhaled corticosteroid can control symptoms in
patients with moderate or persistent asthma. Oral theophylline can also
suppress the symptoms of asthma, particularly nocturnal symptoms, but requires
careful titration of dosage and monitoring of serum concentrations. A five- to
ten-day course of oral corticosteroids can control severe acute asthma
symptoms unresponsive to other drugs.

COST OF SOME DRUGS FOR ASTHMA
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