Case Study

Tom is a cross-country skier who is

training for the Winter Olympics.
Living in Minnesota, he endures
prolonged periods in the cold, dry air.
He has been experiencing shortness of breath and coughing
for several hours after he completes his workout.
A physician has already diagnosed him with exercise-induced
bronchoconstriction and has prescribed a metered-dose
inhaler containing albuterol for use prior to exercising.
What effect will this drug have on his training regimen and his
overall performance?
Tom worries that albuterol, a sympa-
thomimetic, is a banned drug and that
taking it will disqualify him from the
upcoming U.S. Olympic team trials.
Are there effective alternative drugs
he could use?
COMMENT
Albuterol is a widely prescribed
bronchodilator of the class of
drugs known as beta-2 agonists.
Safe when used as prescribed, overuse of this
type of drug can lead to tolerance.
Even though albuterol is a sympathomimetic
and therefore has adrenergic-like properties,
it hardly should be considered an ergogenic
agent.
Although it is banned for use during
competition when taken systemically, its use
is acceptable when administered via an inhaler.
A variety of other drug categories are
potential alternatives to albuterol for Tom, but
none appears to be as effective, for reasons
discussed in this chapter
Introduction
A marathon runner exchanges the equivalent of an estimated 2
months of ventilatory volume during a 2.5 h race.
This amount of ventilation can lead not only to an increased
drying of respiratory airways but also to a higher intake of
pollutants and allergens.
In some people, in fact, exercise can even precipitate
bronchospasmand anaphylaxis (Montgomery 1993).
Another type of allergic reaction, such as urticaria, has been
associated with temperature extremes, sun exposure, or water
exposure (Briner 1993).
Some elite athletes can develop exercise-induced hypoxemia,
independently of bronchoconstriction.
Even apparently healthy athletes sometimes require the use of
bronchodilators or respiratory anti-inflammatory drugs.
Notable examples are the Olympians Jackie Joyner-Kersee,
Amy Van Dyken, and Tom Dolan, all of whom are asthmatic.
This chapter discusses pulmonary drugs as banned substances :
bronchodilators,
respiratory anti-inflammatory agents,
type-1 histamine receptor antagonists.
The clinical hallmarks of Asthma:
Coughing, Shortness of breath,
Chest tightness, Wheezing
Smooth muscle contraction
Vascular congestion
Bronchial wall edema
Thick, tenacious secretion
Therapeutic of Asthma:
Short-term relief: Bronchodilation
b
2
-Adrenoceptor stimulants
Methylxanthines
Antimuscarinic agents
Long-term control : Anti-inflammation
Cromolyn, Nedocromil.
Corticosteroid,
Leukotriene pathway inhibitors
Pathogenesis
Pathogenesis
Allergens
Drugs (adrenoceptor
antagonist)
Infection
Air pollution
Cold
Exercise
Emotional stress
Clinical features
ECG changes indicative of
right ventricular
hypertrophy and
pulmonary hypertension
Vital capacity < 50%
1 - second forced
expiratory volume (FEV1):
reduced to 30% of
expected
maximum/a minimum
midexpiratory flow rates:
reduced to
20% or less
Air trapping
Time
1 sec
FEV
1
Exercise-Induced Bronchoconstriction
About 12 million (5%) Americans have asthma.
Some clinicians report exercise-induced bronchoconstriction
(EIB) occurs in 40% to 90%of these patients with asthma, but
nearly all people with asthma have respiratory symptoms at
least occasionally when exercising vigorously in cold, dry air.
10-15%of Olympic athletes have asthma.
A free running test was used to screen male high school varsity
football players, and 9%were found to exhibit significant EIB
A prevalence of 35%of skaters occurred in cold air.
More striking still, among cross-country skiers, the incidence of
asthma or asthma symptoms is reported to be as high as 80%.
Basic Pharmacology of asthma
Basic Pharmacology of Bronchodilators
Drugs used for Asthma
Bronchodilators
Sympathomimetic b-agonists
Albuterol (Ventolin)
Bitolterol (Tomalate)
Ephedrine
Epinephrine
Formoterol
Isoetherine (Bronkosol)
Isoproterenol (Isuprel)
Metaproterenol (Alupent)
Pirbuterol (Maxair)
Salmeterol (Serevent)
Terbutaline (Brethine)
Methylxanthines
Aminophylline
Theophylline
Oxtriphylline
Antimuscarinic Agents
Ipratropium (Atrovent)
Anti-inflammatory agents
Corticosteroid (Aerosol)
Beclomethasone (Banceril)
Dexamethasone (Decadron)
Flunisolide (AeroBid)
Fluticasone (Flovent)
Triamcinolone acetonide
Methylprednisolone
Prednisone (Deltasone)
Mast cell stabilizer
Cromolyn sodium(Intal)
Nedocromil (Tilade)
Lipo-oxygenase inhibitor
Zileuton (Zyflo)
Leukotriene Antagonists
Zafirlukast (Accolate)
Montelukast (Singulair)
1. Beta-Receptor Agonists
Beta-agonists stimulation beta-receptors leads to relaxation
of the bronchiolar smooth muscle.
In susceptible athletes, beta-agonists can prevent EIB, which,
if it were to develop, could impair aerobic performance.
Isoproterenol was one of the first beta-agonist drugs.
These newer, specificity for b
2
receptors (pulmonary tissue)
than for b
1
receptors (cardiac tissue), and longer duration.
Because of their potency and their rapid onset of action, b-
agonists are the preferred therapy for prevention of EIB.
Inhaled Albuterol b2-receptor agonist, one of the most widely
prescribed drugs for asthma.
no a-stimulating properties ( epinephrine)
less b
1
-stimulating properties (isoproterenol, epinephrine)
no CNS or psychological actions (amphetamine, cocaine).
Introduction to Respiratory Drugs
Sympathomimetic b-agonists
b-agoists
Table 5.2 Effects of Common Anti-Asthma
Medications on Exercise-Induced
Bronchoconstriction
Agent
Dose
(puffs)
Timing before
exercise (min)
Effectiveness
Duration
(hrs )
Beta-2 aerosols
Salmeterol
2 10-15 +++ 10-12
Albuterol 2 10-15 +++ 2.0-2.5
Terbutaline 2 10-15 +++ 2.0-2.5
Cromolyn sodium 2 10-15 ++ 1.5-2.0
Nedocromil
sodium
2 10-15 ++ 1.5-2.0
Methylxanthines N/A 30-60 +/- ?
Anticholinergics 2 30-60 +/- ?
Introduction to Respiratory Drugs
Methylxanthine Drugs
1. Chemistry:
Theophylline: 1,3-dimethylxanthine
Theobromine: 37 dimethylxanthine
Caffeine: 1,3,7-trimethylxanthine
From tea, coffee, cocoa
2. Pharmacokinetics: BBB
3. Mechanism of action:
(1) Inhibit phosphodiesterase (PDE4)
Cilomilast; roflumilast
(2) Inhibit the receptors of adenosine.
(3) Activate the Ryanodine receptor
(4) Increases in CD4 and CD8 lymphocytes
(5) Anti-inflammatory action
Cilomilast
roflumilast
Pharmacodynamics:
CNS: increased alertness; reduced fatigue;
nervousness; insomnia, medullary
stimulation, convulsions.
CVS: chronotropic; Inotropic
low doses:catecholamine release ;
presynaptic adenosine receptors
high doses:cAMP (PDE4); Ca influx
GI: secretion of gastric acid & enzymes
Kedney: weak diuretics
Smooth Muscle Effects: Bronchodilation
Clinical Used:
most effective xanthine bronchodilator
Relieves airway obstruction;
reduces symptoms severity in acute
asthma
long-termcontrol of asthma alone or
with GCSs.
Muscarinic antagonists
Nature source:Datura stramonium
for asthma in India atropine Man drake
Mechanism of Action:
inhibition of the muscarinic receptors .
Clinical Use of Muscarinic Antagonists:
Atropine sulfate: aerosol
Ipratropium bromide
a more selective 4 ammonium
high doses in air route
poorly absorbed into the circulation
does not readily enter CNS
Tiotropium
COPD. 24-hour duration
smooth muscle
contraction
adenylate
cyclase
cAMP
G1 proteins
Muscarinic
receptors (M3)

Ipratropium
Introduction to Respiratory Drugs
Corticosteroids
Mechanism of Action:
Phosphlipase A
2
inhibitor
Pharmacological effects
Anti-inflammatory activity
(1) Block leukotriene synthesis
(2) Inhibit cytokine production
(3) Reduction of mucosal oedema
(4) Adhesion protein activation
Immunosuppressive activity
Reverse b2-receptor down-regulation
Corticosteroids
CLINICAL USES
Asthma
Chronic
bronchitis
COPD
Rhinitis
Aerosol corticosteroid
Beclomethasone (Banceril)
Dexamethasone (Decadron)
Flunisolide (AeroBid)
Fluticasone (Flovent)
Triamcinolone acetonide
(Azmacort)
Oral corticosteroids
Methylprednisolone (Solu-Medrol)
Prednisone (Deltasone)
SIDE EFFECTS
Metabolic effects,
Growth suppression,
Fluid retention, osteoporosis,
Increase susceptibility to infection,
Cataract, GI symptoms,
Adrenal suppression
5. Mast Cell Stabilizers
Cromolyn & Nedocromil
Mechanism of Action:
alteration delayed chloride channels.
inhibition antigen challenge
inhibition inflammatory response
inhibitory mast cells
little inhibitory from basophils.
inhibits mast cell.
Clinical Use
blocks the Bronchoconstriction
by antigen inhalation,
by exercise, by aspirin,
by a variety of causes of asthma.
before exercise
before unavoidable exposure to an allergen.
reducing symptoms of allergic rhinoconjunctivitis
reducing symptoms of allergic hay fever
Leukotriene inhibitors
Zileuton
5-lipoxygenase
inhibitor:
Zafirlukast,
Montelukast
Leukotriene
receptor
(cys-LT1)
antagonist:
Cant be used in
child.
For long-term
montelukast
Figure 5.1
Mean (:t SEM) changes in FEV-1 after exercise challenge after 12 weeks of
treatment with montelukast or placebo. Treatment with montelukast was
associated with a significant (p = 0.002) reduction in EIB.
Introduction to Respiratory Drugs
Effects on Pharmacokinetics
Exercise has both acute and long-term effects on the
pharmacokinetics of drugs, but only limited data are available
Theophylline probably because acute toxicity from
theophylline is more serious than from any of the other
respiratory agents. Note that aerobic exercise diverts blood
flow away from the liver and kidneys.
This phenomenon interferes with the clearance of flow-limited
drugs, but it enhances the clearance of capacity-limited drugs.
Caffeine, dexamethasone, diphenhydramine, terbutaline, and
theophylline are all examples of respiratory agents that are
flow-limited.
Since some of these drugs are administered episodically and by
inhalation. But for theophylline, a drug that is
(a) administered systemically,
(b) administered daily, and
(c) potentially toxic,
the fitness level of the subject may affect the metabolic rate.
Unfortunately, this issue has not been adequately studied, and
caution is in order.
Cardiovascular Actions
However, b-receptors in the heart are predominantly of the b
1
subtype, and selective b
2
agonists have little effect on HR.
Albuterol has little effect on maximum exercise HR in elite
athletes with and without a history of asthma.
Epinephrine is both a b
1
and b
2
agonist; However, in the
presence of a b
2
drug, epinephrine less bind to the b
2
receptor.
Among the bronchodilators, theophylline stimulates resting
HR and can produce a mild diuresis, but has negligible effects
on exercise HR.
As for the respiratory anti-inflammatory agents, we can start
with the antihistamines.
Since resting HR is mainly under the control of the ANS (e.g.,
vagal innervation of the SA node), drugs with antimuscarinic
anticholinergic activity can increase resting HR.
To the contrary, diphenhydramine, an antihistamine with
anticholinergic properties, had no effect on exercise HR in the
12 volunteers who were exercised to exhaustion in a study.
Table 5.3 Physiologic Effects
Mediated by Beta-2 Receptors
Site Action
Vascular smooth muscle Relaxation
Bronchiolar smooth
muscle
Relaxation
GI tract smooth muscle Relaxation
GD tract smooth muscle Relaxation
Skeletal muscle Glycogenolysis, K+ uptake,:
Liver Glycogenolysis, gluconeoge]
Musculoskeletal Actions
The respiratory agents have effects on musculoskeletal
function that should be discussed, at least briefly.
For example, animal data reveal that 14 consecutive days
of ingesting clenbuterol increases contractilestrength of
skeletal muscle.
However, expressed per gram of muscle, power output was
similar between animals receiving the beta-agonist
clenbuterol and those receiving placebo.
The authors, Dodd and col-leagues (1996), concluded that
clenbuterol increased muscle strength and muscle size due
to hypertrophy of both slow-twitch and fast-twitch fibers
Theophylline has been shown to stimulate diaphragmatic
contractil-ity in asthmatics, but just how this action
impacts the exercise response is unclear.
Intravenous aminophylline had no effect on respiratory
muscle strength, ventilatory endurance, or exercise
performance in nonasthmatics during treadmill exercise .
Table 5.4 Contractile Properties for
Control and Clenbuterol- Treated Animals
Treatment
Absolute
tension (g)
Po
(g. g-l)
Vmax
(mm . S-l)
Fatigue
times (s)
Control
2,137 + 107 930 + 42 127.9 + 5.1 57.7 + 1.7
Clenbuterol
2,442 + 99* 931 + 37
151.2 +
3.7*
47.0 + 2.0*
Triathletes and Bronchodilators
Clinical research has estimated that
roughly 10-15%of Olympic athletes have
EIB (Storms 1999).
If that's true:, then why do 98% of
triathletes claim they are asthmatic?
Les McDonald, head of the International
Triathlon Union (ITU), insists the figure is
accurate, since his office in Vancnuver,
British Columbia, is where these athletes
must send their medical paperwork.
McDonald suspects that many of the
world's top triathletes are not actually
asthmatic, but have registered as such to
justify use of inhaled bronchodila-tor
drugs in hopes of enhancing their race
performance.
At the World Cup stop in Sydney, athletes
were seen on camera walking dawn to the
start of the race taking one last "hit" from
their inhalers before jumping in the water.
Figure 5.2 Changes in the strength of the knee extensors in drug-treated
and placebo-treated patients. The values are means with bars indicating
Figure 5.3 Changes (arrows) in maximal power (open bars) and intracellular threshold (IT)
power (hatched bars) during repeated exercise testing of the control and theophylline-treated
subjects. Tl represents the initial test condition; T2 represents the repeat test given 72 h later.
Values are mean:t SD. Theophylline treatment significantly (asterisk indicates p < 0.05)
increased maximal exercise capacity of the subjects and delayed the onset of the IT. Neither the
maximal power achieved nor the power at the onset of the IT was altered in the control group.
GINA (Global Initiative for Asthma) guidelines
Severe
persistent
Moderate
persistent
Mild
persistent
Intermittent
Short-acting
2
p.r.n
Inhalated Corticosteroids
Long-acting
2
Oral Anti-leukotriene
Reliever
Controller
mediators
Avoidance
mast cell
Cromolyn &
Nedocromil
early response:
brochoconstriction
late response:
inflammation
b-agonists
Theophylline
Anticholinergics
Corticosteroid
Leukotriene antagonist
5-lipoxygenase inhibitor
Brochoconstriction
symptoms
Brochial
hyperreactivity
Pathogenesis:
Antigens, drugs, Infections, Pollution
Avoiding Potential Complications
With the exception of theophylline, all the respiratory drugs, with
a few notable exceptions:.
. Exercise can affect the pharmacokinetics of theophylline.
. Antihistamines with strong anticholinergic properties may affect
temperature regulation.
. Antihistamines that induce drowsiness can affect exercise
performance.
. Beta-agonists can induce hand tremor, which may be
detrimental in shooting events.
The heat leaves the body by one of four mechanisms: conduction,
convection, radiation, or evaporation. Drugs with anticholinergic
(including antihistamines), can interfere with the sweating
response, inhibit heat loss from evaporation.
Astemizole associated with abnormalities of cardiac conduction
(Q- T prolongation) and cardiac arrhythmias (torsade depointes);
Corticosteroids be used chronically could detectable reductions in
bone mineral density (BMD in adult women with asthma but not
children. If these drugs allow the asthmatic to exercise,
conceivably the beneficial effects of exercise on BMD may offset
the detrimental effects of corticosteroid therapy.
NCAA and USOC Status
Note first that the NCAA and the USOC ban all the beta-receptor agonists
listed in table 5.1 for use during competition when administered
systemically (oral or parenteral injection).
NCAA permits some beta-agonists if administered by inhalation; however,
the USOC permits inhaled albuterol, salmeterol, and terbutaline only with
prior written permission.
All of the beta-agonists (except for salmeterol) have short half-lives;
discontinuation 2 to 3 days prior to competition.
Clenbuterol, banned by both the NCAA, USOC and United States.
Ipratropium and theophylline are not banned by either governing body.
The NCAA places no restriction on the use of corticosteroid
anti-inflammatory agents; however, the USOC bans the use of
corticosteroids by most routes of administration. With prior written
permission, the USOC allows the use of inhaled corticosteroids.
The USOC bans the use of sedating antihistamines for sports involving
riflery, and some of these drug combinations may contain other types of
banned substances (e.g., sympathomimetics).
The status of the newer drugs (e.g., zileuton, zafirlukast) is still unclear,
but judging by their actions and side effects, it seems unlikely that these
drugs would be banned.
Guidelines for Exercisers
Exercisers should keep in mind the
following points:.
Avoid herbal products or dietary
supplements that contain ephedra
or ephedrine..
Avoid antihistamines with
significant anticholinergic activity
during endurance activities..
While inhaled beta-2 receptor
agonists are the preferred type of
drug for preventing EIB, the USOC
does not permit the use of this
type of medication without written
permission
Guidelines for Trainers and Coaches
These are tips for helping active individuals in managing EIB:
If the individual has been prescribed an inhaler containing
cromolyn or a rapid-onset beta-agonist (e.g., albuterol), it can
be used just prior to beginning exercise.
Not all inhalers for EIB are alike: beta-agonist drugs (e.g.,
albuterol) are effective with the first dose, but if the inhaler is
salmeterol, it should be used at least 30 min prior to beginning
exercise
If the individual has been prescribed a steroid inhaler,
encourage daily use; single doses (i.e., episodic use) of
corticosteroid inhalersjust prior to exercise are ineffective in
preventing EIB.
Remember that both the NCAA and the USOC prohibit systemic
use of beta-agonists..
Since EIB does not lead to long-term deterioration of lung
function, generally there is no need for continuous (i.e., daily)
drug therapy (McFadden and Gilbert 1994); theophylline,
however, must be administered daily to be effective.
Guidelines for Trainers and Coaches
Advice give a person with asthma who wants to exercise or sports?
First, keep in mind that though exercise can induce bronchospasm in
susceptible individuals, long-term training may decrease in symptoms.
Postexercise bronchodilation has actually been documented (1996).
Note that some Olympic athletes have asthma; so a diagnosis of
asthma should not deter any athlete from setting lofty goals or cause
him or her to shy away from intense exercise.
Second, symptoms do not occur during exercise but rather
immediately after completion; they then reach a peak within 5 to 10
min. Recovery is usually complete in some 30 to 60 min postexercise
(McFadden 1994).
Third, not all sports or types of exercise induce EIB. Intense, short
bouts of activity are less of a problem than are prolonged events or
exercise sessions.
Furthermore, running is worse than jogging, and jogging is worse than
walking.
Exercise during winter months is worse than during the fall, and the
fall months are worse than the summer months (McFadden 1994).
Finally, despite uncertainty about the pathophysiology of EIB,
exposure to cold, dry air is a known stimulus to the condition.