Exercise Pharmacology by fDQ7Zq

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									 Exercise Pharmacology
Bronchodilators and Respiratory
   Anti-Inflammatory Agents
and clinical exercise physiology
                  By Steve Lome D.O.


     This presentation is available for download at
    http://www.learntheheart.com/benedictine.html
                 What are respiratory
                  bronchodilators?
     A bronchodilator is a substance that acts through a
     specific mechanism to relax the smooth muscle within the
     bronchial tree thus allowing for easier air exchange.

Names of respiratory bronchodilators
Pure ß2 agonists        Other ß2 Agonists (not used in asthma)
 albuterol (Proventil)  ephedine

 salmeterol (Serevent)  epinephrine (Primatene)

Methylxanthines         Antimuscarinic/Anticholinergic
 caffeine               ipratropium (Atrovent)

 theophylline           glycopyrrolate (Robinul)
             What are respiratory anti-
              inflammatory agents?
      A respiratory anti-inflammatory agent is a substance that
      reduces the swelling within the bronchial tree. This also
      reduces mucous secretions and allows for easier flow of
      air and ventilation.
Names of respiratory anti-inflammatory agents
Inhaled steroids               Leukotriene modifiers
 Fluticasone (Flovent)         Montelukast (Singulair)

 Budesonide (Pulmicort)        Zafirlukast (Accolate)

Mast cell stabilizers           Zileuton (Zyflo)

 Cromolyn (Intal)             Histamine-1 antagonists
                     What is asthma?
       Asthma is characterized by 1) An increase in the
       responsiveness of the airways to various stimuli causing
       reversible bronchoconstriction and 2) A chronic low grade
       inflammatory process.
Pathologic features                 Clinical features
 Hypertrophied smooth muscle         Dyspnea

 Hypertrophied mucous glands         Anxiety

 Infiltration by eosinophils and     Nocturnal symptoms

lymphocytes                           Cough
                 What is asthma?

Criteria needed for diagnosis
1) Intermittent airway obstruction indicated by a history of
   nighttime cough, recurrent wheeze, or recurrent chest
   tightness.
2) Reversible airflow obstruction as documented by
   pulmonary function testing, worsening symptoms in the
   presence of triggers, or symptoms that occur at night.
3) All other possible diagnosis excluded.
What is asthma?
             What is exercise induced
            bronchoconstriction (EIB)?
       Exercise induced bronchoconstriction, AKA exercise
       induced asthma, has similar physiology/pathology as
       asthma, only the symptoms occur after exercise. The
       primary aim of treatment is prophylaxis of symptoms.
Important facts about EIB
 Jackie Joyner-Kersee and Florence  CCBs are used in

Griffith-Joyner have significant EIB   hypertensives with EIB
 Acute episodes can be avoided by  Swimming causes less

warm-up periods before exercise.       EIB than running.
 Nasal breathing reduces EIB, but      Exercising in a warm

this is difficult during intense       humid environment helps.
exercise.
                Exercised induced
               bronchoconstriction

Diagnosis of EIB
At least a 15% drop in FEV1 needed for diagnosis
Mild          15-29% drop in FEV1 after exercise
Moderate      30-44% drop in FEV1 after exercise
Severe        >45% drop in FEV1 after exercise
                           What is COPD?
    COPD (Chronic Obstructive Pulmonary Disease) is a term
    used for people with chronic bronchitis, emphysema, or a
    combination of the two.
Chronic bronchitis               Emphysema
 “Blue bloater”                    “Pink Puffer”
 Excessive mucous production       Destruction of airways

 Normal perfusion/CO               Decreased perfusion/CO

 Decreased ventilation             Normal ventilation

 Frequent cough with sputum        Little to no cough

 Little increase in lung volume    Marked increased lung volume

 Often cyanotic                    No cyanosis

 Severe right heart failure        Little right heart failure

 Low O2 and High CO2               Low O2 and normal CO2
The “Blue Bloater”
The “Pink Puffer”
The widened anterior-posterior
      diameter in COPD
                Treatment of COPD
Treatment of COPD
• Smoking cessation
• Pulmonary rehabilitation
• ß2 agonists
• Antimuscarinic/Anticholinergics
• Inhaled corticosteroids
• Theophylline
                 Respiratory medications

    Classification of respiratory medications
Pure ß2 agonists           Other ß2 Agonists (not used in asthma)
 albuterol (Proventil)     ephedine

 salmeterol (Serevent)     epinephrine (Primatene)

Methylxanthines            Antimuscarinic/Anticholinergic
 caffeine                  ipratropium (Atrovent)

 theophylline              glycopyrrolate (Robinul)

Inhaled steroids           Leukotriene modifiers
 Fluticasone (Flovent)     Montelukast (Singulair)

 Budesonide (Pulmicort)    Zafirlukast (Accolate)

Mast cell stabilizers       Zileuton (Zyflo)

 Cromolyn (Intal)         Histamine-1 antagonists
          Pure ß2 receptor agonists

Pure ß2 receptor agonists
Albuterol (Proventil or Ventolin) – short acting
Salmeterol (Serevent) – long acting
Metaproterenol (Alupent)
Terbutaline
          Pure ß2 receptor agonists

Pure ß2 receptor agonists
•   Remember that bronchodilation is mediated in part by
    stimulation of ß2 receptors. This occurs due to relaxation
    of bronchial smooth muscle.
•   While these drugs are specific for ß2 receptors, a small
    amount of ß1 stimulation occurs as well.
•   While these drugs are primarily inhaled, a small amount of
    the drug can be absorbed through the lungs or GI tract
    (with improper use) into the general circulation. This
    relates to some of the side effects of these medications.
          Pure ß2 receptor agonists

Pure ß2 receptor agonists
•   ß2 receptor agonists are by far the most potent of the
    bronchodilators.
•   These medications are used universally for the treatment
    of asthma and COPD.
•   Their side effects include tachycardia (due to ß1
    stimulation), insomnia (due to CNS effects), anxiety (also
    due to CNS effects), and tremor. These occur only with
    relatively high doses of these medications.
•   Levo-albuterol (Xopenex) has less ß stimulation.
          Pure ß2 receptor agonists

Pure ß2 receptor agonists – Clinical uses
•   Short acting inhaled ß2 agonists are used on an as needed
    basis in mild asthma.
•   Long acting ß2 agonists are used on a daily basis in people
    with moderate-severe asthma.
•   All can be used in people with any degree of COPD.
•   Nebulizer treatments and MDI (metered dose inhalers)
    deliver the same amount of medication to the lungs when
    used properly.
                   Methylxanthines

Methylxanthines
•   Theophylline and caffeine are considered methylxanthines.
•   Theophylline is given orally for the treatment of asthma.
    Its use is falling out of favor due to it’s questionable
    efficacy and its toxicities. Theophylline has a very narrow
    theraputic window, meaning it is easy to achieve toxic
    levels of the drug.
•   The mechanisms of action is unclear.
•   There are numerous drug interactions with theophylline
    which can also affect the blood levels of the drug.
                  Methylxanthines

Methylxanthines
•   Smoking decreases absorption of theophylline. So if a
    person taking the drug stops smoking, levels can become
    toxic very fast!
•   Theophylline is a good choice for prophylaxis of EIB, and it
    may have ergogenic properties, AND it is not banned!
     Antimuscarinic/Anticholinergic

Antimuscarinic/Anticholinergic
Ipratropium (Atrovent)
Glycopyrrolate (Robinul)
Note: Very commonly, a combination of a ß2 agonist and a
   antimuscarinic/anticholinergic medication is used.
      Antimuscarinic/Anticholinergic

Antimuscarinic/Anticholinergic
•   While stimulation of the SNS (more specifically ß2
    receptors) leads to bronchodilation, stimulation of the PNS
    (parasympathetic nervous system) leads to inhibition of
    bronchodilation, although NOT bronchoconstriction.
•   Stimulation of muscarinic or cholinergic receptors leads to
    an increase in PNS activity. Thus blockade of muscarinic or
    cholinergic receptors inhibit the inhibition of
    bronchodilation, leading to some bronchodilation.
•   This affect is not as dramatic as simply stimulating ß2
      Antimuscarinic/Anticholinergic

Antimuscarinic/Anticholinergic
              ***IMPORTANT CONCEPT***
•   The one SNS affect that is actually mediated by
    muscarinic/cholinergic receptors is sweating.
•   Thus anticholinergic/antimuscarinic drugs can inhibit
    sweating, which leads to increased body temperature
    during exercise.
•   Note: Many over-the-counter anti-histamine drugs exert a
    significant amount of anticholinergic/antimuscarinic
    activity.
            Inhaled corticosteroids

Inhaled corticosteroids
Fluticasone (Flovent)
Flunisolide (Aerobid)
Budesonide (Pulmicort)
Triamcinolone (Azmacort)
            Inhaled corticosteroids

Inhaled corticosteroids
•   These medications have very strong anti-inflammatory
    properties, however they take a significant amount of time
    to take effect (weeks).
•   Administration of these agents via inhalation significantly
    reduces the systemic toxicities seen when these drugs are
    taken orally. However some systemic absorption can occur
    if used properly this is minimal.
•   Side effects of systemic corticosteroids include osteopenia
    and osteoperosis, diabetes type II, and HTN.
            Inhaled corticosteroids

Inhaled corticosteroids
•   Documented decreases in bone mineral density (BMD) has
    been seen in asthmatic women and asthmatic children
    taking inhaled corticosteroids for prolonged durations (3-8
    years). Other studies have shown no effect.
•   Extensive reviews of research have concluded that inhaled
    steroids are safe when excessive doses are avoided, even
    if used for many years.
•   If these drugs allow asthmatics to exercise, conceivably
    the beneficial effects of exercise on BMD may predominate
               Mast cell stabilizers

Mast cell stabilizers
Cromolyn sodium (Intal)
•   Mast cells are part of the immune system that help to
    mediate allergic reactions.
             Leukotriene modifiers

Leukotriene receptor antagonists
Montelukast (Singulair)
Pranlukast (Ultair)
Zafirlukast (Accolate)

Lipoxygenase inhibitors
Zileuton (Zyflo)
**Note: Together, the above two classes are called leukotriene
   modifiers.
             Leukotriene modifiers

Leukotriene-modifier drugs
•   Since leukotrienes cause bronchoconstriction, blockade of
    the enzyme that makes leukotrienes (lipoxygenase) or
    blockade of leukotriene receptors, can be beneficial in
    people with asthma.
Arachidonic Acid Cascades
                            SIGMA-ALDRICH
      Histamine-1 receptor blockers

Histamine-1 receptor blockers
•   There are too many H-1 blockers to name!
•   Histamine is a substance that helps to modulate the
    allergic response to environmental substances.
•   Blocking histamine-1 receptors exerts an anti-allergic
    action which would be helpful in people with asthma.
•   It is important to note that many anti-histamine
    medications have some antimuscarinic/anticholinergic
    properties which may contribute to their theraputic benefit.
           How Respiratory Agents
              Affect Exercisers

Cardiovascular actions – ß2-agonists
•   Remember that ß-receptors in the heart are mostly of the
    ß1 subtype.
•   When administered via inhalation in standard doses, very
    little drug becomes absorbed.
•   When administered via inhalation in high doses, studies
    have shown an increase in exercise heart rate when
    exercise intensity is low-moderate.
           How Respiratory Agents
              Affect Exercisers

Cardiovascular actions – ß2-agonists
               ***IMPORTANT CONCEPT***
•   At low levels of exercise intensity, HR increases in
    response to norepinephrine stimulation of ß1 receptors in
    the heart.
•   At high levels of exercise intensity, the additional increase
    in HR that is seen is due mainly to epinephrine-mediated
    stimulation of the few ß2 receptors in the heart .
•   In the presence of an exogenous ß2 agonist, epinephrine
    does not bind as much to ß receptors due to competition.
           How Respiratory Agents
              Affect Exercisers

Cardiovascular actions – ß2-agonists
               ***IMPORTANT CONCEPT***
•   Exogenous ß2 agonists like albuterol do not stimulate ß2
    receptors to the same degree as epinephrine. Epinephrine
    is a more potent stimulant of ß2 receptors.
•   So during intense exercise in the presence of albuterol,
    epinephrine does not stimulate the ß2 receptors in the
    heart as much.
           How Respiratory Agents
              Affect Exercisers

Cardiovascular actions – ß2-agonists
               ***IMPORTANT CONCEPT***
•   This explains why albuterol does not increase exercise
    heart rate during intense exercise, but it does during low-
    moderate intensity exercise.
           How Respiratory Agents
              Affect Exercisers

Cardiovascular actions
•   Antimuscarinic/anticholinergic medications do not affect
    exercise HR.
•   Remember that resting HR is mostly determined by PNS
    tone. Blocking the PNS with these medications can
    significantly increase resting HR.
•   Inhaled antimuscarinic/anticholinergic medications usually
    do not achieve high enough blood concentrations to cause
    this effect.
           How Respiratory Agents
              Affect Exercisers

Pulmonary actions and oxygen uptake
•   Many studies have shown that inhaled albuterol exerted
    significant bronchodilation in athletes, yet no beneficial
    effect on performance occurred.
•   VO2max is not affected by albuterol in people with and
    without asthma.
•   Theophylline, ipratropium, and nedocromil have no affect
    on VO2max.
•   The affects of leukotriene modifiers is unknown.
           How Respiratory Agents
              Affect Exercisers

Metabolic actions – ß2 agonists
•   Lactate concentrations normally rise when there is a
    greater dependence on carbohydrates for fuel or when
    oxygen delivery does not meet the demand of the tissues.
•   ß2 agonists can stimulate gluconeogensis and
    glycogenolysis, thus increasing the amount of
    carbohydrates used during exercise.
•   ß2 agonists also bronchodialate, so they can help increase
    the amount of oxygen delivered to tissues.
•   Overall, no change or a slight rise in lactate levels is seen.
           How Respiratory Agents
              Affect Exercisers

Metabolic actions – Theophylline
•   Theophylline has been shown to delay the onset of
    intracellular metabolic acidosis in muscle cells. This may
    indicate that it enhances the oxidative capacity of skeletal
    muscle.
•   Theophylline also has been shown to antagonize
    adenosine receptors. Adenosine is thought to be important
    during exercise for proper redistribution of blood flow to
    the specific exercising muscle group.
           How Respiratory Agents
              Affect Exercisers

Metabolic actions – Theophylline
•   Theophylline has also been shown to decrease
    erythropoeitin production. The affect of this on exercise
    performance is unknown.
           How Respiratory Agents
              Affect Exercisers

Musculoskeletal actions
•   Clenbuterol has been show to result in skeletal muscle
    hypertrophy. This results in an increase in the overall
    contractile strength of skeletal muscle. Power output is
    unchanged per gram of skeletal muscle.
•   Clenbuterol is not FDA approved in the US, but it is still
    abused.
         How Respiratory Agents
       Affect Exercise Performance

Exercise performance
               ***IMPORTANT CONCEPT***
•   In general, the lungs DO NOT limit exercise performance,
    since ventilation delivers more than enough O2 to tissues.
•   In the untrained person, exercise is primarily limited by
    cardiac output and peripheral VO2, not by ventilation or
    pulmonary gas diffusion.
•   Some athletes do demonstrate oxygen desaturation at VO2
    max or when cardiac output is very high. These individuals
    may then be limited by ventilation.
         How Respiratory Agents
       Affect Exercise Performance

Exercise performance
              ***IMPORTANT CONCEPT***
•   Since asthmatics or people with exercise induced
    bronchoconstriction (EIB) also demenstrate oxygen
    desaturations, pulmonary function in these individuals
    most likely do limit exercise performance.
•   Also, exercise capacity in elderly athletes have been shown
    to be limited by pulmonary function.
         How Respiratory Agents
       Affect Exercise Performance

Exercise performance and ß2 agonists
•   Multiple studies have shown that when administered via
    inhalation, ß2 agonists are not ergogenic in both trained
    and untrained subjects, asthmatic and non-asthmatic
    subjects, and at normal or high doses. These drugs are
    still widely abused in athletes.
•   Oral albuterol has been shown to significantly increase the
    muscle strength after long term use (21-56 days). This
    affect is only seen in untrained individuals and is most
    likely due to muscle hypertrophy.
         How Respiratory Agents
       Affect Exercise Performance

Exercise performance and ß2 agonists
•   Clinical research has shown that 10-15% of Olympic
    athletes have EIB. If that is true, then whe do 98% of
    triathletes claim they are asthmatic? They register as
    asthmatic so they can use bronchodilators prior to their
    race in hopes of enhancing performance.
•   At the World Cup stop in Sydney, athletes were seen on
    camera taking one last “hit” from their albuterol inhalers
    just before starting. They would then pass it on to the next
    athlete.
             How Respiratory Agents
           Affect Exercise Performance

    Exercise performance and Theophylline
    Ergogenic effects               Ergolytic effects
 Inhibition of bronchoconstriction  Diuretic affect similar to

 Enhanced FFA mobilization         hydrochlorothiazide
 Increased circulating epinephrine  Adenosine antagonism

 Increased cardiac output           Decreased production of

 Increased diaphragmatic
                                    erythropoeitin
contractility
 CNS stimulation
         How Respiratory Agents
       Affect Exercise Performance

Exercise performance and Theophylline
•   Studies have been limited and conflicting, however it
    appears that theophylline does indeed exert an overall
    ergogenic affect, as seen theorized on the previous slide.
•   Caffeine has been widely researched and is clearly
    ergogenic. Despite the similarities, there are many
    significant differences between caffeine and theophylline
    (see ch13)
            NCAA and USOC Status

NCAA and USOC Status
•   All ß2 receptor agonists are banned by the NCAA and
    USOC when administered systemically (oral, IV, or
    intramuscular)
•   All inhaled ß2 agonists are allowed by the NCAA. Only
    inhaled albuterol, salmeterol, and terbutaline are allowed
    by the USOC with prior written permission.
•   Clenbuterol is banned by both and not licensed for human
    use in the US.
           NCAA and USOC Status

NCAA and USOC Status
•   Iptratropium and theophylline are not banned by either
    organization.
•   The NCAA places no restrictions on corticosteroids,
    however the USOC only allows them with prior written
    permission.
•   The USOC banned all sedating anti-histamines for sports
    involving riflery.
             Guidelines for trainers

Guidelines for trainers
•   Many Olympic athletes have asthma. So this diagnosis
    should not deter someone from starting an exercise
    program or setting high goals for their exercise training.
•   Most symptoms of EIB do not occur during exercise, but
    immediately after exercise. Recovery is usually complete
    about 30-60 minutes after exercise.
•   Exercise in cold temperatures is much worse for people
    with EIB.
             Guidelines for trainers

Guidelines for trainers
•   Albuterol inhalers can be used immediately before exercise
    begins, but salmeterol must be used about 30 minutes
    prior to exercise due to it’s slower onset of action.
•   Steroid inhalers must be used on a daily basis to be
    effective. They are not effective if taken only sporadically
    or immediately before exercise.

								
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