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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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