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  1. 1. Bronchodilators and Other Respiratory Agents
  2. 2. Drugs Affecting the Respiratory System <ul><li>Bronchodilators </li></ul><ul><ul><li>Xanthine derivatives </li></ul></ul><ul><ul><li>Beta-agonists </li></ul></ul><ul><li>Anticholinergics </li></ul><ul><li>Antileukotriene agents </li></ul><ul><li>Corticosteroids </li></ul><ul><li>Mast cell stabilizers </li></ul>
  3. 3. Bronchodilators: Xanthine Derivatives <ul><li>Plant alkaloids: caffeine, theobromine, and theophylline </li></ul><ul><li>Only theophylline is used as a bronchodilator </li></ul><ul><li>Examples: aminophylline dyphilline oxtriphylline theophylline (Bronkodyl, Slo-bid, Theo-Dur,Uniphyl) </li></ul>
  4. 4. Bronchodilators: Xanthine Derivatives Mechanism of Action <ul><li>Increase levels of energy-producing cAMP* </li></ul><ul><li>This is done competitively inhibiting phosphodiesterase (PDE), the enzyme that breaks down cAMP </li></ul><ul><li>Result: decreased cAMP levels, smooth muscle relaxation, bronchodilation, and increased airflow </li></ul><ul><li>*cAMP = cyclic adenosine monophosphate </li></ul>
  5. 5. Bronchodilators: Xanthine Derivatives Drug Effects <ul><li>Cause bronchodilation by relaxing smooth muscles of the airways. </li></ul><ul><li>Result: relief of bronchospasm and greater airflow into and out of the lungs. </li></ul><ul><li>Also causes CNS stimulation. </li></ul><ul><li>Also causes cardiovascular stimulation: increased force of contraction and increased HR, resulting in increased cardiac output and increased blood flow to the kidneys (diuretic effect). </li></ul>
  6. 6. Bronchodilators: Xanthine Derivatives Therapeutic Uses <ul><li>Dilation of airways in asthmas, chronic bronchitis, and emphysema </li></ul><ul><li>Mild to moderate cases of asthma </li></ul><ul><li>Adjunct agent in the management of COPD </li></ul><ul><li>Adjunct therapy for the relief of pulmonary edema and paroxysmal nocturnal edema in left-sided heart failure </li></ul>
  7. 7. Bronchodilators: Xanthine Derivatives Side Effects <ul><li>Nausea, vomiting, anorexia </li></ul><ul><li>Gastroesophageal reflux during sleep </li></ul><ul><li>Sinus tachycardia, extrasystole, palpitations, ventricular dysrhythmias </li></ul><ul><li>Transient increased urination </li></ul>
  8. 8. Bronchodilators: Beta-Agonists <ul><li>Large group, sympathomimetics </li></ul><ul><li>Used during acute phase of asthmatic attacks </li></ul><ul><li>Quickly reduce airway constriction and restore normal airflow </li></ul><ul><li>Stimulate beta 2 adrenergic receptors throughout the lungs </li></ul>
  9. 9. Bronchodilators: Beta-Agonists Three types <ul><li>Nonselective adrenergics </li></ul><ul><ul><li>Stimulate alpha 1 , beta 1 (cardiac), and beta 2 (respiratory) receptors. </li></ul></ul><ul><ul><li>Example: epinephrine </li></ul></ul><ul><li>Nonselective beta-adrenergics </li></ul><ul><ul><li>Stimulate both beta 1 and beta 2 receptors. </li></ul></ul><ul><ul><li>Example: isoproterenol (Isuprel) </li></ul></ul><ul><li>Selective beta 2 drugs </li></ul><ul><ul><li>Stimulate only beta 2 receptors. </li></ul></ul><ul><ul><li>Example: albuterol </li></ul></ul>
  10. 10. Bronchodilators: Beta-Agonists Mechanism of Action <ul><li>Begins at the specific receptor stimulated </li></ul><ul><li>Ends with the dilation of the airways </li></ul><ul><li>Activation of beta 2 receptors activate cAMP, which relaxes smooth muscles of the airway and results in bronchial dilation and increased airflow. </li></ul>
  11. 11. Bronchodilators: Beta-Agonists Therapeutic Uses <ul><li>Relief of bronchospasm, bronchial asthma, bronchitis, and other pulmonary disease. </li></ul><ul><li>Useful in treatment of acute attacks as well as prevention. </li></ul><ul><li>Used in hypotension and shock. </li></ul><ul><li>Used to produce uterine relaxation to prevent premature labor. </li></ul><ul><li>Hyperkalemia—stimulates potassium to shift into the cell. </li></ul>
  12. 12. Bronchodilators: Beta-Agonists Side Effects <ul><li>Alpha-Beta Beta 1 and Beta 2 Beta 2 </li></ul><ul><li>(epinephrine) (isoproterenol) (albuterol) </li></ul><ul><li>insomnia cardiac stimulation hypotension restlessness tremor vascular headache anorexia anginal pain tremor cardiac stimulation vascular headache tremor vascular headache </li></ul>
  13. 13. Respiratory Agents: General Nursing Implications <ul><li>Encourage patients to take measures that promote a generally good state of health in order to prevent, relieve, or decrease symptoms of COPD. </li></ul><ul><ul><li>Avoid exposure to conditions that precipitate bronchospasms (allergens, smoking, stress, air pollutants) </li></ul></ul><ul><ul><li>Adequate fluid intake </li></ul></ul><ul><ul><li>Compliance with medical treatment </li></ul></ul><ul><ul><li>Avoid excessive fatigue, heat, extremes in temperature, caffeine </li></ul></ul>
  14. 14. Respiratory Agents: General Nursing Implications <ul><li>Encourage patients to get prompt treatment for flu or other illnesses, and to get vaccinated against pneumonia or flu. </li></ul><ul><li>Encourage patients to always check with their physician before taking any other medication, including OTC. </li></ul>
  15. 15. Respiratory Agents: General Nursing Implications <ul><li>Perform a thorough assessment before beginning therapy, including: </li></ul><ul><ul><li>Skin color </li></ul></ul><ul><ul><li>Baseline vital signs </li></ul></ul><ul><ul><li>Respirations (should be <12 or >24 breaths/min) </li></ul></ul><ul><ul><li>Respiratory assessment, including PO 2 </li></ul></ul><ul><ul><li>Sputum production </li></ul></ul><ul><ul><li>Allergies </li></ul></ul><ul><ul><li>History of respiratory problems </li></ul></ul><ul><ul><li>Other medications </li></ul></ul>
  16. 16. Respiratory Agents: General Nursing Implications <ul><li>Teach patients to take bronchodilators exactly as prescribed. </li></ul><ul><li>Ensure that patients know how to use inhalers, MDIs, and have the patients demonstrate use of devices. </li></ul><ul><li>Monitor for side effects. </li></ul>
  17. 17. Respiratory Agents: Nursing Implications <ul><li>Monitor for therapeutic effects </li></ul><ul><ul><li>Decreased dyspnea </li></ul></ul><ul><ul><li>Decreased wheezing, restlessness, and anxiety </li></ul></ul><ul><ul><li>Improved respiratory patterns with return to normal rate and quality </li></ul></ul><ul><ul><li>Improved activity tolerance </li></ul></ul><ul><li>Decreased symptoms and increased ease of breathing </li></ul>
  18. 18. Bronchodilators: Nursing Implications Xanthine Derivatives <ul><li>Contraindications: history of PUD or GI disorders </li></ul><ul><li>Cautious use: cardiac disease </li></ul><ul><li>Timed-release preparations should not be crushed or chewed (causes gastric irritation) </li></ul>
  19. 19. Bronchodilators: Nursing Implications Xanthine Derivatives <ul><li>Report to physician: </li></ul><ul><li>Palpitations Nausea Vomiting </li></ul><ul><li>Weakness Dizziness Chest pain </li></ul><ul><li>Convulsions </li></ul>
  20. 20. Bronchodilators: Nursing Implications Xanthine Derivatives <ul><li>Be aware of drug interactions with: cimetidine, oral contraceptives, allopurinol </li></ul><ul><li>Large amounts of caffeine can have deleterious effects. </li></ul>
  21. 21. Bronchodilators: Nursing Implications Beta-Agonist Derivatives <ul><li>Albuterol, if used too frequently, loses its beta 2 -specific actions at larger doses. </li></ul><ul><li>As a result, beta 1 receptors are stimulated, causing nausea, increased anxiety, palpitations, tremors, and increased heart rate. </li></ul>
  22. 22. Bronchodilators: Nursing Implications Beta-Agonist Derivatives <ul><li>Patients should take medications exactly as prescribed, with no omissions or double doses. </li></ul><ul><li>Patients should report insomnia, jitteriness, restlessness, palpitations, chest pain, or any change in symptoms. </li></ul>
  23. 23. Anticholinergics: Mechanism of Action <ul><li>Acetylcholine (ACh) causes bronchial constriction and narrowing of the airways. </li></ul><ul><li>Anticholinergics bind to the ACh receptors, preventing ACh from binding. </li></ul><ul><li>Result: bronchoconstriction is prevented, airways dilate. </li></ul>
  24. 24. Anticholinergics <ul><li>Ipratropium bromide (Atrovent) is the only anticholinergic used for respiratory disease. </li></ul><ul><li>Slow and prolonged action </li></ul><ul><li>Used to prevent bronchoconstriction </li></ul><ul><li>NOT used for acute asthma exacerbations! </li></ul>
  25. 25. Anticholinergics: Side Effects <ul><li>Dry mouth or throat Gastrointestinal distress </li></ul><ul><li>Headache Coughing </li></ul><ul><li>Anxiety </li></ul><ul><li>No known drug interactions </li></ul>
  26. 26. Antileukotrienes <ul><li>Also called leukotriene receptor antagonists (LRTAs) </li></ul><ul><li>New class of asthma medications </li></ul><ul><li>Three subcategories of agents </li></ul>
  27. 27. Antileukotrienes <ul><li>Currently available agents: </li></ul><ul><li>montelukast (Singulair) </li></ul><ul><li>zafirlukast (Accolate) </li></ul><ul><li>zileuton (Zyflo) </li></ul>
  28. 28. Antileukotrienes: Mechanism of Action <ul><li>Leukotrienes are substances released when a trigger, such as cat hair or dust, starts a series of chemical reactions in the body. </li></ul><ul><li>Leukotrienes cause inflammation, bronchoconstriction, and mucus production. </li></ul><ul><li>Result: coughing, wheezing, shortness of breath </li></ul>
  29. 29. Antileukotrienes: Mechanism of Action <ul><li>Antileukotriene agents prevent leukotrienes from attaching to receptors on cells in the lungs and in circulation. </li></ul><ul><li>Inflammation in the lungs is blocked , and asthma symptoms are relieved. </li></ul>
  30. 30. Antileukotrienes: Drug Effects <ul><li>By blocking leukotrienes: </li></ul><ul><li>Prevent smooth muscle contraction of the bronchial airways </li></ul><ul><li>Decrease mucus secretion </li></ul><ul><li>Prevent vascular permeability </li></ul><ul><li>Decrease neutrophil and leukocyte infiltration to the lungs, preventing inflammation </li></ul>
  31. 31. Antileukotrienes: Therapeutic Uses <ul><li>Prophylaxis and chronic treatment of asthma in adults and children over age 12 </li></ul><ul><li>NOT meant for management of acute asthmatic attacks </li></ul><ul><li>Montelukast is approved for use in children age 2 and older </li></ul>
  32. 32. Antileukotrienes: Side Effects <ul><li>zileuton zafirlukast </li></ul><ul><li>Headache Headache </li></ul><ul><li>Dyspepsia Nausea </li></ul><ul><li>Nausea Diarrhea </li></ul><ul><li>Dizziness Liver dysfunction </li></ul><ul><li>Insomnia </li></ul><ul><li>Liver dysfunction </li></ul><ul><li>montelukast has fewer side effects </li></ul>
  33. 33. Antileukotrienes: Nursing Implications <ul><li>Ensure that the drug is being used for chronic management of asthma, not acute asthma. </li></ul><ul><li>Teach the patient the purpose of the therapy. </li></ul><ul><li>Improvement should be seen in about 1 week. </li></ul>
  34. 34. Antileukotrienes: Nursing Implications <ul><li>Check with physician before taking any OTC or prescribed medications—many drug interactions. </li></ul><ul><li>Assess liver function before beginning therapy. </li></ul><ul><li>Medications should be taken every night on a continuous schedule, even if symptoms improve. </li></ul>
  35. 35. Corticosteroids <ul><li>Anti-inflammatory </li></ul><ul><li>Used for CHRONIC asthma </li></ul><ul><li>Do not relieve symptoms of acute asthmatic attacks </li></ul><ul><li>Oral or inhaled forms </li></ul><ul><li>Inhaled forms reduce systemic effects </li></ul><ul><li>May take several weeks before full effects are seen </li></ul>
  36. 36. Corticosteroids: Mechanism of Action <ul><li>Stabilize membranes of cells that release harmful bronchoconstricting substances. </li></ul><ul><li>These cells are leukocytes, or white blood cells. </li></ul><ul><li>Also increase responsiveness of bronchial smooth muscle to beta-adrenergic stimulation. </li></ul>
  37. 37. Inhaled Corticosteroids <ul><li>beclomethasone dipropionate (Beclovent, Vanceril) </li></ul><ul><li>triamcinolone acetonide (Azmacort) </li></ul><ul><li>dexamethasone sodium phosphate (Decadron Phosphate Respihaler) </li></ul><ul><li>flunisolide (AeroBid) </li></ul>
  38. 38. Inhaled Corticosteroids: Therapeutic Uses <ul><li>Treatment of bronchospastic disorders that are not controlled by conventional bronchodilators. </li></ul><ul><li>NOT considered first-line agents for management of acute asthmatic attacks or status asthmaticus. </li></ul>
  39. 39. Inhaled Corticosteroids: Side Effects <ul><li>Pharyngeal irritation </li></ul><ul><li>Coughing </li></ul><ul><li>Dry mouth </li></ul><ul><li>Oral fungal infections </li></ul><ul><li>Systemic effects are rare because of the low doses used for inhalation therapy. </li></ul>
  40. 40. Inhaled Corticosteroids: Nursing Implications <ul><li>Contraindicated in patients with psychosis, fungal infections, AIDS, TB. </li></ul><ul><li>Cautious use in patients with diabetes, glaucoma, osteoporosis, PUD, renal disease, CHF, edema. </li></ul><ul><li>Teach patients to gargle and rinse the mouth with water afterward to prevent the development of oral fungal infections. </li></ul>
  41. 41. Inhaled Corticosteroids: Nursing Implications <ul><li>Abruptly discontinuing these medications can lead to serious problems. </li></ul><ul><li>If discontinuing, should be weaned for a period of 1 to 2 weeks, and only if recommended by physician. </li></ul><ul><li>REPORT any weight gain of more than 5 pounds a week or the occurrence of chest pain. </li></ul>
  42. 42. Mast Cell Stabilizers <ul><li>cromolyn (Nasalcrom, Intal) </li></ul><ul><li>nedocromil (Tilade) </li></ul>
  43. 43. Mast Cell Stabilizers <ul><li>Indirect-acting agents that prevent the release of the various substances that cause bronchospasm </li></ul><ul><li>Stabilize the cell membranes of inflammatory cells (mast cells, monocytes, macrophages), thus preventing release of harmful cellular contents </li></ul><ul><li>No direct bronchodilator activity </li></ul><ul><li>Used prophylactically </li></ul>
  44. 44. Mast Cell Stabilizers: Therapeutic Uses <ul><li>Adjuncts to the overall management of COPD </li></ul><ul><li>Used solely for prophylaxis, NOT for acute asthma attacks </li></ul><ul><li>Used to prevent exercise-induced bronchospasm </li></ul><ul><li>Used to prevent bronchospasm associated with exposure to known precipitating factors, such as cold, dry air or allergens </li></ul>
  45. 45. Mast Cell Stabilizers: Side Effects <ul><li>Coughing Taste changes </li></ul><ul><li>Sore throat Dizziness </li></ul><ul><li>Rhinitis Headache </li></ul><ul><li>Bronchospasm </li></ul>
  46. 46. Mast Cell Stabilizers: Nursing Implications <ul><li>For prophylactic use only </li></ul><ul><li>Contraindicated for acute exacerbations </li></ul><ul><li>Not recommended for children under age 5 </li></ul><ul><li>Therapeutic effects may not be seen for up to 4 weeks </li></ul><ul><li>Teach patients to gargle and rinse the mouth with water afterward to minimize irritation to the throat and oral mucosa </li></ul>
  47. 47. LEARNING OBJECTIVES <ul><li>To appreciate basic pathogenesis of and therapeutic strategies for the management of asthma and chronic obstructive pulmonary disease (COPD) </li></ul><ul><li>To understand the mechanism of action of the three major classes of bronchodilators </li></ul><ul><li>To appreciate prospects for new therapies for asthma and COPD </li></ul>Asthma and COPD are common disorders (affecting 10 and 30 million Americans, respectively) and show several similarities in their clinical features. The goal of this lecture and the lecture on anti-inflammatory agents will be to highlight the fundamental pharmacological basis to manage the pathological changes associated with these diseases and to restore normal functionality.
  48. 48. ASTHMA <ul><li>The clinical hallmarks of asthma are recurrent, episodic bouts of coughing, shortness of breath, chest tightness, and wheezing. In mild asthma, symptoms occur only occasionally but in more severe forms of asthma frequent attacks of wheezing dyspnea occur, especially at night, and chronic activity limitation is common. </li></ul>
  49. 49. Pathological Features of Asthma <ul><li>Asthma is characterized physiologically by increased responsiveness of the trachea and bronchi to various stimuli and by widespread narrowing of the airways. </li></ul><ul><li>Chronic pathological features: </li></ul><ul><ul><li>contraction of airways smooth muscle, leading to reversible airflow obstruction, </li></ul></ul><ul><ul><li>mucosal thickening from edema and cellular infiltration with airway inflammation and persistent airway hyperreactivity, </li></ul></ul><ul><ul><li>airway remodeling. </li></ul></ul>
  50. 50. Anatomy of Asthma
  51. 51. Impact of Inflammation on Small Airways Acute Fatal Asthma Normal Chronic Severe Asthma From the lecture tomorrow by A. Petrov, MD
  52. 52. Mechanisms of airway inflammation in asthma Allergen exposure initiates a complex, self-amplifying process among cells, cytokines, and neurogenic components, resulting in chronic, symptomatic inflammation with bronchial hyperresponsiveness. Mast cells in the bronchial lumen & epithelium & within the bronchial wall become activated, releasing a mediators, which initiate an acute phase reaction (within min), including bronchospasm, resulting in airflow obstruction.
  53. 53. Cellular mediators and cytokines in COPD
  54. 54. Current and Future Asthma Treatment The worldwide asthma market is estimated to exceed US $7 billion and is increasing rapidly. Approximately 5% of asthmatic patients remain poorly controlled. Despite considerable effort by the pharmaceutical industry, it has proven very difficult to develop new classes of therapeutic agents for asthma .
  55. 55. Chronic Obstructive Pulmonary Disease <ul><li>COPD is characterized by airflow limitation caused by chronic bronchitis or emphysema often associated with long term tobacco smoking. This is usually a slowly progressive and largely irreversible process, which consists of increased resistance to airflow, loss of elastic recoil, decreased expiratory flow rate, and overinflation of the lung. </li></ul><ul><li>COPD is clinically defined by a low FEV1 value that fails to respond acutely to bronchodilators, a characteristic that differentiates it from asthma. </li></ul><ul><li>The degree of broncodilatory response at the time of testing, however, does not predict the degree of clinical benefit to the patient and thus bronchodilators are given irrespective of the acute response obtained in the pulmonary function laboratory. </li></ul>
  56. 56. Control Severe COPD Pathology of Small Airways i.e. less then 2mm in diameter From Danielle Morse, MD
  57. 57. Schematic representation of the disposition of inhaled drugs Lung Topical effect ~2-10% Liver First pass Metabolism (inactivation) GI Tract Mouth Deposition ~90% swallowed Lung Pulmonary absorption BLOOD STREAM Drug systemic effect + inactive metabolite
  58. 58. Aerosol & Spacer Technology
  59. 59. Aerosol Delivery of Drugs <ul><li>The size of the particle is a critical delivery determinant. </li></ul><ul><li>Particles > 10  m are deposited primarily in the mouth & oropharynx. </li></ul><ul><li>Particles < 0.5  m are inhaled to the alveoli and exhaled without being deposited in the lungs. </li></ul><ul><li>The most effective particles have a diameter of 1-5  m. </li></ul><ul><li>Other important factors for deposition are rate of breathing and breathing-holding after inhalation. </li></ul>
  60. 60. Role of beta agonists in asthma and COPD  2 agonists have other beneficial effects including inhibition of mast cell-mediator release, prevention of microvascular leakage and airway edema, and enhanced mucocillary clearance. The inhibitor effects on mast cell actions suggest that  2 agonists may modify acute inflammation.
  61. 61. Classes of Bronchodilators <ul><li> Agonists Albuterol, levalbuterol, metaproterenol, terbutaine, isoproterenol, & epinephrine </li></ul><ul><li>PDE inhibitors Theophylline </li></ul><ul><li>Anticholinergics Ipratropium & tiotropium </li></ul>
  62. 62. Signal Transduction Pathway for Bronchodilation Bronchodiliation PDE3
  63. 63. Classification of  agonists  2 agonists were developed through substitutions in the catecholamine structure of norepinephrine (NE). NE differs from epinephrine in the terminal amine group, and modification at this site confers beta receptor selectivity; further substitutions have resulted in  2 selectivity. The selectivity of  2 agonists is obviously dose dependent. Inhalation of the drug aids selectivity since it delivers small doses to the airways and minimizes systemic exposure.  agonists are generally divided into short (4-6 h) and long (>12 h) acting agents. Table 1. Beta Agonists Short acting Generic name Duration of action  2-selectivity Albuterol 4-6 h +++ Levalbuterol 8 h +++ Metaproterenol 4-6 h ++ Isoproterenol 3-4 h ++ Epinephrine 2-3 h - Long acting Salmeterol 12 + h +++ Formoterol 12 + h +++
  64. 64. Chemicals Epinephrine Isoproterenol Albuterol Metaproterenol Salmeterol Fomoterol
  65. 65. Classification of  agonists  2 agonists were developed through substitutions in the catecholamine structure of norepinephrine (NE). NE differs from epinephrine in the terminal amine group, and modification at this site confers beta receptor selectivity; further substitutions have resulted in  2 selectivity. The selectivity of  2 agonists is obviously dose dependent. Inhalation of the drug aids selectivity since it delivers small doses to the airways and minimizes systemic exposure.  agonists are generally divided into short (4-6 h) and long (>12 h) acting agents. Table 1. Beta Agonists Short acting Generic name Duration of action  2-selectivity Albuterol 4-6 h +++ Levalbuterol 8 h +++ Metaproterenol 4-6 h ++ Isoproterenol 3-4 h ++ Epinephrine 2-3 h - Long acting Salmeterol 12 + h +++ Formoterol 12 + h +++
  66. 66. Pulmonary and cardiac effects of  adrenergic receptor agonists Log dose FEV 1 (% maximal increase) 100 0 100 0 Heart rate (%maximal increase) Isoproterenol Albuterol
  67. 67. Pharmacological Approaches to Asthma Control Selective  2 agonist ATP cAMP Theophyline 5’-AMP Relaxation Ach Ipratopium Vagus nerve
  68. 68. Theophylline
  69. 69. Theophylline
  70. 70. Pharmacology of Theophylline <ul><li>ADME </li></ul><ul><li>Absorption : oral. The dose of theophylline required to yield therapeutic concentrations varies among subjects, largely because of differences in clearance. </li></ul><ul><li>Metabolism. Concurrent administration of phenobarbitol or phenytoin increases activity of cytochrome P-450 (CYP), which results in increased metabolic breakdown. </li></ul><ul><li>Elimination. Increased clearance is seen in children and in cigarette and marijuana smokers. Reduced clearance is also seen with the common drugs that interfere with the CYP system, such as cimetidine, erythromycin, ciprofloxacin, allopurinol, zileuton, and zafirlukast. Viral infections and vaccinations may also reduce clearance. </li></ul>
  71. 71. Pharmacological Approaches to Asthma Control Selective  2 agonist ATP cAMP Theophyline 5’-AMP Relaxation Ach Ipratopium Vagus nerve
  72. 72. Anticholinergic Drugs <ul><li>Human airways are innervated by a supply of efferent, cholinergic, parasympathetic autonomic nerves. </li></ul><ul><li>Motor nerves derived from the vagus form ganglia within and around the walls of the airways. This vagally derived innervation extends along the length of the bronchial tree, but predominates in the large and medium-sized airways. </li></ul><ul><li>Postganglionic fibers derived from the vagal ganglia supply the smooth muscle and submucosal glands of the airways as well as the vascular structures. Release of acetylcholine (ACh) at these sites results in stimulation of muscarinic receptors and subsequent airway smooth muscle contraction and release of secretions from the submucosal airway glands. </li></ul>
  73. 73. Anticholinergic Drugs (cont) <ul><li>Three pharmacologically distinct subtypes of muscarinic receptors exist within the airways: M1, M2 and M3 receptors. </li></ul><ul><li>M1 receptors are present on peribronchial ganglion cells where the preganglionic nerves transmit to the postganglionic nerves. M2 receptors are present on the postganglionic nerves; they are activated by the release of acetylcholine and promote its reuptake into the nerve terminal. M3 receptors are present on smooth muscle. </li></ul><ul><li>Muscarinic receptor activation of these M3 receptors leads to a decrease in intracellular cAMP levels, resulting in contraction of airway smooth muscle and bronchoconstriction. </li></ul>
  74. 74. Anticholinergic Drugs (cont) <ul><li>Atropine is the prototype anticholinergic bronchodilator. </li></ul><ul><li>Ipratropium is a quaternary amine, which is poorly absorbed across biologic membranes. </li></ul><ul><li>Atropine and ipratropium antagonize the actions of Ach at parasympathetic, postganglionic, effector cell junctions by competing with Ach for M3 receptor sites. </li></ul><ul><li>This antagonism of Ach results in airway smooth muscle relaxation and bronchodilation. </li></ul>
  75. 75. Anticholinergic Drugs (cont) <ul><li>Ipratropium is given exclusively by inhalation from a metered-dose inhaler or a nebulizer. Inhaled ipratropium has a slow onset ( ~30 min) and a relatively long duration of action ( ~6 h). </li></ul><ul><li>Tiotropium, a structural analog of ipratropiem, has been approved for treatment of COPD. Like iprotropiem, tiotropiem has high affinity for all muscarinic receptor subtypes but it dissociates from the receptors much more slowly than ipratropium, esp. M3 receptors. This permits once a day dosing. It is formulated for use with an oral inhalator. </li></ul><ul><li>Clinical trials of anticholinergic therapy have generally failed to show significant benefit in asthma. This relative lack of efficacy in asthma contrasts with COPD, in which anticholinergic agents are among the most effective therapies. </li></ul>Ipratopium Tiotropium Atropine
  76. 76. Approved in US February 2004
  77. 77. Future Pharmacological Agents for Asthma & COPD <ul><li>Vasoactive intestinal peptide (VIP) analogs. VIP is a potent relaxant of constricted human airways in vitro but it is degraded too quickly in the airway epithelium to be effective. A more stable cyclic analog of VIP (Ro-25-1553) has a prolonged effect in asthmatic patients by inhalation. </li></ul><ul><li>Prostaglandin E2. PGE agonists that are selective for lung receptors subtypes are being considered for exploration as bronchodilators/anti-inflammatory drugs. </li></ul><ul><li>Atrial natriuretic peptides (ANP). Intravenous infusion of ANP produces a significant bronchodilator response and protect against bronchoconstriction induced by inhaled broncoconstrictors such as methacholine. ANP, however, is a peptide and subject to rapid enzymatic degradation. A related peptide, urodilatin, is less susceptible to degradation and has a longer duration of action. It is as potent as salbutamol when given iv. </li></ul><ul><li>Phosphodiesterase 4 (PDE4) inhibitors. Because of theophylline, other PDE4 inhibitors are being tested. The PDE4 inhibitor cilomilast has been clinically tested for COPD but the drug causes emesis, a common side effect with this class (this could be due to inhibition of PDE4D). There is hope that selective inhibitors of PDE4B might have more therapeutic potential. </li></ul>
  78. 78. PDE4 Inhibitors
  79. 79. Future Pharmacological Agents for Asthma & COPD <ul><li>Pharmacogenomics. Current data suggest that the 16th amino acid position of the  2 adrenergic receptor is associated with a major, clinically significant pharmacogenomic effect, namely down regulation of the receptor and responsiveness of patients using  -agonists. Investigations of the effect of this and other polymorphisms on the response to long-acting  -agonists are currently being conducted. </li></ul>
  80. 80. Conclusions <ul><li>Aerosol delivery of drugs is effective for asthma. </li></ul><ul><li>Some key drugs classes for acute treatment </li></ul><ul><ul><li> Agonists Albuterol, levalbuterol, metaproterenol, terbuta;ine, isoproterenol, & epinephrine </li></ul></ul><ul><ul><li>PDE inhibitors Theophylline </li></ul></ul><ul><ul><li>Anticholinergics Ipratropium & tiotropium </li></ul></ul><ul><li>New agents are coming! </li></ul>