1. Bronchodilators and Other Respiratory Agents

50. Anatomy of Asthma www.freelivedoctor.com

51. Impact of Inflammation on Small Airways Acute Fatal Asthma Normal Chronic Severe Asthma From the lecture tomorrow by A. Petrov, MD www.freelivedoctor.com

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. www.freelivedoctor.com

53. Cellular mediators and cytokines in COPD www.freelivedoctor.com

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 . www.freelivedoctor.com

56. Control Severe COPD Pathology of Small Airways i.e. less then 2mm in diameter From Danielle Morse, MD www.freelivedoctor.com

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 www.freelivedoctor.com

58. Aerosol & Spacer Technology www.freelivedoctor.com

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. www.freelivedoctor.com

62. Signal Transduction Pathway for Bronchodilation Bronchodiliation PDE3 www.freelivedoctor.com

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. www.freelivedoctor.com 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. Chemicals Epinephrine Isoproterenol Albuterol Metaproterenol Salmeterol Fomoterol www.freelivedoctor.com

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. www.freelivedoctor.com 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. Pulmonary and cardiac effects of  adrenergic receptor agonists Log dose FEV 1 (% maximal increase) 100 0 100 0 Heart rate (%maximal increase) Isoproterenol Albuterol www.freelivedoctor.com

67. Pharmacological Approaches to Asthma Control Selective  2 agonist ATP cAMP Theophyline 5’-AMP Relaxation Ach Ipratopium Vagus nerve www.freelivedoctor.com

68. Theophylline www.freelivedoctor.com

69. Theophylline www.freelivedoctor.com

71. Pharmacological Approaches to Asthma Control Selective  2 agonist ATP cAMP Theophyline 5’-AMP Relaxation Ach Ipratopium Vagus nerve www.freelivedoctor.com

76. Approved in US February 2004 www.freelivedoctor.com

78. PDE4 Inhibitors www.freelivedoctor.com