Respiratory drugs

1. Respiratory drugs

2. I. Bronchodilators • Bronchodilators are indicated for the treatment of asthma (both acute and chronic) and COPD (emphysema and bronchitis).

3. There are 3 major categories of bronchodilators: beta adrenergics, anticholinergics, and xanthines

4. A. Beta adrenergic bronchodilators1. adrenergic receptors • In the late 1940’s, two types of adrenergic receptors were identified and were classified as α and β, based on their different responses to various adrenergic drugs.

5. These receptors were eventually further differentiated into subtypes: α1, α2, β1, β2, and β3.

6. Alpha receptors are primarily found in vascular smooth muscle.

7. Stimulation of α1 receptors leads to excitation/contraction/vasoconstriction, whereas stimulation of α2 receptors leads to relaxation/vasodilation.

8. Beta receptors are found in fat cells and in both cardiac and smooth muscle.

9. The predominant type in cardiac muscle are β1 receptors.

10. β2 receptors are found in both cardiac and smooth muscle (bronchial, skeletal, and vascular).

11. β3 receptors are found in fat cells.

12. Similar to alpha receptors, stimulation of β1 receptors causes excitation/contraction/vasoconstriction

13. and stimulation of β2 receptors causes relaxation/vasodilation.

14. 2. beta adrenergic agents • The beta adrenergic bronchodilators are classified chemically as catecholamines (or derivatives of catecholamines).

15. The basic catecholamine structure consists of a benzene ring with 2 OH groups. Attached to the benzene ring is a secondary amine side chain.

16. The composition of the side chain is related to the type of receptor the drug has a preference for:

17. the LARGER the side chain, the MORE SPECIFIC is the receptor interraction.

18. Epinephrine has a small methyl group (the CH3) attached to the amine nitrogen. It activates equally, both α and β receptors.

19. Isoproterenol has a larger isopropyl group attached to the amine nitrogen, and stimulates β receptors, but not α to any significant degree.

20. Many bronchodilators have an even larger group (t-butyl or bigger) attached to the amine nitrogen. These drugs are specific for β2 receptors.

21. Catecholamines are rapidly inactivated by the enzyme catechol-O-methyltransferase (COMT), found throughout the body.

22. This enzyme forms an ether linkage through its attachment of a methyl group to the OH group on C-3 of benzene.

24. This inactivation limits the duration of action of catecholamine drugs to a few hours.

25. To counteract this, pharmaceutical companies have formulated drugs which have a CH2—OH group (albuterol, pirbuterol, salmeterol);

26. or an amide group (formoterol, arformoterol) at this site rather than an OH group.

27. This has effectively doubled or quadrupled the duration of the drug.

28. Catecholamines are not normally administered orally because they undergo Phase II biotransformations in the GI tract (attachment of a sulfate or glucuronate at C-4) which inactivates them.

29. 3. Bronchodilator mechanism of action • Although some adrenergic bronchodilators can stimulate α and β1 receptors, the majority of these agents have selective β2 actions.

30. Attachment to a β2 receptor leads to activation of a G protein on the cytoplasmic side of the membrane.

31. The G protein stimulates the enzyme adenylate cyclase to increase the synthesis of the secondary messenger cAMP.

32. An increase in cAMP results in an increase in the inactivation of a myosin kinase, causing smooth muscle relaxation.

33. Beta adrenergic bronchodilators are indicated for the relaxation of airway smooth muscle in treating asthma and COPD.

34. They are the most widely used and are believed to be the most effective agents for short term relief of asthma.

35. Long term control is generally most effectively achieved with an inhaled corticosteroid.

36. 4. Very short acting agents • Very short acting agents have an onset on between 1-5 minutes and a duration of less than 3 hours.

37. a. epinephrine (Adrenalin CI, Epinephrine Mist, AsthmaHaler Mist, AsthmaNefrin, Epi Pen) • onset: minutes • duration: 1-3 hours

38. Epinephrine stimulates both α and β receptors, and therefore has a number of effects.

39. It is a powerful bronchodilator that also causes elevation of blood pressure, tachycardia, headache, and insomnia.

40. It has been administered by inhalation using a metered dose inhaler, MDI (Primatene Mist) or small volume nebulizer, SVN.

41. The FDA has determined that traditional MDI’s which use a CFC propellant cannot be sold in the U.S. after December 2008 (according to the Montreal Protocol, which attempts to limit CFC’s in the atmosphere).

43. Wyeth, which produces Primatene Mist has not released a version with the required hydrofluoralkane, HFA propellant as of January 2009.

44. Epinephrine is also available in a pre-measured form (EpiPen) for intramuscular injections, and targeted for individuals susceptible to anaphylactic reactions

45. b. isoproterenol (Isuprel) • Isoproterenol has both β1 and β2 actions and is only available today parenterally, to treat patients in shock or who experience bronchospasm during anesthesia. It is no longer manufactured for use in a SVN.

46. c. isoetharine • Isoetharine is a β2 specific agent with a very rapid onset (about 1 minute) generally administered by SVN.

47. 5. Short acting agents • Short acting agents have an onset of between 1-15 minutes and a duration of up to 8 hours.

48. Technically, they are not catecholamines, but are derivatives of catecholamine that are not as susceptible to deactivation by COMT.

49. a. metaproterenol (Alupent) • This is administered via SVN or orally as it is not susceptible to inactivation in the GI tract.

50. b. albuterol (Teva’s Proair HFA; Schering Plough’s Proventil HFA; and GlaxoSmithKline’s Ventolin HFA) • These are all newly formulated bronchodilators. Albuterol is also available via SVN and in an oral formulation.