Anti-Inflammatory and Anti-asthmatic Agents

1. Anti-Inflammatory and Anti-asthmatic Agents MODULE F

2. Objectives • List two mast cell stabilizers. • Describe and diagram the antigen/antibody reaction on mast cells • Explain which antibody is elevated in allergic asthma. • List three mediators that are released with inflammation. • Explain the effects of chemical mediators such as histamine and leukotrienes on airway epithelium.

3. Objectives • Given signs and symptoms, differentiate between the early and late phase of an inflammatory response. • Describe how cromolyn sodium and nedocromil are anti-inflammatory agents. • State the generic and trade names, modes of action, adverse reactions, routes of administration, dosages, and adverse reactions for cromolyn sodium and nedocromil sodium. • State the origin of corticosteroid secretion. • Describe why corticosteroids are now considered first line drugs in the treatment of asthma. • Describe the pathway for the release and control of corticosteroids in the body.

4. Objectives • Define HPA insufficiency. • Differentiate between systemic and inhaled corticosteroids. • List three actions of steroids on inflammation. • Describe the process of weaning a patient from steroids. • List four side effects or adverse reactions of steroid administration. • State the trade and generic names of the inhaled steroids discussed in class.

5. Objectives • Describe how a RCP can decrease the incidence of oral fungal infections when administering aerosolized steroids. • List three leukotrienes inhibitors discussed in class. • State two side effects of leukotrienes. • State how leukotrienes are administered. • Describe the cellular mechanism for leukotriene production. • State three medication types that are used for upper-airway congestion. • State the IgE inhibitor used to treat asthma.

6. Anti-Inflammatory Drugs • Non-Steroidal Anti-inflammatory • Mast Cell Stabilizers or anti-asthmatics • Leukotriene Antagonists (anti-leukotrienes) • Adrenocorticosteroid Anti-inflammatory • Corticosteroids or Steroids

8. Mechanism of Inflammation • Mast Cells, eosinophils, macrophages, basophils are found in submucosa. • The cells contain granules that are storehouses of the chemical mediators of lung inflammation. • Antigen-Antibody reactions causes the influx of Ca+2 into the cells and release of mediators. • IgE primary antibody

9. Mechanism of Inflammation • Mediator Release • Bronchospasm • Vasodilation resulting in mucosal edema • Increased vascular permeability • Increased mucus gland secretion

10. Mediators of Inflammation • Histamine • Platelet Activating Factor • Eosinophil Chemotactic Factor of Anaphylaxis (ECF-A) • Neutrophil Chemotactic Factor of Anaphylaxis (NCF-A) • Leukotrienes (formerly known as slow-reacting substance of anaphylaxis – SRS-A) • Prostaglandins

11. Explanation of Mast Cell rupture (Degranulation) • Figure 7-1, p. 132 • Mast cells are found throughout the body and their sensitization explains the watery eyes, runny nose, etc. that accompanies an allergic reaction.

12. Phases of Inflammatory Response in Asthma • Early phase - Immediate • Late phase – 6 to 8 hours after exposure

13. Early Phase • Local vasodilation • Increased vascular permeability • Redness • Bronchoconstriction • Wheezing • Coughing • Dyspnea • Hypoxemia

14. Late Phase • Effect of WBC (lymphocyte) and other mediators • Hypersecretion of mucus and mucosal swelling • Traffic Jam • Breakdown of Mast Cell releases Arachidonic Acid • Production of leukotrienes • Prostaglandin

15. FIGURE 7-2, page 134

16. Goal of Therapy • Stop Mast Cell from degranulating • Prophylactic Anti-asthmatics • Stop specific inflammatory processes • Corticosteroids • Broad spectrum response • Leukotriene Inhibitors • Antihistamines • Prostaglandin Inhibitors

17. Mast Cell Stabilizers • Prevent Ca+2 influx into the cell, thereby preventing mediator release. • cromolyn sodium • Intal, Nasalcrom • nedocromil sodium • Tilade • Ketotifen (Experimental) • Zaditen • These medications do not operate through the C’AMP system and do not stimulate b or a receptor sites • Best used in limited populations and mild asthma

18. Indications for Mast Cell Stabilizers • Prophylactic management of Asthma. • Pre-treatment for expected exposure. • Prevention of exercise induced asthma • Allergic rhinitis • Do not use to treat an asthmatic attack

19. cromolyn sodium (1973) • Small Volume Nebulizer • Concentration: 1% • Supplied in a 2 mL ampule (unit dose) containing 20 mg (20 mg/2 mL). • Give one ampule QID; may need to add additional diluent (2 mL may nebulize too quickly). • MDI: • 0.8 mg/inhalation • 2 inhalations QID • Ophthalmic and Nasal solutions available

20. Hazards/Adverse Reactions • Generally well tolerated • Nasal congestion • Throat irritation • Hoarseness • Dry mouth • Cough • Feeling of chest tightness • Wheezing/Sneezing/Epistaxis • Give b2 agonist prior to administering Cromolyn

21. nedocromil sodium (1992) • Tilade • MDI: • 1.75 mg/inhalation • 2 inhalations QID • Side Effects similar to cromolyn

22. Adrenocorticosteroids • Secreted from the adrenal cortex. • Epinephrine secreted from adrenal medulla. • Multiple functions of medication. • Anti-inflammatory. • Orally, parenterally, aerosol. • First line drugs in the management of asthma. • Reliever and controller medication. • Given to control allergies.

23. Adrenal Gland ADRENAL CORTEX

24. HPA Axis • Hypothalamic Pituitary Adrenal Axis • Low blood levels of steroids. • Hypothalamus is stimulated. • Sends impulse to Anterior Pituitary Gland which stimulates Corticotropin Releasing Factor (CRF). • This stimulates the formation of Adrenocorticotropin hormone (ACTH ). • ACTH in bloodstream stimulates Adrenal Cortex to produce and release Corticosteroids. • Increases blood levels of corticosteroids.

25. FIGURE 7-3, page 137

26. HPA Axis • Diurnal or Circadian Rhythm • Levels are highest around 8:00 a.m. • Off-shift workers. • Giving a patient steroids can suppress the body’s HPA axis (Body stops producing steroids). • If you stop the added steroids abruptly, the patient will experience HPA insufficiency and death can occur.

27. HPA Insufficiency • Once adrenal suppression has occurred, the patient must be weaned slowly from systemic steroids. • This will allow for recovery of the body’s own secretion. • HPA insufficiency begins 1 day after use of systemic steroid administration.

28. Prevention of HPA Insufficiency • Low dose steroid for 5 days or less. • Take steroids in the morning when natural levels are high. • High dose tapered regimen lasting 5-6 days. • Alternate day therapy.

29. Buffalo Hump & Moon Face FIGURE 7-5, page 139

30. Cushing's Syndrome • Increased secretion of corticosteroids caused by a tumor of the adrenal glands • Cushingoid appearance • Central obesity • Moon face • Buffalo hump

31. Aerosolized Steroids • Advantage is that aerosolized steroids do not increase the blood levels of steroids • Does not cause HPA insufficiency • Less side effects • Goal is to try to gain control of asthma with the aerosolized steroids • May take 4-8 weeks for maximum improvement

32. Oral vs. Aerosol Corticosteroids

33. Common Inhaled Steroids Page 140

34. Adverse Reactions of Aerosolized Steroids • Fungal Infections may occur after aerosol • Rinse mouth and use spacer • Throat irritation, hoarseness, dry mouth and coughing have occurred • HPA insufficiency may occur during transfer from systemic to aerosol steroids • Severe asthma may occur following withdrawal of oral/IV steroids

35. Adverse Reactions/Precautions • Aerosolized steroids may not be adequate to control asthma during periods of stress and systemic administration may be necessary

36. Leukotriene ModifiersAnti-LeukotrienesLeukotriene AntagonistsLeukotriene Inhibitors

37. Leukotriene Inhibitors • Indications • Prophylactic treatment of asthma • “Controllers” • Not to be used to treat an asthma attack • zileuton • Zyflo • zafirlukast • Accolate • montelukast • Singulair

39. Leukotriene Inhibitors • zileuton (Zyflo) • 12 years of age or older • Works well in aspirin-sensitive asthmatics • 600 mg orally QID • Elevate liver enzymes • Interaction with • Warfarin • Seldane • Theophylline • Propanolol • 5 - Lipoxygenase inhibitor

40. Leukotriene Inhibitors • zafirlukast (Accolate) • 12 years of age or older • 10 or 20 mg orally BID • Elevates liver enzymes • Interactions • Warfarin • Theophylline • Blocks the leukotriene receptor site (leukotriene receptor antagonist)

41. Leukotriene Inhibitors • montelukast (Singular) • Daily dosing • 4 mg packet of granules (6 to 23 months ) • 4 mg chewable tablet or 4 mg packet of granules (2 to 5 years of age) • 5 mg chewable tablet (child) • 10 mg tablet (adult) • Side effects: headache, influenza, abdominal pain • Blocks the leukotriene receptor site (Leukotriene receptor antagonist)

42. Disadvantage of Anti-leukotrienes • Inhibit one mediator pathway • Asthma involves multiple mediators • 50 – 70% of patients respond to the medication • Trial & Error

43. Upper Airway Congestion • Allergic Rhinitis • Antihistamine • Prevents release of histamine. • Significant side effects • Newer generation are more “forgiving” • Intranasal Medications • Mast Cell Stabilizers (Nasalcrom) • Nasal Steroids • Decongestants • a-adrenergic agents • Vasoconstriction • Table 7-14 (page 140)

44. ciclesonide Omnaris

45. IGE Inhibitors • omalizumab (Xolair)

46. Dosing • http://www.xolair.com/hcp/dosing_calculator2.jsp