Drugs affecting the Respiratory System

1. Drugs affecting the Respiratory System By Linda Self

2. Respiratory System • Key Terms • Ventilation • Perfusion • Diffusion • Pulmonary Circulation • Surfactant • pneumocytes

3. Drugs for Asthma and Other Bronchoconstrictive Disorders Asthma—inflammation, hyperreactivity, and bronchoconstriction GERD may cause microaspiration/resultant nighttime cough Antiasthma medications can also exacerbate GERD

4. Asthma May be triggered by viruses Irritants Allergens Can develop at any age Seen more often in children who are exposed to airway irritants during infancy

5. Asthma Bronchoconstriction Inflammation Mucosal edema Excessive mucous

6. Pathophysiology of Asthma Mast cells Chemical mediators such as histamine, prostaglandins, acetylcholine, cGMP, interleukins, leukotrienes are released when triggered. Mobilization of eosinophils. All cause movement of fluid and proteins into tissues. Bronchoconstrictive substances antagonized by cAMP

7. Chronic Obstructive Pulmonary Disease Combination of chronic bronchitis and emphysema Bronchoconstriction and inflammation are more constant, less reversibility Anatomic and physiologic changes occur over years Leads to increasing dyspnea and activity intolerance

8. Drug Therapy Bronchodilators and anti-inflammatories

9. Categories of Asthma • Step 1-Mild Intermittent—symptoms 2 days/week or less or 2 nights/month or less. No daily medication needed; treat with inhaled beta2 agonist • Step 2-Mild persistent—symptoms >2/week but <1x/day or >2 nights/month. In those >5 years old, use inhaled corticosteroid, leukotriene modifier, Intal (cromolyn), or sustained release theophylline

10. Categories of Asthma cont. • Step 2—Mild persistent • Children 5 years and younger—inhaled corticosteroid by nebulizer of MDI with a holding chamber. Can also use leukotriene modifier or Intal by nebulizer • Step 3—Moderate persistent. Symptoms daily and > one night per week. • Older than 5yo—low to med. Dose corticosteroid and long acting beta 2 agonist. Alternatives p. 714

11. Asthma • Step 3— • Children < 5 yo: low dose inhaled corticosteroid and a long acting beta 2 agonist or medium dose inhaled corticosteroid • Step 4—Severe persistent—symptoms continual during daytime and frequently at night. • >5yo—high dose inhaled corticosteroid, long acting beta 2 agonist; intermittent admin. of oral corticosteroids

12. Asthma Step 4— Children less than 5 yo—same as for adults and older children

13. Bronchodilators Adrenergics—stimulate beta 2 receptors in smooth muscle of bronchi and bronchioles Receptors stimulate cAMP =bronchodilation Cardiac stimulation is an adverse effect of these medications

14. Bronchodilators--adrenergics Cautious use in hypertension and cardiac disease Selective beta 2 agonists by inhalation are drugs of choice Epinephrine sc in acute bronchoconstriction

15. Short acting bronchodilators Proventil (albuterol) Xopenex (levalbuterol)

16. Short Acting Bronchodilators Treatment of first choice to relieve acute asthma Aerosol or nebulization May be given by MDI Overuse will diminish their bronchodilating effects>>>>tolerance

17. Other bronchodilators Foradil (formoterol) and Serevent (salmeterol) are long acting beta 2 adrenergic agonists used only for prophylaxis. Black box warning on Serevent—use in deteriorating asthma can be life-threatening Alupent (metaproterenol)—intermediate acting. Useful in exercise induced asthma, tx acute bronchospasm.

18. Other bronchodilators Brethine (terbutaline)—selective beta 2 adrenergic agonist that is a long-acting bronchodilator When given subq, loses selectivity Also used to decrease premature uterine contractions during pregnancy

19. Anticholinergics Block the action of acetylcholine in bronchial smooth muscle when given by inhalation Action reduces intracellular guanosine monophosphate (GMP) which is a bronchoconstrictive substance Atrovent (ipratropium)—caution in BPH, narrow-angle glaucoma Spiriva (tiotropium)

20. Xanthines Theophylline Mechanism of action unclear Bronchodilate, inhibit pulmonary edema, increase action of cilia, strengthen diaphragmatic contractions, over-all anti-inflammatory action Increases CO, causes peripheral vasodilation, mild diuresis, stimulates CNS

21. Xanthines Contraindicated in acute gastritis and PUD Second line Narrow therapeutic window—therapeutic range is 5-15 mcg/mLh Multiple drug interactions

22. Anti-Inflammatory Agents Suppress inflammation by inhibiting movement of fluid and protein into tissues; migration and function of neutrophils and eosinophils, synthesis of histamine in mast cells, and production of proinflammatory substances Benefits: decreased mucous secretion, decreased edema and reduced reactivity

23. Corticosteroids Second action is to increase the number and sensitivity of beta 2 adrenergic receptors Can be given PO or IV Pulmonary function usually improves within 6-8 hours Continue drugs for 7-10 days

24. Steroids Fewer long term side effects if inhaled End-stage COPD may become steroid dependent In asthma, systemic steroids generally are used only temporarily Taper high dose oral steroids to avoid hypothalamic-pituitary axis suppression

25. Steroids For inhalation: Beclovent—beclomethasone Pulmicor—budesonide Aerobid—flunisolide Flovent—fluticasone Azmacort—triamcinolone Most inhaled steroids are being reformulated with HFA

26. Steroids Systemic use: prednisone, methylprednisolone, and hydrocortisone In acute, severe asthma—a systemic corticosteroid may be indicated when inhaled beta 2 agonists are ineffective

27. Leukotriene Modifiers Leukotrienes are strong chemical mediators of bronchoconstriction and inflammation Increase mucous secretion and mucosal edema Formed by the lipoxygenase pathway of arachidonic acid metabolism in response to cellular injury Are release more slowly than histamine

28. Leukotriene Modifier Drugs Developed to counteract the effects of leukotrienes Indicated for long term treatment of asthma in adults and children Prevent attacks induced by some allergens, exercise, cold air, hyperventilation, irritants and ASA/NSAIDs Not useful in acute attacks

29. Leukotriene Modifiers • Injured cell • Arachidonic acid • XXXX • Lipooxygenase • Leukotrienes • XXXX • Bronchi, WBCs • Bronchoconstriction

30. Leukotriene Modifier Drugs Singulair (montelukast) and Accolate (zafirlukast) are leukotriene receptor antagonists Can be used in combination with bronchodilators and corticosteroids Less effective than low doses of inhaled steroids Should not be used during lactation Can cause HA, nausea, diarrhea, other

31. Mast Cell Stabilizers Intal (cromolyn) Tilade (nedocromil) Prevent release of bronchoconstrictive and inflammatory substances when mast cells are confronted with allergens and other stimuli Prophylaxis only Inhalation, nebulizer or MDI, nasal spray as well

32. Immunosuppressant Monoclonal Antibody Xolair (omalizumab) works by binding to IgE, blocking receptors on surfaces of mast cells and basophils Prevents release of chemical mediators of allergic reactions Adjunctive therapy Can cause life-threatening anaphylaxis

33. Antihistamines and Allergic Disorders Histamine is the first chemical mediator released in immune and inflammatory responses Concentrated in skin, mucosal surfaces of eyes, nose, lungs, CNS and GI tract Located in mast cells and basophils Interacts with histamine receptors on target organs called H1 and H2

34. Antihistamines H1 receptors are located mainly on smooth muscle cells in blood vessels and the respiratory and GI tracts H1 binding causes: pruritus, flushing, increased mucous production, increased permeability of veins—edema, contraction of smooth muscle in bronchi>>bronchoconstriction and cough

35. Antihistamines With H2 receptor stimulation, main effects are increased secretion of gastric acid and pepsin, decreased immunologic and proinflammatory reactions, increased rate and force of myocardial contraction

36. Allergic Reactions Are exaggerated responses by the immune sysem that produce tissue injury and possible serious disease Allergic reactions may result from specific antibodies, sensitized T lymphocytes, or both, formed durng exposure to an antigen.

37. Types of Responses to Cell-Mediated Invasion • Type I—immediate hypersensitivity, IgE induced response triggered by the interaction of antigen with antigen-specific IgE bound on mast cells • Anaphylaxis is an example • Does not occur on first exposure to an antigen • Can develop profound vasodilation resulting in hypotension, laryngeal edema, bronchoconstriction

38. Allergic Reactions Type II—IgG or IgM mediated which generate direct damage to cell surfaces. Examples include: blood transfusion reactions, hemolytic disease of newborns, hypersensitivity reactions to drugs such as heparin or penicillin

39. Allergic Reactions Type III is an IgG or IgM mediated reaction characterized by formation of antigen-antibody complexes that induce inflammatory reaction in tissues. Prototype is Serum Sickness. Immune response can occur following antitoxin administration, pcn or sulfa drugs

40. Type IV Hypersensitivity Delayed hypersensitivity Cell mediated response where sensitized T lymphocytes react with an antigen to cause inflammation, release of lymphokines , direct cytotoxicity or both Classic examples are tuberculin test, contact dermatitis and some graft rejections

41. Allergic Rhinitis • IgE mediated • Inflammation of nasal mucosa caused by a hypersensitivity reaction to inhaled allergens • Presents with itching of throat, eyes and ears • Seasonal and perennial • Can lead to chronic fatigue, difficulty sleeping, sinus infections, postnasal drip, cough and headache

42. Intranasal Drugs for Allergic Rhinitis Atrovent nasal spray Beconase (beclomethasone) Rhinocort (budesonide) Flonase (fluticasone) Nasonex (mometasone) Nasalcrom (a mast cell stabilizer)

43. Allergic Contact Dermatitis Type IV hypersensitivity reaction Poison ivy an example Usually occurs >24h after re-exposure

44. Other reactions • Allergic food reactions—result from ingestion of a protein • Most common food allergy is shellfish, others include milk, eggs, peanuts • Allergic drug reactions—unpredictable, may occur 7-10 days after initial exposure • Pseudoallergic drug reactions—resemble immune responses but do not produce antibodies, i.e. anaphylactoid

45. Antihistamines Inhibit smooth muscle constriction in blood vessels and the respiratory and GI tracts Decrease capillary permeability Decrease salivation and tear formation Act by binding with the histamine receptor

46. Indications for Use Allergic rhinitis Anaphylaxis Allergic conjunctivitis Drug allergies Transfusions of blood products Dermatologic conditions Nonallergic such as motion sickness, nausea and vomiting, sleep

47. Precautions Caution in pregnancy BPH Bladder neck obstruction Narrow angle glaucoma

48. First Generation H1 Receptor Antagonists Bind to central and peripheral receptors Can cause CNS depression or stimulation Have substantial anticholinergic effects Examples: Chlor-Trimeton (chlorpheniramine) Benadryl (diphenhydramine) Vistaril (hydroxyzine) Phenergan (promethazine)

49. Second Generation H1 Receptor Antagonists Selective or nonsedating Do not cross blood brain barrier Examples: Astelin (azelastine) Allegra (fexofenadine) Claritin (loratadine) Clarinex (desloratadine) Zyrtec Xyzal

50. Nasal Decongestants Relieve nasal obstruction and discharge Adrenergic Rebound nasal swelling called “rhinitis medicamentosa” Afrin Sudafed (pseudoephedrine) Contraindicated in severe hypertension, CAD, narrow angle glaucoma, TCAs or MAOIs