Respiratory tract drugs

1. Respiratory tract drugs Lu-Tai Tien, Ph.D. School of Medicine Fu-Jen Catholic University

3. 藥物投予方式 • 吸入 • 藥物可直接運送至呼吸道上，而其吸入劑又不致造成全身性副作用 • 較為普遍 • 口服 • 靜脈注射

4. Classification of drugs • Drugs used to treat asthma • Drugs used to treat allergic rhinitis • Drugs used to threat chronic obstruction pulmonary diseases (COPD) • Drugs used to treat cough

5. From Lippincott’s 3nd edition

6. allergens not all atopic have asthma dust mites, pollen pollutants SOx food additives bisulfite antioxidants cold air drugs aspirin exercise industrial chemicals and byproducts aluminum smelters cedar dust lung infection predisposing before age of two genetic predisposition more boys than girls in childhood more women than men from 2nd decade onwards. Familial risk of allergies Stimuli / Other Factors

7. Control of Airway Diameter • Parasympathetic • ACh is the neurotransmitter at airway smooth muscle • it acts at M3 receptors- activation causes formation of IP3 (increasing Ca2+) and diacylglycerol F tension is the result • No sympathetic innervation • β2 adrenoceptors are present in airway smooth muscle • normally epinephrine released from adrenal medulla activates • Other nerves - bradykinin, neurokinins

8. Therapies for Asthma • Treatments that mitigate an asthma attack • Treatments that relax airway smooth muscle • Treatments that mitigate chronic inflammation

9. Relaxing airway contraction • Inhibition of Bronchoconstriction • Phosphodiesterase Inhibitors • Muscarinic receptor antagonists • β-adrenoceptor agonists

10. Phosphodiesterase Inhibitors • Methylxanthine (caffeine is in this group) • Theophylline (aminophylline is the ethylenediamine complex) • The therapeutic index of Theophylline is slow • Causing severe toxicity (the conc. > 20 μg/mL in blood) • Inhibits the breakdown of cyclic AMP by inhibiting phosphodiesterase • cAMP produced by β2-adrenoceptor activation initiates a phosphorylation cascade causing relaxation of airway smooth muscle • They are adenosine receptor antagonists

11. Clinical Use of Phosphodiesterase Inhibitors • Given orally • Sustained release preparations are available • Blood levels should be controlled • therapeutic range 5-20 mg/L • below 5 no therapeutic effect • above 20 side effects become a problem • anorexia, headache, abdominal discomfort, anxiety • seizures and arrhythmias occur at high concentrations (>40 mg/L)

12. Muscarinic antagonists • 阻斷迷走神經所傳導的呼吸道平滑肌收縮及黏液的分泌 • e.g. Ipratropium • 病人無法忍受 β-adrenergic agonists 時可用此藥代替 • Atropine is not used now • dries mucus membranes, too many side effects • doesn’t reverse bronchoconstriction • in asthma bronchoconstriction is mostly due to leukotrienes and other substances not muscarinic receptor stimulation • can cause viscid mucus plugs to form

13. Ipratropium • Quaternary muscarinic antagonist • Given by nebulization (霧化) so effects limited to airway • Not routinely used as the only drug in the treatment of asthma • Has definite value in the treatment of acute asthma exacerbation when used in addition to β-agonists • Used in the treatment of chronic obstructive pulmonary disease - COPD

15. Adrenergic agonists • 擬腎上腺素 • β2-adrenergic agonist 治療輕度氣喘 • 直接作用在呼吸道平滑肌鬆弛，為一有效的支氣管擴張劑 • Short and long acting drugs

16. Short acting drugs • 15-30 min可產生療效, 可緩解症狀 4 – 6 hours • 治療急性支氣管收縮，因不具抗發炎作用，所以，不可做為治療慢性氣喘的唯一藥物 • Metaproterenol, albuterol, terbutaline, bitolterol, pirbuterol • all can be given by inhalation – nebulization • metaproterenol, terbutaline, albuterol can be given orally • terbutaline injectable – subcutaneous • 若由吸入途徑給藥可能會降低全身性給藥所造成的 心跳增快，血糖過高，血鉀過低，血鎂過低等副作用

17. Long acting drugs • Salmeterol, formoterol • long acting - 12 hours or more • forms slow release depot in tissue (lipid soluble) • long duration of action used to treat nocturnal asthma • not used as monotherapy always with inhaled steroids • 作為一般處方用藥，不用在急性症狀緩解治療

18. Other b-Agonists • Epinephrine • good bronchodilator - not selective (all a and b) • short lived • used in emergencies, subcutaneous injection - severe asthma, hypersensitivity reactions, anaphylaxis • Available OTC (Over-The-Counter) • Ephedrine (麻黃素) • long history of use in China • β2 selective, not used much in asthma now • Not as easily now available since methamphetamine can be made from this drug • CNS stimulant, amphetamine look-alike, “truck stop” pharmacology

19. Side Effects of β-agonists • Not completely selective • Can increase heart rate • Can cause arrhythmias • Headache - vasodilation

20. Anti-allergy agents- Omalizumab • Recombinant humanized antibody against the Cε3 domain of IgE • Complexes IgE preventing activation of mast cells and basophils thus prevents the release of inflammatory mediators • Market name: Xolair • Used only after primary treatments have failed • The drug is administered subcutaneously in 1 to 3 injections every 2 or 4 weeks • Not recommended when living in environments where the presence of parasites is common

21. Inhibition of Leukotrienes • Inhibition of the formation of leukotrienes • 5-lipoxygenase inhibitor • Zileuton • Increases the lifetime of theophylline and drugs metabolized by CYP3A4 • Inhibition of the action of leukotrienes • leukotriene receptor antagonists (LTRA) • Zafirlukast (LTD4), montelukast (LTD4) • Zafirlukast (po), montelukast (po)

22. Arachidonic acid Zileuton - 5-Lipoxygenase Cyclooxygenase Leukotrienes Prostaglandins LTB4 LTC4 LTD4 LTE4 Contraction of airway smooth muscle cells CystLT1 LTC4 LTD4 + Zafirlukast Montelukast (CystLT1 antagonists)

23. Properties Leukotriene receptor antagonists • Not all patients respond • Aspirin sensitivity results from LTD4 release • Aspirin (or NSAID) sensitivity may be caused by inhibiting cyclooxygenase and shunting of arachidonic acid metabolism into the leukotriene pathway • Takes 3-14 days to work - used for chronic therapy • Contraindications - liver disease, pregnancy (crosses placenta), breast feeding (excreted) • Fewer of the above concerns with montelukast as compared to zafirlukast or zileuton

24. Steroids • Systemic steroids • corticosteroids (e.g., prednisone, prednisolone) • used to treat severe persistent asthma • significant side effects • water retention - moon face (Cushingoid features) • Immunosuppression • Steroids reverse inflammation and reduce sensitivity of airway smooth muscle to stimulation • adrenal suppression-must taper dose when discontinuing after prolonged therapy

25. Inhaled Steroids • Beclomethasone, Budesonide, Flunisolide, Fluticasone, Mometasone and Triamcinolone • given by inhaled route • minimal systemic effects (better topical:systemic ratio) • reduces need for oral steroids • Used as first line therapy for newly diagnosed cases - decreases chronic inflammation and might reverse remodeling of the airways • Oral candidiasis - thrush - gargle and spit, use a spacer

26. Corticosteroid Actions • Decrease the following • Secretion from, and numbers of eosinophils • Cytokines from T-lymphocytes • Number of mast cells • Secretion and production of cytokines by macrophages • Leakiness of endothelia (vasoconstriction) • Mucus secretion and hypertrophy of mucus cells • Upregulation of β-adrenergic receptors

27. Corticosteroids • 中至重度氣喘患者，凡每日由口吸入　 β2 –adrenergic agonists 一次以上的患者，吸入性的 corticosteroids 乃是首選 • 嚴重的氣喘患者有時需短期使用全身性的 glucocorticoide

28. Corticosteroids on lung • Steroids 對呼吸道平滑肌無直接作用 • 吸入性的 glucocorticoides 可降低巨噬 細胞，嗜伊紅性白血球及 T 淋巴球參與發炎的數目及反應 • 長期吸入 steroids 可降低呼吸道平滑肌對許多刺激支氣管收縮的物質如過敏原，刺激物，冷空氣及運動等的反應

29. Side effects of corticosteroids

30. Cromolyn/Nedocromil • Mechanism • inhibits the degranulation of mast cells - by inhibiting chloride conductance channels in the mast cell membranes which reduces intracellular calcium increases • works only prophylactically (預防性的) • cannot terminate an attack • Can reduce late phase response when given after an initial attack - inhibits eosinophil degranulation

31. Treatments by Cromolyn/Nedocromil • Given by nebulization • solution that is nebulized • Microfine powder - Spinhaler • few side effects because it is poorly absorbed and not metabolized • side effects primarily in airway • can induce bronchoconstriction, chest tightness, coughing, xerostomia • effects minimized by taking β2-agonist concomitantly • Used to treat allergic rhinitis • available OTC

32. Cromolyn and nedocromil • 抗發炎藥物 • 非支氣管擴張劑，所以，不用於急性氣喘治療 • 副作用小，可用於小孩與孕婦

33. Treatment of Asthma

34. Asthma 的治療 氣喘不一定會導致慢性阻塞性肺部疾病 (COPD) 誤解和誤診而造成惡化 罹病率造成可觀的入院和門診治療花費 治療目的: 使症狀緩解，進一步避免氣喘再發生

35. Study question • 有關 β-adrenergic receptor agonists 的敘述何者不正確 ? • (A) 為一有效之支氣管擴張劑 • (B) 可用於急性氣喘時症狀之治療例如Salmeterol • (C) 會引起心跳過快及血鉀過低等副作用 • (D) 不具抗發炎效用 • Answer: (B)

36. THE END