1. The role of medicine in respiratory diseases management Eti Nurwening Sholikhah Department of Pharmacology and Therapy Faculty of Medicine Universitas Gadjah Mada Yogyakarta

2. 2 The respiratory system is subject to many disorders that interfere with respiration and other lung functions, including – Respiratory tract infections – Allergic disorders – Inflammatory disorders – Conditions that obstruct airflow (e.g. asthma and chronic obstructive pulmonary disease, COPD)

3. 3 Learning Objectives The students understand the drugs that act on the respiratory system include – Bronchodilators – Corticosteroids – Cromoglycates – Leukotriene receptor antagonists – Antihistamines – Cough preparations – Nasal decongestants

9. 9 Bronchodilators Drugs used to relieve bronchospasms associated with respiratory disorders Includes: – Adrenoceptor agonists Selective β 2 -agonists & other adrenoceptor agonists – Antimuscarinic bronchodilators – Xanthine derivatives

10. 10 Adrenoceptor agonists – (i) Selective beta 2 agonists Stimulate beta 2 receptors in smooth muscle of the lung, promoting bronchodilation, and thereby relieving bronchospasms They are divided into short-acting & long acting types

11. 11 DrugFormulationDosage AdultChild SalbutamolOral tablet (C.R)8 mg twice daily4 mg twice daily Inhaler (MDI), 100mcg/dose100-200mcg up to three to four times daily Same as adult Syrup, 2mg/5ml4 mg three to four times daily 1-2 mg three to four times daily (≥2 yr) TerbutalineOral tablet (S.R)5-7.5 mg two times daily - Inhaler 500mg / dose ( Turbuhaler) 500 mcg up to four times daily - Inhaler 250mg / dose (MDI)250-500mcg up to 3-4 times daily Same as adult Short-acting β-2 agonists

12. 12 Long-acting β-2 agonists DrugFormulationDosage AdultChild FormoterolInhaler 4.5mcg / dose (Turbuhaer) 4.5-9 mcg once or twice daily Same as adult Inhaler 9mcg / dose (Turbuhaer) SalmeterolInhaler 25mcg / dose (MDI) 50-100 mcg twice dailySame as adult 50 mcg / dose (Accuhaler)50 mcg twiceSame as adult

13. 13 Adverse effects – Tachycardia and palpitations – Headache – Tremor

14. 14 – (ii) Other adrenoceptor agonists Less suitable & less safe for use as bronchodilators because they are more likely to cause arrhythmias & other side effects – Ephedrine » Adults: 15-60 mg tid po » Child: 7.5-30 mg tid po Adrenaline (epinephrine) injection is used in the emergency treatment of acute allergic and anaphylactic reactions

15. 15 Antimuscarinic bronchodilators – Blocks the action of acetylcholine in bronchial smooth muscle, this reduces intracellular GMP, a bronchoconstrictive substance – Used for maintenance therapy of bronchoconstriction associated with chronic bronchitis & emphysema

16. DrugFormulationDosage AdultChild IpratropiumInhaler 20 mcg / dose (MDI) 20-80 mcg three to four times a day 20-40 mcg three to four times a day (≥6yrs) TiotropiumInhaler 18 mcg /dose 18 mcg dailyNot recommended in children and adolescents

17. 17 Adverse effects: – Dry mouth – Nausea – Constipation – Headache

18. 18 Xanthine Derivatives – Main xanthine used clinically is theophylline – Theophylline is a bronchodilator which relaxes smooth muscle of the bronchi, it is used for reversible airway obstruction – One proposed mechanism of action is that it acts by inhibiting phosphodiesterase, thereby increasing cAMP, leading to bronchodialtion

19. 19 DrugFormulationDosage AdultChild TheophyllineTablet 200 / 300 mg (S.R.) 200 – 300 mg twice daily 10 mg / kg ((≥2yrs) twice daily Capsule 50 / 100 mg (Slow release) 7-12 mg/ kg / day in two divided doses 10-16 mg / kg / day in two divided doses (9–16yrs) 13-20 mg / kg / day in two divided doses (30 months – 8 yrs) Syrup 80 mg / 15 ml 25 ml q6h1 ml / kg (Max 25 ml) q6h (≥2yrs) AminophyllineInjection 25 mg / ml 10 ml 500 mcg / kg / hr IV infusion, adjust when necessary 1 mg / kg /hr (6 months – 9 years) 800 mcg / kg /hr (10 – 16 yrs) IV infusion, adjust when necessary

20. 20 – Adverse effects: Toxicity is related to theophyline levels (usually 5-15 µg/ml) 20-25 µg/ml : Nausea, vomiting, diarrhea, insomnia, restlessness >30 µg/ml : Serious adverse effects including dysrhythmias, convulsions, cardiovascular collapse which may result in death

21. METHYLXANTHINES POSSIBLE ACTIONS 1.Relaxation of smooth muscle, particularly bronchial smooth muscle 2.Stimulate the central nervous system 3.Weakly positive chronotropes and inotropes 4.Mild diuretics.

22. 22 Corticosteroids Used for prophylaxis of chronic asthma Suppressing inflammation – Decrease synthesis & release of inflammatory mediators – Decrease infiltration & activity of inflammatory cells – Decrease edema of the airway mucosa Decrease airway mucus production Increase the number of bronchial beta 2 receptors & their responsiveness to beta 2 agonists

23. 23 DrugFormulationDosage AdultChild Beclometha sone Inhaler 50 mcg / dose (MDI) 200 mcg twice daily / 100mcg three to fours times daily Up to 800 mcg daily 50 – 100 mcg two to four times daily Inhaler 250 mcg / dose (MDI) 500 mcg twice daily / 250 mcg four times daily Not recommended

24. 24 Drug (Cont’d)FormulationDosage AdultChild BudesonideInhaler 50 mcg / dose (MDI) 200 mcg twice daily Up to 1.6 mg daily 50 – 400 mcg twice daily Up to 800 mcg daily Inhaler 200mcg / dose (MDI) Inhaler 100 mcg / dose (Turbuhaler) 200-800 mcg once daily in evening Up to 1.6 mg daily in two divided doses 200-800 mcg daily in two divided doses / 200-400 mcg once daily in evening (<12 yrs) Inhaler 200 mcg / dose (Turbuhaler) Inhaler 400 mcg / dose (Turbuhaler)

25. 25 Drug (Cont’d)FormulationDosage AdultChild FluticasoneInhaler 25mcg / dose (MDI)100 – 1000 mcg twice daily 50-100 mcg twice daily (4-16 yrs) Inhaler 50 mcg / dose (MDI) Inhaler 125 mcg / dose (MDI) Inhaler 250 mcg / dose (MDI) Inhaler 50 mcg / dose (Accuhaler) Inhaler 100 mcg / dose (Accuhaler) Inhaler 250 mcg / dose (Accuhaler) Acute attacks of asthma should be treated with short courses of oral corticosteroids, starting with a high dose for a few days

26. 26 Adverse effects – Inhaled corticosteroids: Candidiasis of the mouth or throat Hoarseness Can slow growth in children Adrenal suppression may occur in long-term, high dose therapy Increases the risk of cataracts

27. 27 Cromoglycates Stabilise mast cells & prevent the release of bronchoconstrictive & inflammatory substances when mast cells are confronted with allergens & other stimuli Only for prophylaxis of acute asthma attacks

28. 28 DrugFormulatio n Dosage AdultChild Cromoglycate Na Inhaler (1 mg & 5mg/dose) 10 mg four times daily, may be increased to six to eight times daily Same as adult Nebuliser solution 10 mg / ml 2 ml 20 mg four times daily, may be increased six times daily Same as adult Nedocromil Sodium Inhaler 2 mg / dose (MDI) 4 mg two to four times daily Sames as adult (>6 yrs)

29. 29 Leukotriene receptor antagonists Act by suppressing the effects of leukotrienes, compounds that promote bronchoconstriction as well as eosinophil infiltration, mucus productions, & airway edema Help to prevent acute asthma attacks induced by allergens & other stimuli Indicated for long-term treatment of asthma

30. 30 Dosage: – Montelukast (5 & 10 mg tablets) Adult: 10 mg daily at bedtime Child: – (2-5yrs) 4 mg daily at bedtime – (6-14yrs) 5 mg daily at bedtime

31. 31 Adverse effects: – GI disturbances – Hypersensitivity reactions – Restlessness & headache – Upper respiratory tract infection – Manufacturer advises to avoid these drugs in pregnancy & breast-feeding unless essential

32. Management of Chronic Asthma for adults & schoolchildren above 5yrs Step 1: Occasional relief short-acting beta 2 agonist Step 2: Add regular preventer therapy Standard-dose inhaled corticosteroid

33. Step 3: Add long-acting inhaled beta2 agonist; dose of inhaled corticosteroid may also be increased Step 4: Add high dose of inhaled corticosteroids

34. Step 5: Add regular oral corticosteroid E.g. prednisolone

35. 35 Stepping down: – Review treatment every 3 months – If symptoms controlled, may initiate stepwise reduction Lowest possible dose oral corticosteroid Gradual reduction of dose of inhaled corticosteroid to the lowest dose which controls asthma

36. 36 Antihistamines H 1 receptor antagonists – Inhibit smooth muscle constriction in blood vessels & respiratory & GI tracts – Decrease capillary permeability – Decrease salivation & tear formation Used for variety of allergic disorders to prevent or reverse target organ inflammation

37. 37 All antihistamines are of potential value in the treatment of nasal allergies, particularly seasonal allergic rhinitis (hay fever) Reduce rhinorrhoea & sneezing but are usually less effective for nasal congestion Are also used topically in the eye, in the nose, & on the skin

38. 38 First-generation H 1 receptor antagonists – Non-selective/sedating – Bind to both central & peripheral H 1 receptors – Usually cause CNS depression (drowsiness, sedation) but may cause CNS stimulation (anxiety, agitation), especially in children – Also have substantial anticholinergic effects

39. 39 DrugDosage AdultChild Chorphenirami ne (4 mg tablet, 2mg/ml Elixir & expectorant) 4 mg q4-6hr, max: 24 mg daily 1-2yrs: 1 mg twice daily 2-12yrs: 1- 2 mg q4-6h, Max:12 mg daily Hydroxyzine (25 mg tablet) 25 mg at night; 25mg three to four times daily when necessary 6 months-6yrs: 5-15 mg daily; 50 mg daily in divided dose if needed >6yrs: 15-25 mg daily; 50-100 mg daily in divided dose if needed Diphendramine (10 mg/5ml Elixir) 25-50 mg q4-6h6.25-25 mg q4-8 hr ( >1 yr)

40. DrugDosage AdultChild Promethazine (10 & 25 mg tablets, 5mg/5ml Elixir) 25 mg at night; 25 mg twice daily if needed 2-10yrs: 5-25 mg daily in 1 to 2 divided dose Azatadine (1 mg tablet) 1 mg twice daily1-12 yrs: 0.25-1 mg twice daily

41. Adverse effects: – Sedation – Dry mouth – Blurred vision – GI disturbances – Headache – Urinary retention – Hydroxyzine is not recommended for pregnancy & breast-feeding

42. 42 Second-generation H 1 receptor antagonists – Selective/non-sedating – Cause less CNS depression because they are selective for peripheral H 1 receptors & do not cross blood-brain barrier – Longer-acting compared to first-generation antihistamines

43. 43 DrugDosage AdultChild Acrivastine (Semprex) 8 mg three times daily Not recommended Cetirizine (Zyrtec)10 mg daily5 mg daily / 2.5 mg twice daily (2-6 yrs) Desloratadine (Aerius) 5 mg daily1.25 mg daily (2-5 yrs) 2.5 mg daily (6-11yrs) Fexofenadine (Telfast) 120-180 mg dailyNot recommended Loratadine (Clarityne) 10 mg daily`5 mg daily (2-5 yrs)

44. 44 Adverse effects: – May cause slight sedation – Some antihistamines may interact with antifungal, e.g. ketoconazole; antibiotics, e.g. erythromycin; prokinetic drug-- cisapride or grapefruit juice, leading to potentially serious ECG changes e.g. Terfenadine

45. 45 Cough preparations There are three classes of cough preparations: – Antitussives – Expectorants – Mucolytics

46. 46 Antitussives – Drugs that suppress cough – Some act within the CNS, some act peripherally – Indicated in dry, hacking, nonproductive cough that interfere with rest & sleep

47. 47 DrugDosage Codeine phosphate 25mg/5ml syrup 15-30 mg three to four times daily Pholcodine 5mg/5ml Elixir5-10 mg three to four times daily Dextromethorphan 10mg/5ml in Promethazine Compound Linctus 10-30 mg q4-8h Diphenhydramine 10 mg/ 5ml25 mg q4h, Max:150 mg daily

48. 48 Adverse effects: – Drowsiness – Respiratory depression (for opioid antitussives) – Constipation (for opioid antitussives) – Preparations containing codeine or similar analgesics are not generally recommended in children & should be avoided altogether in those under 1 year of age

49. 49 Expectorants – Render the cough more productive by stimulating the flow of respiratory tract secretions – Guaifenesin is most commonly used – Available alone & as an ingredient in many combination cough & cold remedies

50. 50 Mucolytics – Reacts directly with mucus to make it more watery. This should help make the cough more productive

51. 51 Dosage – Acetylcysteine 100 mg two to four times daily 200 mg two to three times daily 600 mg once daily – Bromhexine 8-16 mg three times daily po – Carbocisteine 750 mg three times daily, then 1.5 g daily in divided doses

52. 52 Sympathomimetics are used to reduce nasal congestion Stimulate alpha 1 -adrenergic receptors on nasal blood vessels, which causes vasoconstriction & hence shrinkage of swollen membranes Nasal Decongestants

53. 53 Topical administration: – Response is rapid & intense Oral administration: – Response are delayed, moderate & prolonged

54. 54 DrugFormulationDosage AdultChild OxymetazolineNasal Drops 0.025% 20 ml -2-3 drops q12h (2-5 yrs) Nasal Spray 0.05% 15 ml 2-3 sprays q12hSame as adults for children >6 yrs PhenylephrineNasal Drops 0.5% 10 ml Several drops q2- 4h - XylometazolineNasal Drops 0.05% / 0.1% 2-3 drops q8-10h (0.1%) 2-3 drops q8-10h (2-12 yrs) (0.05%)

55. 55 Adverse effects: – Rebound congestion develops with topical agents when used for more than a few days – CNS stimulation (such as restlessness, irritability, anxiety and insomnia) occurs with oral sympathomimetics

56. 56 Adverse effects (Cont’d): – Sympathomimetics can cause vasoconstriction by stimulating α-1 adrenergic receptors. More common with oral agents – Sympathomimetics cause CNS stimulation, and can produce effects similar to amphetamine. Hence, these drugs are subject to abuse

57. 57 Intranasal Corticosteroids – Most effective for treatment of seasonal and perennial rhinitis – Have inflammatory actions and can prevent or suppress all major symptoms of allergic rhinitis including congestion, rhinorrhea, sneezing, nasal itching and erythema

58. 58 DrugFormulationDosage AdultChild Beclomethasone Dipropionate Nasal Spray 50 mcg / dose 1 spray in each nostril four times daily Max. 10 sprays / day 4-6 sprays / day Nasal Spray 50 mcg dose (Aqueous) 2 applications into each nostril twice to four times daily Max. 400 mcg daily Same as adult (>6 yrs) Not recommended in children <6yrs

59. Drug (Cont’d)FormulationDosage AdultChild BudesonideNasal Spray 50 mcg / dose (Aqueous) 1-2 sprays into each nostril twice daily; after 2-3days: 1 spray into each nostril twice daily Not recommended for age 12 yrs or below Turbuhaler 100mcg / dose 400 mcg in the morning given as 2 applications into each nostril; then reduce to the smallest amount necessary -

60. DrugFormulationDosage AdultChild FluticasoneNasal Spray 50 mcg / dose (Aqueous) 2 sprays into each nostril in the morning Max: 8 sprays/day 1 spray into each nostril in the morning (4-11yrs) Max: 4 sprays/day MometasoneNasal Spray 50 mcg / dose 2 sprays in each nostril once daily; 1spray in each nostril as maintenance Max: 8 sprays/day 1 spray in each nostril once daily (3-11yrs)

61. 61 Adverse effects: – Mild – Most common effects are drying of nasal mucosa & sensations of burning or itching

62. 62 Chronic Obstructive Pulmonary Disease (COPD) Umbrella term for various conditions characterized by limitation of airflow that is not fully reversible Chronic airflow limitation caused by a mixture of small airway disease and parenchymal destruction Airflow limitation is often progressive Associated with an abnormal inflammatory response of lungs to noxious substances PREVENTABLE and TREATABLE disease

63. 63 Relationship between COPD and emphysema/chronic bronchitis Emphysema – Destruction of the gas exchanging surfaces of the lung (alveoli) – Pathological term that describes only one of several structural abnormalities present in patients with COPD Chronic bronchitis – Presence of cough and sputum production for at least 3 months in each of two consecutive years – Remains a clinically and epidemiologically useful term, but does not reflect the major impact of airflow limitation on morbidity and mortality in COPD patients The emphasis on these conditions are not included in the definition of COPD in current relevant clinical guidelines

64. 64 Asthma and COPD Underlying cause is different – Asthma: eosinophilic inflammation – COPD: neutrophilic inflammation COPD can coexist with asthma While asthma can usually be distinguished from COPD, in some individuals with chronic respiratory symptoms and fixed airflow limitation it remains difficult to differentiate the two diseases

65. 65 Pharmacotherapy None of the current available medications can alter the natural course of COPD or modify the rate of decline in lung function Aims (as per GOLD report) – Relieve symptoms – Prevent disease progression – Improve exercise tolerance – Improve health status – Prevent and treat complications – Prevent and treat exacerbations – Reduce mortality

66. 66 Bronchodilators Bronchodilator medications are central to symptom management in COPD Inhaled therapy is preferred The choice between beta agonist, anticholinergic, theophylline, or combination therapy depends on availability and individual response in terms of symptom relief and side effects

67. 67 Bronchodilators are prescribed on an as- needed or on a regular basis to prevent or reduce symptoms Long-acting inhaled bronchodilators are more effective and convenient Combining bronchodilators may improve efficacy and decrease the risk of side effects compared to increasing the dose of a single bronchodilator

68. 68 Corticosteroids Effects of oral and inhaled corticosteroids in COPD are much less dramatic than in asthma, and their role in the management of stable COPD is limited to specific indications

69. 69 Oral corticosteroids Use of a short course (two weeks) of oral corticosteroids to identify COPD patients who might benefit from long-term treatment with oral or inhaled corticosteroids is recommended Due to lack of evidence of benefit, and the issue of side effects, long-term treatment with oral corticosteroids is not recommended in COPD

70. 70 Inhaled corticosteroids Regular treatment is appropriate for symptomatic Stage III and Stage IV CPOD and repeated exacerbations (for example, 3 in the last 3 years) Treatment has been shown to reduce the frequency of exacerbations and thus improve health status More effective when combined with a long- acting beta agonist

71. 71 Drugs acting on the respiratory system, especially for asthma, can be administered by inhalation, the advantages are: – Enhance therapeutic effects – Minimize systemic effects – Rapid relief of acute attacks

72. 72 There are various types of inhalation devices: – Metered-dose inhalers (MDIs) Pressurized devices that deliver a measured dose of drug with each activation With CFC or non-CFC propellant Hand-mouth coordination is required

73. 73 Spacers: – Use with MDIs – Increase delivery of drug to the lungs & decrease deposition of drug on the oropharyngeal mucosa – Especially important for inhaled corticosteroids

74. 74 – Dry-powder inhalers (DPIs) Include Turbuhalers & Accuhalers Drugs are in the form of dry, micronized powder No propellant is employed Breath activated, much easier to use

75. 75 – Nebulizers Small machine to convert a drug solution into mist Droplets in the mist are much finer than those produced by inhalers Through face mask or mouth piece held between the teeth Take several minutes to deliver the same amount of drug contained in 1 puff from an inhaler