Doctor of Medicine. Alastair Stewart Dept. of Pharmacology 8 th Floor, Medical Building Rm. N802

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2 Doctor of Medicine Alastair Stewart Dept. of Pharmacology 8 th Floor, Medical Building Rm. N802 astew@unimelb.edu.au

3 Drugs affecting airway structure and function 2 Objectives Understand and know the mechanism of action and adverse effects of glucocorticoids Understand the indications and benefits of therapeutic combinations Contrast treatment approaches and long term outcomes in COPD and asthma Be familiar with drug treatments in fibrosis

4 Muscarinic receptors Ipratropium bromide non-selective - may not be optimal as blocks auto-inhibition Tiotropium bromide Once daily less bronchodilatation than b 2 -agonists N M1 + + Pre-ganglionic nerve ACh Post-ganglionic nerve used in COPD M2 M3 + - ACh Airway smooth muscle Contraction

5 Preventers: muscarinic receptor antagonists Prevent manifestations of reflex airway obstruction - less effective than b 2 -agonists (in asthma), as or more effective in COPD stimuli irritant receptors - histamine c-fibres - tachykinins, bradykinin initiating responses enhanced by viral infection/epithelial damage efferent responses - cholinergic M3 muscarinic receptors on ASM Ipratropium bromide - non selective Tiotropium bromide -functionally M3-selective (SAMA) (LAMA) once daily

6 Reductions in Glucocorticoids in asthma activity, recruitment and survival of eosinophils; T lymphocytes activation of mast cell cytokine production macrophage cytokine production in proliferation, cytokine and collagen production by smooth muscle and fibroblasts Decrease inflammatory cell number and activation Decrease probability and severity of episode of asthma

7 Glucocorticoid Mechanisms Leung et. al. J Allergy Clin Immunol (2003) Glucocorticoid-induced leucine zipper (GILZ) MAPK phosphatase-1 (MKP-1) Inhibitor of kba (IkBa) Transrepression Transactivation Proinflammatory IL-8 COX-2 ICAM-1 kb RE NFkB GRE GILZ MKP1 IkBa Antiinflammatory NOS2 GCS + GR GR/GCS (GCS/GR)2

8 Cytokine receptor Glucocorticoid Transactivation Anti-inflammatory effectors IKK UbUbUb IkBa IkBa P IkBa P NFkB GILZ degradation NFkB kbre TRE AP-1 Pro-inflammatory gene expression Cytokines Cytokine receptors Chemokines Inducible enzymes (NOS2;COX2) Adhesion molecules Integrins (AP-1) Fos/Jun-P Jun MKP-1 JNK-P JNK Cytokine receptor

9 Glucocorticoids used to treat asthma Inhaled GCS indicated if need b 2 -agonist > 3 times/week (i.e., Mild persistent asthma) Topical (inhaled GCS) beclomethasone diproprionate budesonide fluticasone propionate mometasone ciclosenide Start at effective dose - step down Available in combination with b 2 -agonist (LABA) Systemic (oral GCS) prednisolone - oral administration A. Several days - for acute exacerbations B. Chronically severe asthma only

10 Measuring Variability of Peak Expiratory Flow

11 Glucocorticoids - adverse effects Inhaled GCS - well tolerated dysphonia, oral candidiasis, serum cortisol mouthwash - reduces local absorption Oral GCS- dose and indication-limiting SEs osteoporosis, diabetes, muscle wasting, hypertension growth suppression (used cautiously in children) suppression of adrenal/pituitary/hypothalamic axis need to wean off chronic use to avoid withdrawal

12 Regulation of endogenous glucocorticoids

13 Methylxanthines and Phosphodiesterase Inhibitors Theophylline PDE inhibition/smooth muscle relaxant Adenosine antagonism HDAC2 activation relevant mechanism not known Dose-limiting side effects nausea, vomiting diarrhea, CNS stimulation (low safety margin) cardiostimulation - dysrythmias Selective PDEIs eg Roflumilast Reduced incidence and severity of side effects (compared with theophylline) approved for COPD, not asthma Barnes, PJ (2004) New Drugs for asthma.

14 Stepwise management - pharmacotherapy Diagnosis Symptom control & risk factors (including lung function) Inhaler technique & adherence Patient preference Symptoms Exacerbations Side-effects Patient satisfaction Lung function Asthma medications Non-pharmacological strategies Treat modifiable risk factors STEP 5 PREFERRED CONTROLLER CHOICE Other controller options RELIEVER STEP 1 STEP 2 Consider low dose ICS Low dose ICS Leukotriene receptor antagonists (LTRA) Low dose theophylline* As-needed short-acting beta2-agonist (SABA) STEP 3 Low dose ICS/LABA* Med/high dose ICS Low dose ICS+LTRA (or + theoph*) STEP 4 Med/high ICS/LABA Add tiotropium# High dose ICS + LTRA (or + theoph*) As-needed SABA or low dose ICS/formoterol** Refer for add-on treatment e.g. anti-ige Add tiotropium# Add low dose OCS *For children 6-11 years, theophylline is not recommended, and preferred Step 3 is medium dose ICS **For patients prescribed BDP/formoterol or BUD/ formoterol maintenance and reliever therapy # Tiotropium by soft-mist inhaler is indicated as add-on treatment for adults ( 18 yrs) with a history of exacerbations GINA 2015, Box 3-5 (2/8) (upper part) Global Initiative for Asthma

15 Biologics in treatment of chronic allergic disease asthma, atopic dermatitis, Chronic sinusitis with nasal polyps Nature Reviews Drug Discovery, 15:35-50 (2015)

16 Clinical Need for new treatments for severe asthma - still Exacerbations in severe steroid-dependent asthma Modest efficacy Expensive Large unmet need FDA-validated Phase III pivotal trial: suppression of steroid withdrawal exacerbations Global Initiative for Asthma

17 G O lobal Initiative for Chronic bstructive L D ung isease Global Initiative for Chronic Obstructive Lung Disease

18 Global Strategy for Diagnosis, Management and Prevention of COPD Risk Factors for COPD Genes Exposure to particles Tobacco smoke Occupational dusts, organic and inorganic Indoor air pollution from heating and cooking with biomass in poorly ventilated dwellings Outdoor air pollution Lung growth and development Gender Age Respiratory infections Socioeconomic status Asthma/Bronchial hyperreactivity Chronic Bronchitis 2015 Global Initiative for Chronic Obstructive Lung Disease

19 Spirometry: Obstructive Disease 5 Normal 4 Volume, liters FEV 1 = 1.8L FVC = 3.2L FEV 1 /FVC = 0.56 Obstructive Time, seconds 2015 Global Initiative for Chronic Obstructive Lung Disease

20 Lung function decline

21 Definition of COPD COPD is a preventable and treatable disease with some significant extrapulmonary effects that may contribute to the severity in individual patients. Its pulmonary component is characterized by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lung to noxious particles or gases. There is loss of lung parenchyma, small airways inflammation, fibrosis and thickening and pulmonary hypertension

22 Classification of Severity of Airflow Limitation in COPD* In patients with FEV 1 /FVC < 0.70: GOLD 1: Mild GOLD 2: Moderate GOLD 3: Severe FEV 1 > 80% predicted 50% < FEV 1 < 80% predicted 30% < FEV 1 < 50% predicted GOLD 4: Very Severe FEV 1 < 30% predicted *Based on Post-Bronchodilator FEV Global Initiative for Chronic Obstructive Lung Disease

23 Professor Peter J. Barnes, MD National Heart and Lung Institute, London UK

24 Professor Peter J. Barnes, MD National Heart and Lung Institute, London UK

25 Professor Peter J. Barnes, MD National Heart and Lung Institute, London UK

26 Professor Peter J. Barnes, MD National Heart and Lung Institute, London UK

27 Professor Peter J. Barnes, MD National Heart and Lung Institute, London UK

28 Global Strategy for Diagnosis, Management and Prevention of COPD Therapeutic Options: COPD Medications Beta 2 -agonists Short-acting beta 2 -agonists (SABA) Long-acting beta 2 -agonists (LABA) Anticholinergics Short-acting anticholinergics (SAMA) Long-acting anticholinergics (LAMA) Combination short-acting beta 2 -agonists + anticholinergic in one inhaler Combination long-acting beta 2 -agonist + anticholinergic in one inhaler Methylxanthines Inhaled corticosteroids Combination long-acting beta 2 -agonists + corticosteroids in one inhaler Systemic corticosteroids Phosphodiesterase-4 inhibitors 2015 Global Initiative for Chronic Obstructive Lung Disease

29 Global Strategy for Diagnosis, Management and Prevention of COPD Therapeutic Options: Bronchodilators Bronchodilator medications are central to the symptomatic management of COPD. Bronchodilators are prescribed on an as-needed or on a regular basis to prevent or reduce symptoms. The principal bronchodilator treatments are beta 2 - agonists, anticholinergics, theophylline or combination therapy. The choice of treatment depends on the availability of medications and each patient s individual response in terms of symptom relief and side effects Global Initiative for Chronic Obstructive Lung Disease

30 Global Strategy for Diagnosis, Management and Prevention of COPD Therapeutic Options: Bronchodilators Long-acting inhaled bronchodilators are convenient and more effective for symptom relief than short-acting bronchodilators. Long-acting inhaled bronchodilators reduce exacerbations and related hospitalizations and improve symptoms and health status. Combining bronchodilators of different pharmacological classes may improve efficacy and decrease the risk of side effects compared to increasing the dose of a single bronchodilator Global Initiative for Chronic Obstructive Lung Disease

31 Global Strategy for Diagnosis, Management and Prevention of COPD Therapeutic Options: Inhaled Corticosteroids Regular treatment with inhaled corticosteroids improves symptoms, lung function and quality of life and reduces frequency of exacerbations for COPD patients with an FEV 1 < 60% predicted. Inhaled corticosteroid therapy is associated with an increased risk of pneumonia. Withdrawal from treatment with inhaled corticosteroids may lead to exacerbations in some patients Global Initiative for Chronic Obstructive Lung Disease

32 Global Strategy for Diagnosis, Management and Prevention of COPD Therapeutic Options: Combination Therapy An inhaled corticosteroid combined with a long-acting beta 2 -agonist is more effective than the individual components in improving lung function and health status and reducing exacerbations in moderate to very severe COPD. Combination therapy is associated with an increased risk of pneumonia. Addition of a long-acting beta 2 -agonist/inhaled glucorticosteroid combination to an anticholinergic (tiotropium) appears to provide additional benefits Global Initiative for Chronic Obstructive Lung Disease

33 Idiopathic Pulmonary Fibrosis Fatal interstitial lung disease (median survival 2.8 years) Scarring thickens and stiffens alveolar walls - impaired oxygen transfer - increased respiratory work - respiratory failure Currently no effective therapies Annual Incidence of ~8 per 100,000 mainly in 60+ yo age 2014 phase III trial successes Pirfenidone TGFb modifier Nintedanib- Triple kinase inhibitor Decelerate annual rate of loss of lung function (FVC)

34 Lung remodelling in IPF Normal lung Fibrotic lung Collagen deposition Author s own Thickening of the alveolar wall

35 Pulmonary Arterial Hypertension (PAH) Idiopathic - Familial mutation in BMPII receptors Secondary pulmonary fibrosis COPD Altitude chronic hypoxia

36 PAH - treatment ERA endothelin receptor antagonists bosentan - non-selective Sitaxentan ETA-selective ambisentan- Endothelin-1 (an Endothelial Cell-derived Vasoconstrictor Growth factor) Prostanoids (prostacyclin analogues) PDEI PDE V - sildenafil camp cgmp Decreased resistance of pulmonary vessels

37 Global Strategy for Diagnosis, Management and Prevention of COPD Following slides are FYI Not directly examinable 2015 Global Initiative for Chronic Obstructive Lung Disease

38 Global Strategy for Diagnosis, Management and Prevention of COPD Therapeutic Options: Systemic Corticosteroids Chronic treatment with systemic corticosteroids should be avoided because of an unfavorable benefit-torisk ratio Global Initiative for Chronic Obstructive Lung Disease

39 Global Strategy for Diagnosis, Management and Prevention of COPD Therapeutic Options: Phosphodiesterase-4 Inhibitors In patients with severe and very severe COPD (GOLD 3 and 4) and a history of exacerbations and chronic bronchitis, the phospodiesterase-4 inhibitor, roflumilast, reduces number of exacerbations requiring treatment with oral glucocorticosteroids Global Initiative for Chronic Obstructive Lung Disease

40 Global Strategy for Diagnosis, Management and Prevention of COPD Therapeutic Options: Theophylline Theophylline is less effective and less well tolerated than inhaled long-acting bronchodilators and is not recommended if those drugs are available and affordable. There is evidence for a modest bronchodilator effect and some symptomatic benefit compared with placebo in stable COPD. Addition of theophylline to salmeterol produces a greater increase in FEV 1 and reduction in breathlessness than salmeterol alone. Low dose theophylline reduces exacerbations but does not improve postbronchodilator lung function Global Initiative for Chronic Obstructive Lung Disease

41 Global Strategy for Diagnosis, Management and Prevention of COPD Therapeutic Options: Other Pharmacologic Treatments Influenza vaccines can reduce serious illness. Pneumococcal polysaccharide vaccine is recommended for COPD patients 65 years and older and for COPD patients younger than age 65 with an FEV 1 < 40% predicted. The use of antibiotics, other than for treating infectious exacerbations of COPD and other bacterial infections, is currently not indicated Global Initiative for Chronic Obstructive Lung Disease

42 Global Strategy for Diagnosis, Management and Prevention of COPD Therapeutic Options: Other Pharmacologic Treatments Alpha-1 antitrypsin augmentation therapy: not recommended for patients with COPD that is unrelated to the genetic deficiency. Mucolytics: Patients with viscous sputum may benefit from mucolytics; overall benefits are very small. Antitussives: Not recommended. Vasodilators: Nitric oxide is contraindicated in stable COPD Global Initiative for Chronic Obstructive Lung Disease

43 Global Strategy for Diagnosis, Management and Prevention of COPD Manage Stable COPD: Pharmacologic Therapy RECOMMENDED FIRST CHOICE GOLD 4 GOLD 3 GOLD 2 GOLD 1 C A ICS + LABA or LAMA SAMA prn or SABA prn ICS + LABA and/or LAMA LABA or LAMA D B 2 or more or > 1 leading to hospital admission 1 (not leading to hospital admission) 0 Exacerbations per year CAT < 10 mmrc 0-1 Breathlessness: strenuous exercise only CAT > 10 mmrc > 2 walking on level ground 2015 Global Initiative for Chronic Obstructive Lung Disease

44 Global Strategy for Diagnosis, Management and Prevention of COPD Manage Stable COPD: Pharmacologic Therapy (Medications in each box are mentioned in alphabetical order, and therefore not necessarily in order of preference.) Patient Recommended First choice Alternative choice Other Possible Treatments A SAMA prn or SABA prn LAMA or LABA or SABA and SAMA Theophylline B LAMA or LABA LAMA and LABA SABA and/or SAMA Theophylline C ICS + LABA or LAMA LAMA and LABA or LAMA and PDE4-inh. or LABA and PDE4-inh. SABA and/or SAMA Theophylline D ICS + LABA and/or LAMA ICS + LABA and LAMA or ICS+LABA and PDE4-inh. or LAMA and LABA or LAMA and PDE4-inh. Carbocysteine N-acetylcysteine SABA and/or SAMA Theophylline

45 Global Strategy for Diagnosis, Management and Prevention of COPD Manage Exacerbations An exacerbation of COPD is: an acute event characterized by a worsening of the patient s respiratory symptoms that is beyond normal dayto-day variations and leads to a change in medication Global Initiative for Chronic Obstructive Lung Disease

46 Consequences Of COPD Exacerbations Impact on symptoms and lung function Negative impact on quality of life EXACERBATIONS Accelerated lung function decline Increased economic costs Increased Mortality 2015 Global Initiative for Chronic Obstructive Lung Disease

47 Global Strategy for Diagnosis, Management and Prevention of COPD Manage Exacerbations: Treatment Options Oxygen: titrate to improve the patient s hypoxemia with a target saturation of 88-92%. Bronchodilators: Short-acting inhaled beta 2 -agonists with or without short-acting anticholinergics are preferred. Systemic Corticosteroids: Shorten recovery time, improve lung function (FEV 1 ) and arterial hypoxemia (PaO 2 ), and reduce the risk of early relapse, treatment failure, and length of hospital stay. A dose of 40 mg prednisone per day for 5 days is recommended Global Initiative for Chronic Obstructive Lung Disease