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Alastair Stewart Dept. of Pharmacology 8th Floor, Medical Building Rm. N802 • [email protected]
Doctor of Medicine
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
Drugs affecting airway structure and function 2
Muscarinic receptors
N
M1
M2
M3
+
+
-
+
+
+
+
Pre-ganglionic nerve
Post-ganglionic nerve
Airway smooth muscle ACh -
ACh
Ipratropium bromide
non-selective - may not be optimal as blocks auto-inhibition Tiotropium bromide Once daily less bronchodilatation than b2-agonists used in COPD
Contraction
Preventers: muscarinic receptor antagonists Prevent manifestations of reflex airway obstruction - less effective than b2-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 (SAMA) Tiotropium bromide -functionally M3-selective (LAMA) once daily
Glucocorticoids in asthma Reductions in 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
GCS + GR GR/GCS (GCS/GR)2
NFkB
kB RE GRE
IL-8
COX-2
ICAM-1
NOS2
GILZ
MKP1
IkBa
Leung et. al. J Allergy Clin Immunol (2003)
Glucocorticoid Mechanisms
Glucocorticoid-induced leucine zipper (GILZ) MAPK phosphatase-1 (MKP-1) Inhibitor of kBa (IkBa)
Pro- inflammatory
Anti- inflammatory
Transactivation Transrepression
IKK UbUbUb IkBa IkBa–P IkBa–P NFkB NFkB kBRE
degradation
Pro-inflammatory gene expression TRE
AP-1
Cytokine receptor
Cytokine receptor
(AP-1) Fos/Jun-P JNK-P JNK
Jun
MKP-1
GILZ
Cytokines Cytokine receptors Chemokines Inducible enzymes (NOS2;COX2) Adhesion molecules Integrins
Glucocorticoid Transactivation Anti-inflammatory effectors
Glucocorticoids used to treat asthma Inhaled GCS indicated if need b2-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 Systemic (oral GCS) prednisolone - oral administration A. Several days - for acute exacerbations B. Chronically – severe asthma only
Available in combination with b2-agonist (LABA)
Measuring Variability of Peak Expiratory Flow
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”
Regulation of endogenous glucocorticoids
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.
© Global Initiative for Asthma
Stepwise management - pharmacotherapy
*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)
Diagnosis Symptom control & risk factors (including lung function) Inhaler technique & adherence Patient preference
Asthma medications Non-pharmacological strategies Treat modifiable risk factors
Symptoms Exacerbations Side-effects Patient satisfaction Lung function
Other controller
options
RELIEVER
STEP 1 STEP 2 STEP 3
STEP 4
STEP 5
Low dose ICS
Consider low dose ICS
Leukotriene receptor antagonists (LTRA) Low dose theophylline*
Med/high dose ICS Low dose ICS+LTRA
(or + theoph*)
As-needed short-acting beta2-agonist (SABA) As-needed SABA or low dose ICS/formoterol**
Low dose ICS/LABA*
Med/high ICS/LABA
Refer for add-on
treatment e.g.
anti-IgE
PREFERRED CONTROLLER
CHOICE
Add tiotropium# High dose ICS + LTRA (or + theoph*)
Add tiotropium# Add low dose OCS
Biologics in treatment of chronic allergic disease – asthma, atopic dermatitis, Chronic sinusitis with nasal polyps
Nature Reviews Drug Discovery, 15:35-50 (2015)
© Global Initiative for Asthma
• Modest efficacy • Expensive
Large unmet need
Exacerbations in severe steroid-dependent asthma
FDA-validated Phase III pivotal trial: suppression of steroid withdrawal exacerbations
Clinical Need for new treatments for severe asthma - still
lobal Initiative for Chronic bstructive ung isease
G O L D
© 2015 Global Initiative for Chronic Obstructive Lung Disease
http://www.goldcopd.org
Global Strategy for Diagnosis, Management and Prevention of COPD
Risk Factors for COPD
Lung growth and development Gender Age Respiratory infections Socioeconomic status Asthma/Bronchial hyperreactivity Chronic Bronchitis
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
© 2015 Global Initiative for Chronic Obstructive Lung Disease
Spirometry: Obstructive Disease Vo
lum
e, li
ters
Time, seconds
5
4
3
2
1
1 2 3 4 5 6
FEV1 = 1.8L
FVC = 3.2L
FEV1/FVC = 0.56
Normal
Obstructive
© 2015 Global Initiative for Chronic Obstructive Lung Disease
Lung function decline
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
Classification of Severity of Airflow Limitation in COPD*
In patients with FEV1/FVC < 0.70: GOLD 1: Mild FEV1 > 80% predicted GOLD 2: Moderate 50% < FEV1 < 80% predicted GOLD 3: Severe 30% < FEV1 < 50% predicted GOLD 4: Very Severe FEV1 < 30% predicted *Based on Post-Bronchodilator FEV1
© 2015 Global Initiative for Chronic Obstructive Lung Disease
Professor Peter J. Barnes, MD National Heart and Lung Institute, London UK
Professor Peter J. Barnes, MD National Heart and Lung Institute, London UK
Professor Peter J. Barnes, MD National Heart and Lung Institute, London UK
Professor Peter J. Barnes, MD National Heart and Lung Institute, London UK
Professor Peter J. Barnes, MD National Heart and Lung Institute, London UK
Global Strategy for Diagnosis, Management and Prevention of COPD
Therapeutic Options: COPD Medications
Beta2-agonists
Short-acting beta2-agonists (SABA) Long-acting beta2-agonists (LABA) Anticholinergics
Short-acting anticholinergics (SAMA) Long-acting anticholinergics (LAMA) Combination short-acting beta2-agonists + anticholinergic in one inhaler Combination long-acting beta2-agonist + anticholinergic in one inhaler Methylxanthines
Inhaled corticosteroids Combination long-acting beta2-agonists + corticosteroids in one inhaler Systemic corticosteroids
Phosphodiesterase-4 inhibitors
© 2015 Global Initiative for Chronic Obstructive Lung Disease
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 beta2- 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 Strategy for Diagnosis, Management and Prevention of COPD
Therapeutic Options: Bronchodilators
© 2015 Global Initiative for Chronic Obstructive Lung Disease
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 Strategy for Diagnosis, Management and Prevention of COPD
Therapeutic Options: Bronchodilators
© 2015 Global Initiative for Chronic Obstructive Lung Disease
Regular treatment with inhaled corticosteroids improves symptoms, lung function and quality of life and reduces frequency of exacerbations for COPD patients with an FEV1 < 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 Strategy for Diagnosis, Management and Prevention of COPD
Therapeutic Options: Inhaled Corticosteroids
© 2015 Global Initiative for Chronic Obstructive Lung Disease
An inhaled corticosteroid combined with a long-acting beta2-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 beta2-agonist/inhaled glucorticosteroid combination to an anticholinergic (tiotropium) appears to provide additional benefits.
Global Strategy for Diagnosis, Management and Prevention of COPD
Therapeutic Options: Combination Therapy
© 2015 Global Initiative for Chronic Obstructive Lung Disease
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)
Lung remodelling in IPF Normal lung Fibrotic lung
Thickening of the alveolar wall
Collagen deposition
Author’s own
Pulmonary Arterial Hypertension (PAH)
Idiopathic - Familial – mutation in BMPII receptors Secondary pulmonary fibrosis chronic hypoxia COPD Altitude
PAH - treatment ERA – endothelin receptor antagonists bosentan - non-selective Sitaxentan – ETA-selective ambisentan- Prostanoids (prostacyclin analogues) PDEI – PDE V - sildenafil
Endothelin-1 (an Endothelial Cell-derived Vasoconstrictor Growth factor)
cAMP cGMP
Decreased resistance of pulmonary vessels
Following slides are FYI Not directly examinable
Global Strategy for Diagnosis, Management and Prevention of COPD
© 2015 Global Initiative for Chronic Obstructive Lung Disease
Chronic treatment with systemic
corticosteroids should be avoided because of an unfavorable benefit-to-risk ratio.
Global Strategy for Diagnosis, Management and Prevention of COPD
Therapeutic Options: Systemic Corticosteroids
© 2015 Global Initiative for Chronic Obstructive Lung Disease
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 Strategy for Diagnosis, Management and Prevention of COPD
Therapeutic Options: Phosphodiesterase-4 Inhibitors
© 2015 Global Initiative for Chronic Obstructive Lung Disease
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 FEV1 and reduction in breathlessness than salmeterol alone.
Low dose theophylline reduces exacerbations but does not improve post-bronchodilator lung function.
© 2015 Global Initiative for Chronic Obstructive Lung Disease
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 FEV1 < 40% predicted.
The use of antibiotics, other than for treating infectious exacerbations of COPD and other bacterial infections, is currently not indicated.
Global Strategy for Diagnosis, Management and Prevention of COPD
Therapeutic Options: Other Pharmacologic Treatments
© 2015 Global Initiative for Chronic Obstructive Lung Disease
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 Strategy for Diagnosis, Management and Prevention of COPD
Therapeutic Options: Other Pharmacologic Treatments
© 2015 Global Initiative for Chronic Obstructive Lung Disease
Exa
cerb
atio
ns p
er y
ear
0
CAT < 10 mMRC 0-1
GOLD 4
CAT > 10
mMRC > 2 Breathlessness: strenuous exercise only walking on level ground
GOLD 3
GOLD 2
GOLD 1
SAMA prn or
SABA prn
LABA or
LAMA
ICS + LABA or
LAMA
Global Strategy for Diagnosis, Management and Prevention of COPD
Manage Stable COPD: Pharmacologic Therapy RECOMMENDED FIRST CHOICE
A B
D C
ICS + LABA and/or LAMA
© 2015 Global Initiative for Chronic Obstructive Lung Disease
2 or more or > 1 leading to hospital admission 1 (not leading to hospital admission)
http://www.catestonline.org/
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 RecommendedFirst 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
An exacerbation of COPD is:
“an acute event characterized by a worsening of the patient’s respiratory symptoms that is beyond normal day-to-day variations and leads to a change in medication.”
Global Strategy for Diagnosis, Management and Prevention of COPD
Manage Exacerbations
© 2015 Global Initiative for Chronic Obstructive Lung Disease
Impact on symptoms and lung function
Negative impact on
quality of life
Consequences Of COPD Exacerbations
Increased economic
costs
Accelerated lung function
decline
Increased Mortality
EXACERBATIONS
© 2015 Global Initiative for Chronic Obstructive Lung Disease
Oxygen: titrate to improve the patient’s hypoxemia with a target saturation of 88-92%. Bronchodilators: Short-acting inhaled beta2-agonists with or without short-acting anticholinergics are preferred. Systemic Corticosteroids: Shorten recovery time, improve lung function (FEV1) and arterial hypoxemia (PaO2), 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 Strategy for Diagnosis, Management and Prevention of COPD
Manage Exacerbations: Treatment Options
© 2015 Global Initiative for Chronic Obstructive Lung Disease