Drugs affecting airway and lung remodelling · Floor, Medical Building . ... because of an...

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

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