Therapeutics of Obstructive Airway Disease

Question 1

Categories of drugs used to treat airflow obstruction?

Answer 1

Preventors (anti-inflammatory)

Relievers (bronchodilators and used acutely)

Question 2

Describe importance of taking both medications

Answer 2

Treating acute smooth muscle twitching - bronchospasm - is not enough; the inflammation must also be treated
β2 agonists are relievers
Coritcosteroids are preventors

Patients often told to take blue inhaler when they need but, due to instantaneous relief, they do not take the brown inhaler

Question 3

How is the problem of not taking corticosteroids being prevented?

Answer 3

Combination inhalers with both β2 agonists and corticosteroids (SMART therapy)
Can also have a longer duration of action

Question 4

Describe the asthma treatment pyramid

Answer 4

For mild, intermittent and episodic asthma a reliever is give - short-acting β2-agonist (SABA) as needed

In order of increasing severity:
If SABA required > once a day, they also require a preventor - inhaled corticosteroid but cromones (cromoglycate) can also be given, to melt away mast cells

If still not controlled, ADD-ON drugs to ICS are given, like theophylline, a methyxanthine, Anti-IgE, Anti IL-5, LABA/LAMA, LTRA (leukotrience receptor antagonists)

If still uncontrolled, oral steroids (prednisolone is a cortisol analogue) can be given but tend not to be used long-term as bad side effects

Question 5

Use of steroids in asthma?

Answer 5

Oral steroid (prednisolone) has a low therapeutic ratio and is only used for acute exacerbations - bad side effects like thin skin, fat deposits, etc
Inhaled steroid (beclomethasone) has a higher therapeutic ratio and is used for maintenance therapy, as it is a local therapy and minimises systemic exposure

OPTIMISE DELIVERY TO LUNGS used a SPACER

Question 6

Use of steroids in COPD?

Answer 6

Corticosteroids are used in COPD, to reduce exacerbations, but may cause pneumonia due to local immune suppression

Question 7

How can prednisolone be integrated into asthma treatment?

Answer 7

Can be given to increase PEFR and then, after a few weeks, can be replaced with beclomethasone which keeps PEFR up at constant value

Question 8

Benefits of using a spacer device with inhaled corticosteroids?

Answer 8

Spacer can avoid gagging caused by inhalation
Avoids coordination problems with metered dose inhaler
Reduces oropharyngeal and laryngeal side effects
Reduces systemic absorption from swallowed fraction
Acts as a holding chamber for aerosol
Reduces particle size and velocity
Improves lung deposition

Question 9

Why is particle size important with ICS?

Answer 9

Particles must be small enough to get into lungs, past carina
If over 5 microns, too large
If over 2 microns, still too large but will still treat inflammation in some regions
Below 2 microns - greater distribution of ICS in lungs

Question 10

Use of cromones in obstructive airway diseases?

Answer 10

Anti-inflammatory drugs used only in ASTHMA, LIKE CROMOGLYCATE
MAST CELL STABILISERS but have a weaker anti-inflammatory effect than steroids
Taken via inhaled route only (4 times a day, compliant with QID dosing) but are not used much due to POOR EFFICACY
Cromoglycate is effective in ATOPIC children

Question 11

Describe the leukotriene synthesis pathway

Answer 11

Cell membrane phospholipid is converted to arachidonic acid, which is converted to LTA4 using 5-lipooxygenase + FLAP

LTA4 is converted to LTB4 (end of pathway)
LTA4 is converted to LTC4, which converts to LTD4 to LTE4

Question 12

What are the cysteinyl LTs?

Answer 12

LTC4, LTD4, LTE4

LTD4 is the main pro-inflammatory mediator in asthma as they attract and recruit eosinophils

LTD4 produced by inflammatory cells, like mast cells and eosinophils

Question 13

Role of leukotrienes in asthma?

Answer 13

LTD4 causes:
Oedema - capillaries leak fluid causing swelling
Contraction and proliferation of airway smooth muscle
Increased mucous secretion but decreased mucous transport
Eosinophil influx - release cationic proteins will cause epithelial cell damage
Sensory nerves (C-fibres) become exposed and thus hyper-sensitivity

Question 14

Uses of leukotriene receptor antagonists?

Answer 14

Only used in ASTHMA for anti-inflammatory purposes, however less potent anti-inflammatory properties than ICS
Also, effective for EXERISE-INDUCED BRONCHOCONSTRICTION and allergic rhinitis (with anti-histamine)

Example is Montelukast - given via oral route, once daily and has a high therapeutic ratio
It is a 2nd line treatment and is a complimentary non-steroidal anti-inflammatory additive to inhaled steroid

Question 15

Use of anti-IgEs?

Answer 15

Example is an anti-IgE monoclonal antibody - Omalizumab; inhibits binding to high-affinity IgE receptors and inhibits mediator release from basophils/mast cells
Has no effect on pulmonary function but does reduce exacerbations and steroid sparing

Injected every 24 hrs but is very expensive and so is only used for patients with raised IgE and severe persistent allergic asthma, despite max therapy

Question 16

Examples of another monoclonal antibodies used for severe refractory asthma?

Answer 16

Anti-IL4 - Dupilumab
Anti-IL5 - Mepoluzimab and Reslizumab
Anti-IL13 - Lebrikizumab

Anti-TH2 cytokines are in development

Question 17

Use of β2-agonists?

Answer 17

Stimulate bronchial smooth muscle β2 receptors, so increased cAMP
Used in asthma (ICS/LABA combo) and in COPD (ICS/LABA combo or LAMA/LABA combo)

Can be used in SMART therapy as combination inhalers:
Fluticasone/Salmeterol
Budesonide/Formoterol
Beclometasone/Formoterol

High nebulised doses given in acute attacks

Question 18

Types of β2 agonists?

Answer 18

Short-acting - Salbutamol

Long-acting - Salmeterol, formoterol, indaceterol, vilanterol, oladaterol

Question 19

Describe β2 agonists and their effects

Answer 19

High therapeutic ratio when given via inhaled route
With LABAs, down-regulation and tachyphylaxis (acute, rapid decrease in response to a drug after its administration)
Systemic β2 effects when given systemically/high inhaled doses (tachycardia, fine tremor by acting on β1 and β2 receptors elsewhere)

Question 20

Types of muscarinic (cholinergic receptors) and what they do?

Answer 20

M1 receptors - enhance cholinergic reflex
M2 receptors - inhibit acetylcholine release
M3 receptors - mediate bronchoconstriction and mucous secretion

Question 21

How do anti-cholinergics (muscarinic receptor antagonists) work?

Answer 21

Block post-junctional end plate M3 receptors

Given via inhaled route ONLY and have a high therapeutic ratio

Question 22

Examples of anti-cholinergics?

Answer 22

Long acting, Tiotropium, Aclidinium, Glycopyrronium, Umeclidinium

Question 23

Uses of anti-cholinergics?

Answer 23

Used MOSTLY IN COPD - reduce exacerbations, on its own or as LAMA/LABA combo:
Glycopyrronium/Indacaterol
Aclidinium/Formoterol
Umeclidinium/Vilanterol
Tiotropium/Olodaterol

Also, used in ASTHMA as triple therapy at step 4, as ADD-ON to ICS/LABA

High nebulised doses of Ipratropium are used in acute COPD and in acute asthma

Question 24

Uses of methylxanthines?

Answer 24

Used in ASTHMA and COPD and have a low therapeutic ratio (have p450 drug interaction along with erythromycin)

Example, oral Theophylline for maintenance therapy

Used as ADD-ON to inhaled steroid as complimentary non-steroidal anti-inflammatory

IV (Aminophylline) - acute attacks

Are non-selective phosphodiesterase inhibitors, so increase cAMP and are also adenosine antagonists

Question 25

Uses of PDE4 (phosphodiesterase 4) inhibitors?

Answer 25

Example is Roflumilast (oral tablet)
Anti-inflammatory use in COPD ONLY; have a minimal effect on FEV1

Reduces exacerbations when ADDED-ON to LABA/LAMA

Rarely used but an be used as add-on to LABA/LAMA in frequent exacerbations, instead of ICS

Question 26

Adverse effects of PDE4 inhibitors?

Answer 26

Nausea
Diarrhoea
Headache
Weight loss

Question 27

Uses of mucolytics?

Answer 27

Example is oral Carcocisteine and Erdosteine

Reduce sputum viscosity and aid sputum expectoration and reduce exacerbations IN COPD

Rarely used - ONLY AS ADD-ON TO OTHER TREATMENTS

Question 28

Aims of treatment of chronic asthma?

Answer 28

Abolish symptoms
Minimise β2 use
Normalise FEV1
Reduce PEF variability
Reduce exacerbations
Prevent long-term airway remodelling

Question 29

How can asthma symptoms be reduced?

Answer 29

Avoid triggers
Suppress inflammatory cascade with inhaled corticosteroids +/- non-steroidal anti-inflammatory therapy (like Theophylline, anti-LT, cromoglycate)

Stabilise smooth muscle with LABA/LAMA - only once optimal anti-inflammatory therapy is in place

Question 30

Treatment of acute asthma?

Answer 30

Oral prednisolone or iv hydrocortisone

Nebulised high dose salbutamol +/- nebulised ipratropium =/- iv aminophylline/magnesium

60% O2

ITU assisted mechanical intibated ventilation is falling PaO2 and rising PaCO2 - never use respiratory stimulant

Question 31

Stages of COPD progression?

Answer 31

At risk
Symptomatic
Exacerbations
Respiratory failure

Question 32

Interventions for COPD?

Answer 32

Smoking cessation (does no restore lost FEV1 but subsequent loss rate may return to normal)
Disease management
Pulmonary rehabilitation
Other options

Question 33

How to monitor COPD progression?

Answer 33

Monitor FEV1

Monitor symptoms

Question 34

Describe disease in smokers vs non-smokers

Answer 34

FEV1 falls over lifetime, accelerates with age
Non-smokers and non-susceptible smokers lose FEV1 slowly and almost never develop clinically significant airflow obstruction

Susceptible smokers develop airflow obstruction, becoming disabling or even fatal

Question 35

Treatment of acute COPD?

Answer 35

Nebulised high-dose salbutamol + ipratropium

Oral prednisolone
Antibiotic (amoxycillin/doxycycline) if infection
24-28% O2 against PaO2/PaCO2
Physio to aid sputum expectoration
ITU intubated assisted ventilation only is there is a reversible component, like pneumonia