Asthma 1-4, Environmental Aspects of COPD and Asthma, Cystic Fibrosis, COPD 1-2

What is asthma?

A chronic lung disease, characterised by excessive variation in both:

• Expiratory lung function

• Respiratory symptoms

  • Cough

  • Wheeze

  • Chest tightness

  • Breathlessness (dyspnoea)

Asthma diagnosis investigations

• Spirometry (and FeNO - not compulsory): pre- and post-bronchodilator FEV₁

• History-taking of clinical signs and symptoms

Asthma diagnosis thresholds

Post-bronchodilator FEV1 increase >= 200 mL and >=12% from baseline .

FeNO greater than or equal to 40 ppb.

The 8 management points for Asthma + COPD

1. Action plan + pharmacological therapies

2. Smoking cessation

3. Manage co-morbidities

4. Immunisation

5. Diet

6. Exercise (+ Pulmonary Rehab)

7. Education + Inhaler Technique

8. Monitoring

Poor asthma control

Three or more of the following:

• reliever needed 3 or more times a week

• symptoms experienced 3 or more times a week

• morning or nighttime symptoms present

• any limitations on daily activities

Partial asthma control

One or two of the following:

• reliever needed 3 or more times a week

• symptoms experienced 3 or more times a week

• morning or nighttime symptoms present

• any limitations on daily activities

Good asthma control

• reliever needed <2 times a week

• symptoms experienced <2 times a week

• no morning or nighttime symptoms

• no limitations on daily activities

Factors associated with increased risk of life-threatening asthma (admission history)

1 or more ICU admissions

2 or more hospital admissions in the past year

3 or more ED admissions in the past year

Hospital admission in the last month.

Factors associated with increased risk of life-threatening asthma

High SABA use

Cardiovascular disease

Sensitivity to an unavoidable allergen

No Action Plan

History of sudden acute flareups or delayed hospital presentation

Admission history (ICU, hospital, ED + recent hospitalisation)

Factors associated with an increased risk of flare-ups

Other respiratory conditions

Smoking

Eosinophilic T-helper Cell Type II inflammation

Poor asthma control

Flare-ups in the last year

Difficulty noticing reduced airflow

Socio-economic disadvantage

Mental illness

Asthma exacerbation risk factors

Triggering medications

Poor adherence

Infection

Thunderstorm

Allergen triggers

Occupational sensitisers

1st step on the Asthma treatment ladder (adults)

Low dose

• AIR , or

• ICS + SABA

2nd step on the Asthma treatment ladder (adults)

Low dose

• MART, or

• ICS/LABA + SABA

3rd step on the Asthma treatment ladder (adults)

Medium dose

• MART, or 

• ICS/LABA + SABA

4th step on the Asthma treatment ladder (adults)

Specialist involvement with

High dose

• ICS/LABA + SABA

• LAMA add-on

• Monoclonal antibody add-on

Most potent to least potent ICS

1. Fluticasone furoate (20 mcg)

2. Ciclesonide (80 mcg)

3. Beclometasone, fluticasone propionate (100 mcg)

4. Budesonide (200 mcg)

(equivalent amount to 100 mcg fluticasone propionate)

Alarmins released during asthma in response to airway epithelium damage

• IL-25

• IL-33

• TSLP (thymic stromal lymphopoietin)

Cytokines released during asthma by T helper Type 2 cells

• IL-4

• IL-5

• IL-13

These cytokines released by TH2 cells recruit and activate eosinophils, driving the inflammatory response

The steps in asthma pathophysiology

1. Airway epithelium disrupted

2. Alarmins released

3. Dendritic cells become antigen presenting cells carrying the allergen

4. Antigen presenting cells present the allergen antigens to naive T helper cells

5. T helper cells differentiate into T Helper type II cells

6. IL-4, IL-5, IL-13 is released by the TH2 cells

7. Eosinophils are recruited and inflammation occurs

8. Epithelium undergoes growth-factor-driven remodelling

9. More blood vessels and mucous, hypertrophy, narrow lumen

Asthma treatment in children 6-11 years

1st level: SABA

2nd level (most children): 

• ICS (low dose) + SABA or,

• Montelukast + SABA

3rd level (starting level for severe sx or high risk of exacerbation):

• ICS/LABA (low dose) + SABA or,

• ICS (medium dose) + SABA

4th level:

• ICS/LABA (medium dose) + SABA

5th level: Specialist involvement

Montelukast can be an add-on treatment at any level from level 2.

When to step down asthma treatment?

If patient is stable after 2-3 months and at low risk of exacerbation.

Before stepping up asthma treatment, check:

• Adherence

• Inhaler technique

• Symptoms are due to asthma and not something else

When to step up asthma treatment?

If good symptom control is not achieved despite adherence and correct inhaler technique

Montelukast dosage

15 years-adult: 10 mg once a day

6-15 years: 5 mg once a day

<6 years: 4 mg once a day

Asthma treatment levels for children 1-5 years

1st level (when symptoms are mild or infrequent): SABA

2nd level (frequent or troublesome symptoms, or history of oral corticosteroid to treat an episode in the past): 

• ICS (low dose) + SABA or,

• Montelukast + SABA

3rd level:

• ICS (medium dose) + SABA

4th level: Specialist involvement

Montelukast can be an add-on treatment at any level from level 2.

No LABA for children under 5 years.

Salbutamol and terbutaline (SABA) adverse effects

• tachycardia

• headache

• palpitations

• tremor

• hypokalaemia, hyperglycemia (high doses)

Which LAMA-only formulation is approved in asthma (and what are the requirements)?

Spiriva Respimat Tiotropium 2.5 mcg

• severe asthma not controlled with optimised treatment, inhaler technique and adherence.

• at least one severe exacerbation requiring oral corticosteroids in the last 12 months

• must be used in combination with an ICS/LABA treatment (unless LABA is contraindicated)

Which triple therapy formulations are approved in asthma (and what are the requirements)?

Trelegy (fluticasone furoate/vilanterol/umeclidinium)

Trimbow (beclometasone/formoterol/glycopyrronium)

Enerzair (mometasone/indacaterol/glycopyrronium)

Requirements for asthma:

• 18 year old+ (adults only)

• severe asthma not controlled with optimised treatment, inhaler technique and adherence.

• at least one severe exacerbation requiring oral corticosteroids in the last 12 months

LAMA adverse effects

• Dry mouth

• Throat irritation

• Blurred vision

• Dizziness

• Urinary retention

• Rarely: constipation, acute angle-closure crisis, palpitations, anaphylaxis/allergy

Which triple therapy is only indicated in COPD (and not asthma)?

Breztri (budesonide/glycopyrronium/formoterol)

Inhaled corticosteroid (ICS) side effects

• Pneumonia in COPD patients

• Dysphonia (hoarseness)

• Oral thrush

• Low bone mineral density (osteoporosis)

• Cataracts or Glaucoma (high doses)

• Skin thinning and bruising (high doses, elderly)

• Diabetes

In children:

• Adrenal insufficiency in high doses with dual use of intranasal and inhaled corticosteroids

• Growth suppression by 1.2 cm

How to step down asthma ICS therapy?

Small, gradual dose adjustments by 25-50% at 2-3 month intervals

Oral corticosteroid dosage for acute/emergency asthma flare-up

Prednisone or Prednisolone 0.5-1 mg/kg for 3-5 days or shortest time possible

Montelukast (Leukotriene receptor antagonist) side effects

Headache

Abdominal pain

Diarrhoea

Mood changes, sleeping issues

Eosinophilic granulomatosis with polyangiitis (EGPA) (Churg Strauss syndrome)

When can macrolides be used in asthma?

Low dose azithromycin can be used in severe asthma under specialist supervision for neutrophilic phenotypes.

Medications that exacerbate asthma

• NSAIDs and Aspirin

• Beta-blockers (“-lol”)

• Opioids

Asthma flare-up triggers

• Medications

• Viral or bacterial infection

• Allergen exposure

• Occupational sensitisers

• Stress

• Poor adherence

• Thunderstorms (for those with allergic rhinitis sensitised to rye grass)

Severity levels of an asthma flare up and hospital management

• Mild/Moderate: Can walk and speak whole sentences in one breath. 4-12 puffs salbutamol with spacer

• Severe: Accessory muscle use, can’t speak full sentences, oxygen saturation 90-94%. 12 puffs salbutamol with spacer. Ipratropium 8 puffs with spacer. Start oxygen if required.

• Life-threatening: Drowsiness or collapse, exhaustion, cyanosis, oxygen saturation <90%, poor respiratory effort. Salbutamol + ipratropium continuous nebulisation, start oxygen, ventilate if required.

If poor response (for any level of severity), add IV Magnesium Sulfate.

Within the first hour, start systemic corticosteroids

Asthma first aid

• Salbutamol 4 puffs every 4 minutes, 4 breaths per puff

  • Worse or no better: call 000 and continue first aid.

  • Struggling still? Give 4 more puffs. Still struggling? Then call 000 and first aid.

Repeat doses every 20 minutes (or sooner if needed) for the first hour: 3 doses in an hour

Magnesium sulfate in acute asthma contraindications

• Heart-block,

• Myasthenia gravis

• Elderly using nifedipine

• Existing hypermagnesaemia

What is exercise induced bronchoconstriction?

Acute airway narrowing that can occur as a result of exercise. Can occur in individuals with and without asthma.

Exercise-induced bronchoconstriction management

• Warm ups and cool downs

• avoiding exercise in an at-risk air environment (cold, dry, pollutants or allergens present)

Asthma medications in competitive sport

All beta-2 agonists are prohibited (Therapeutic Use Exemption (TUE) required) with exceptions for some inhaled formulations (salbutamol, salmeterol, formoterol, vilanterol) within limits

Salbutamol limits in competitive sport

Up to:

• 16 puffs (1600 mcg) in 24 hours

• 6 puffs in 8 hours

Salmeterol limit in sport

Up to 200 mcg in 24 hours

Formoterol limit in sports

Up to 54 mcg in 24 hours

Vilanterol limit in sport

Up to 25 mcg in 24 hours

Corticosteroid use in sports

• Inhaled corticosteroids (asthma) allowed

• Intranasal corticosteroids (allergic rhinitis) allowed

• Oral or IV corticosteroids prohibited during competition

Main reasons for the impact of climate change on respiratory health

• Particulate matter below 2.5 microns (PM_2.5) diameter

• Ozone O₃ increasing from greenhouse gas emissions

• Aeroallergen and pollen counts increasing with El nino activity and climate changes

These are resulting in more emergency admissions

Natural phenomena that impact asthma/COPD exacerbations

• Bushfires (increase fine particle matter PM_2.5)

• Heatwaves (hyperventilation + bronchoconstriction + inflammation)

• Thunderstorms (increase fine particle matter PM_2.5)

• Flood (increase fine particle matter PM_2.5)

• Earthquake (increase fine particle matter PM_2.5)

How heatwaves affect asthma

• Hyperventilation

• Increase allergens and moulds

• Heat shock proteins

• Pulmonary C-type nerve fibres TRPs activity and cholinergic reflex (bronchoconstriction) and cytokine production

Greenhouse gases

• Carbon dioxide

• Methane

• Nitrous oxide

• Fluorinated gases (F-gases)

CO₂ gas equivalent and GWP

The Global Warming Potential of a greenhouse gas, expressed in tonnes of CO₂ that it is equivalent to (tCO₂ -e)

Most common inhaler propellant in pMDIs

Hydrofluorocarbon (HFC)

Top 5 common detected pharmaceuticals in aquatic life in Australia

• Memantine

• Codeine

• Fluconazole

• Clotrimazole

• Mianserin

Healthcare contribution to the climate footprint

20% (one-fifth)

The role of pharmacists in sustainable healthcare

Reduce carbon emissions

Green chemistry examples

• CFC-containing inhalers deteriorate ozone

• PFAS chemicals can cause exacerbations

Aspirin induced asthma flare ups mechanism

Inhibiting COX results in upregulation of LOX, which leads to synthesis of leukotrienes that are associated with bronchoconstriction and airway inflammation.

What is cystic fibrosis?

The autosomal recessive disorder caused by mutations in the Cystic Fibrosis Transmembrane conductance Receptor (CFTR), which is an ABC transporter protein for chloride ions.

Less chloride ions are secreted, so less water is drawn into the extracellular space, so extracellular space is filled with thick, viscous, clogging mucous.

What is the most common CFTR gene mutation that causes cystic fibrosis?

DELTA 508

Folding of the CFTR is delayed, and so the cell treats it as defective and sends it to the proteasome for degradation: so a much smaller proportion of CFTR survives to be functional.

The other mutation that is common: G551D, where there is a gating defect so ATP won’t open the receptor.

Cystic fibrosis treatments

• CFTR modulators

• Antibiotics for infections

• Inhaled Corticosteroids for lung function

• Inhaled Mucolytics (dornase alpha, saline, mannitol)

CFTR modulators in cystic fibrosis

• Ivacaftor (allosteric modulator “potentiator” that keeps CFTR open even without ATP)

• Deutivacaftor

• Lumacaftor

• Tezacaftor

• Elexacaftor

• Vanzacaftor

Once daily dosing Cystic Fibrosis triple therapy

Deutivacaftor + Tezacaftor + Vanzacaftor

Current triple therapy available for Cystic Fibrosis

Ivacaftor + Tezacaftor + Elexacaftor

Ivacaftor keeps receptor open

Tezacaftor stabilises TMD1 binding site

Elexacaftor enhances the effect of Tezacaftor

What is COPD?

Chronic, lung disease where air flow limitation is not fully reversible with bronchodilators

Post-bronchodilator FEV₁/FVC less than 0.7

COPD diagnosis investigations

• Spirometry: pre- and post-bronchodilator FEV₁

• History-taking of clinical signs and symptoms

Levels in COPD management

1. SABA or SAMA prn

2. Add LAMA or LABA or both

3. Add ICS

• Consider triple therapy LAMA/LABA/ICS only if LABA/LAMA or ICS/LABA isn’t working, and in the past 12 months:

  • Hospitalisation(s) for exacerbations, or

  • At least 2 moderate exacerbations

What is COPD triple therapy

LAMA/LABA/ICS

What is COPD triple therapy requirement?

When LABA/LAMA or ICS/LABA isn’t working, and in the past 12 months:

• Hospitalisation(s) for exacerbations, or

• At least 2 moderate exacerbations

COPD lung pathology

• Emphysema

• Obstructive bronchiolitis

• Mucous hypersecretion

COPD Severity Scales - Mild COPD

Few symptoms, cough and sputum

Breathless on moderate exertion

Predicted 60-80% FEV₁

COPD Severity Scales - Moderate COPD

Breathless while walking

Limitation on activities

Chest infections

Exacerbations require antibiotics or oral corticosteroids

Predicted 40-59% FEV₁

COPD Severity Scales - Severe COPD

LESS THAN 40% predicted FEV₁

Which COPD medication is most common for daily control?

LAMAs

• Tiotropium

• Glycopyrronium

• Umeclidinium

• Aclidinium

They have a better effect on exacerbation frequency and reduced side effects compared to LABAs in COPD.

However, dual LAMA/LABA is superior to either alone.

What can indacaterol + glycopyrronium + mometasone triple therapy be used for?

Severe asthma only.

Not approved for COPD.

When to review COPD

Every 6 weeks

Mucolytics for COPD

• N-acetylcysteine (NAC)

• ambroxol

• sobrerol

• carbocysteine

• letocteine

• cithiolone

• iodinated glycerol

• N-isobutyrylcysteine (NIC)

• myrtol

• erdosteine