Treatment of Asthma and COPD

Question 1

What are the primary routes of administration of drugs in asthma ? What are the pros or cons of these methods ?

Answer 1

♦ Primarily inhalation of aerosol or dry powder: rapid + reduced systemic side effects (Particle size important)
♦ Oral/injectable

Question 2

What are the major groups of drugs in asthma ?

Answer 2

Bronchodilators (relievers)
Anti-inflammatory drugs (preventers)

Question 3

What are the main inhaler devices used in asthma ?

Answer 3

♦ MDI (metered dose inhaler)
♦ Breath-actuated (e.g. autoinhaler, easibreathe), especially for patients who cannot manage MDI
♦ Accuhaler - dry powder
♦ Via spacer/aerochamber (for patients with coordination problems)

Question 4

What is a common side effect of inhalers ? How can we prevent this ?

Answer 4

-Systemic side effects, because 90% usually swallowed and absorbed form gut.
-Using a spacer or rinsing one’s mouth helps with this

Question 5

How do spacer inhalers work ?

Answer 5

-Large particles of aerosol are deposited in the chamber before the patient inhales. Inhaled aerosol is enriched
-Inhaled aerosol is enriched with small particles that more readily travel to the small airways

Question 6

How do nebulisers work ? When are they used

Answer 6

-Drug (usually reliever, may be antibiotic) broken down into fine mist using oxygen or air
-Used in acute asthma attacks

Question 7

Identify the main drugs to treat and prevent asthma.

Answer 7

1) B2 receptor agonists
• SABA- salbutamol
• LABA- salmeterol

2) Glucocorticoids
• beclometasone, budesonide

3) Cysteinyl leukotriene antagonist (LTRA)
• montelukast

4) Methylxanthines
• theophylline and derivatives

5) Monoclonal antibodies (anti-IgE treatment)
• Omalizumab

6) Muscarinic receptor antagonists (seldom used)
• Ipratropium

Question 8

Describe stepwise pharmacological treatment of asthma.

Answer 8

Anytime need to use SABA three times a week or more, consider moving up.

→ FIRST LINE (intermittent asthma): Short acting beta agonists (stimulate B2, bronchodilate)

→ Step 2: If patient needs to use inhaler frequently: ICS (inhaled corticosteroids) + SABA for exacerbations

→ Step 3: Initial add-on therapy:
inhaled LABA + low dose ICS + SABA for exacerbations
→ No response to LABA:
Higher dose ICS + SABA for exacerbations
Yes response to LABA but still inadequate control:
inhaled LABA + medium dose ICS + SABA for exacerbations

→ Step 4: Still inadequate control:
Higher dose ICS + inhaled LABA + SABA for exacerbations + methylxanthine/LTRA

→ Step 5: Still inadequate control:
Daily steroid tablets + high dose ICS + other treatment to minimise use of steroid tablets+ refer to specialist care

Move down steps if possible to find and maintain lowest controlling step.

Question 9

What is the mechanism of action of beta 2 receptor agonists ? What are their side effects ?

Answer 9

MECHANISM OF ACTION
-Stimulate bronchial smooth muscle beta 2 receptors, relax muscles, dilates airways, reducing breathlessness
-Inhibits mediator release from mast cells and infiltrating leucocytes (i.e. anti-inflammatory?)
-Increases ciliary action of airways epithelial cells - aid mucus clearance

SIDE EFFECTS (if given orally, IV, or high dose inhaled)
-Sympathomimetic effects (e.g. hypertension, excessive cardiac stimulation and cardiac arrhythmias)
-Electrolyte disturbances (e.g. Potassium reduction)
-Hyperglycaemia
-Paradoxical bronchospasm

Question 10

When muscarinic receptor antagonists are used in the treatment of asthma (which is seldom), what is their mechanism of action ?

Answer 10

Inhibit muscarinic receptors in the lungs
Bronchodilators

Question 11

What is the mechanism of action of glucocorticoids ? What are the main side effects of glucocorticoids ?

Answer 11

MECHANISM OF ACTION (anti-inflammatory, i.e. preventers)
-Inhibit formation of cytokines (by Th2 cells)
-Inhibit activation and recruitment to airways of other inflammatory cells (e.g. eosinophils, mast cells)
-Inhibit generation of inflammatory prostaglandins and leukotrienes, thereby reducing mucosal oedema

SIDE EFFECTS
-Systemic effects, especially if chronic high dose inhalation, or IV or oral (osteoporosis, growth retardation, adrenal insufficiency)
-Dysphonia (hoarseness)
-Oropharyngeal candidiasis
-High doses may increase risk of pneumonia

Question 12

Describe the onset and timeline of the effects of inhaled corticosteroids, and explain the effect of this on adherence.

Answer 12

ICSs have slow onset and longer term effects (i.e. months) which include reduction in airway responsiveness to allergens and irritants including exercise.
-This often means adherence to ICSs can be poor as no effects can be seen in the short term.

Question 13

How are glucocorticoids administered ? Give examples of glucocorticoids for the different routes.

Answer 13

Usual route:
-INHALED (e.g. beclomethasone, budesonide)

In acute severe attacks:
-ORAL (e.g. prednisolone)
or
-IV (e.g. hydrocortisone)

Question 14

Describe the mechanism of action of leukotriene receptor antagonists (i.e. LTRA i.e. Lukasts). Also describe their main side effects.

Answer 14

MECHANISM OF ACTION (asthma prophylaxis)
-Block effects of bronchoconstrricting cysteinyl leukotrienes (specifically CysLT1) in the airways, resulting in bronchodilation
-Reduce eosinophil recruitment to the airways, thereby reducing inflammation, epithelial damage, and airway hyper-reactivity
♣ This results in ↓ exercise-induced asthma (and atopic asthma), ↓ both early and late phase bronchoconstrictor responses to allergens

SIDE EFFECTS
-Abdominal pain
-Headache
-Hyperkinesia in children (i.e. increase in muscular activity that can result in excessive movements)

Question 15

Which step in the stepwise treatment of asthma should LTRAs be incorporated in ?

Answer 15

Step 3 or 4

Question 16

How are LTRAs administered ? Give examples of 2 LTRAs.

Answer 16

Oral administration for LTRAs
e.g. Montelukast tablets

Question 17

Describe the mechanism of action of methylxanthines. Describe their side effects.

Answer 17

MECHANISM OF ACTION
♫ Inhibits (non-specifically) phosphodiesterase (PDE)
-Results in increased intracellular cAMP in bronchial smooth result resulting in relaxation (i.e. bronchodilation)
-Anti-inflammatory actions (since PDE also involved with inflammatory cells)

♫ Inhibits adenosine receptor
-Results in bronchodilation

SIDE EFFECTS (dose-related!)
-GI upset
-Arrhythmias
-CNS stimulation
-Hypotension
Narrow therapeutic index!

Question 18

Give 2 examples of methylxanthines.

Answer 18

Theophylline, Aminophylline

Question 19

When are monoclonal antibodies used in the treatment of asthma ?

Answer 19

Monoclonal antibodies are used in the treatment of severe persistent allergic asthma

Question 20

Give an example of monoclonal antibody and state its mechanism of action.

Answer 20

Omalizumab- antibody to IgE, inhibits mediator release from basophils and mast cells (i.e. preventer)

Question 21

Identify the administration route, and onset of effects of monoclonal antibodies in asthma. Name any major cons to using monoclonal antibodies.

Answer 21

-Monoclonal antibodies (i.e. MABS) are injected
-Onset is slow (peaks at 3 to 4 months)
-EXPENSIVE

Question 22

Describe the NICE guidelines for stepwise asthma treatment.

Answer 22

Step 1: SABA
Step 2: SABA + low dose ICS
Step 3: SABA + low dose ICS + LTRA
Step 4: SABA + ICS + LABA +/- LTRA
Step 5: Trial of additional drugs

Question 23

How is asthma evolution monitored during long term treatment ?

Answer 23

Using peak expiratory flow rate:
-In untreated asthma, low peak flow rate (if <50% predicted, severe asthma) + large nocturnal dip present (i.e. reading lower in the morning)
-In treated asthma, diurnal variation is reduced and peak flow rate increases

Question 24

Describe management of acute severe asthma.

Answer 24

1) Immediate treatment (adults):
-Oxygen (to maintain spO2 at 94-98% range)
-Salbutamol or terbutaline + ipratropium via nebuliser
-IV steroids (hydrocortisone) then eventually oral steroids (prednisolone)
-+ or - antibiotics

2) If patient still not improving, consider (in high dependency unit):
-IV magnesium sulphate
-switch from nebulised to IV salbutamol or aminophylline

Acronym SOS I AM.
→ In the meantime, monitor blood gases and patient exhaustion/alertness

Question 25

Identify the main guidelines followed for COPD treatment.

Answer 25

GOLD (global initiative for COPD)
NICE Guidelines

Question 26

Describe management and treatment of COPD.

Answer 26

1) Smoking Cessation: offer support, psychological + nicotine replacement
2) Early use of long acting bronchodilators (modest responses only)
3) ICS (dependant on FEV1 and response to ICS
4) Musarinic Receptor antagonists
5) Immunisation: Pneumovax and Flu vax

6) Methylxanthines (theophylline, aminophyllines)
7) Mucolytics (carbocysteine)- reduces sputum viscosity if productive cough
8) PDE type 4 inhibitor (Roflumilast)- if severe COPD with repeated exacerbations
9) Long term antibiotics (azithromycin)
10) Assessment of co-morbidities (IHD/HF)

Question 27

Describe mechanism of action, and side effects of muscarinic receptor antagonists in COPD.

Answer 27

MECHANISM OF ACTION
-Causes bronchodilation, decreased mucous secretion, may increase mucocilliary clearance
Overall, improves outcomes of CODP and reduces exacerbations

SIDE EFFECTS (uncommon)
Constipation
Dry mouth
Cough
Nausea
Urinary retention
May worsen angle closure glaucoma (so use moutpiece rather than mask to administer)

Question 28

Describe the onset, timeline, and limitations of muscarinic receptor antagonists in the treatment of COPD.

Answer 28

-Onset: Slow (30-60 minutes) cf beta agonists
-Timeline: Both short and long-acting version
-Limitation: not effective against allergen challenge

Question 29

Give an example of both short, and long acting muscarinic receptor antagonist. How selective is each of these drugs for a specific receptor ?

Answer 29

SAMA- Ipratropium (acute- nebulised route), non-selective

LAMA- tiotropium, more selective for M3 receptor

Question 30

Describe the mechanism of action of ICSs in COPD.

Answer 30

-Limited benefit
-Inflammatory cells responsible for COPD (macrophages and neutrophils) less responsive than lymphocytes and eosinophils to the actions of corticosteroids.
-Use ICSs in COPD if FEV1<50% predicted and at least two exacerbations in a year which require antibiotics or oral steroids

Question 31

Which treatment should be given alongside ICSs to make up for risk of osteoporosis ?

Answer 31

Biphosphonates (if ICS given at high dose)

Question 32

Describe pharmacological treatment of stable COPD.

Answer 32

DRUGS
1) If only breathlessness and exercise limitation: SABA or SAMA as required

2) Exacerbations of breathlessness, if FEV1 > 50% : LABA or LAMA (if LAMA, discontinue SAMA)
Exacerbations of persistent breathlessness, if FEV1 < 50%: LABA + ICS in combination inhaler (if ICS not well tolerated, LABA + LAMA) OR LAMA (if LAMA, discontinue
SAMA)

3) Persistent exacerbations of breathlessness: LAMA + LABA + ICS in a combination inhaler

SABAs may be given at any stage as required

DOMICILIARY OXYGEN THERAPY ± NON-INVASIVE POSITIVE PRESSURE VENTILATION (latter if exacerbations of COPD)

Question 33

How is COPD evolution monitored during long term treatment ?

Answer 33

• Primarily based on patient symptoms, ADL, exercise capacity, speed of symptom relief with SABA
• Changes in lung function- spirometry
• Risk of exacerbation (two exacerbations or more within the past year or FEV1 < 50% predicted are indicators of high risk)

Question 34

Describe management of acute severe COPD exacerbations.

Answer 34

• Nebulise SABA and SAMA + oral prednisolone + antibiotic if infected
• Physio (to help break up sputum)
• 24-28% Oxygen (watch PaCO2/PaO2)
• If extreme = Non-invasive ventilation (NIV), Intubation

Question 35

Describe asthma-COPD overload syndrome (ACOD).

Answer 35

• Patients respond better to ICS at reducing exacerbation rate (COPD component) but also good reversibility with SABA (asthma component)
• Difficult to distinguish from asthmatic smokers who have airway remodeling (i.e. reduced FVC)