Pharmacology: Pharmacology of airway control

Question 1

What is the pathophysiology of asthma?

Answer 1

Restricted airway flow via
1. Mucosal oedema
2. Bronchoconstriction due to bronchospasm
3. Mucus plugging
Eventually leads to airway remodelling and bronchial hyperresponsiveness

Question 2

What are the main classes of drugs used to treat asthma?

Give examples

Answer 2

• B2 agonists to target smooth muscle (salbutamol, salmeterol)
• steroids to reduce inflammation (inhaled budesonide, oral prednisolone)

Question 3

Asthma is treated in a stepwise approach, what is classed as good asthma control?

Answer 3

• minimal symptoms
• minimal need for reliever medication
• no exacerbations
• no limitation of physical activity
• normal lung function

Question 4

What is a ‘step 1’ asthmatic patient?

Answer 4

A person with mild intermittent asthma

Managed with short acting B2 antagonist on an as-required basis, if used regularly they should step up

Question 5

What is the effect of B2 agonists?

Answer 5

Predominant action is inhibition of bronchoconstriction on airway smooth muscle
If used intermittently can inhibit mast cell degranulation but on regular use can actually increase mast cell degranulation

Question 6

What is the intracellular mechanism of action of B2 agonists?

Answer 6

Bind to B2 adrenoreceptor which is a GPCR
Gs protein dissociates and activates adenyl cyclase which causes increased cAMP which activates protein kinase A and inhibits myosin light chain kinase, this promotes relaxation and inhibits contraction

Question 7

What are the side effects of B2 agonists?

Answer 7

Predictable due to adrenergic effects

- tachycardia, palpitations, tremor

Question 8

What are the guidelines to step up to an inhaled corticosteroid?

Answer 8

Per week:

• using B2 agonist 3 times or more
• symptoms 3x
• nocturnal waking at least once a week (sign of poorly controlled asthma)
• consider if exacerbation in last 2 years requiring oral steroids

Question 9

What are the benefits of inhaled corticosteroids?

Answer 9

• improve symptoms
• improve lung function
• reduce exacerbations
• prevent death

Question 10

What is the molecular action of steroids?

Answer 10

Pass through membrane and bind to IC receptor
Steroid-receptor complex enters nucleus and binds to DNA
1. Transactivation: increases activation of anti-inflammatory proteins, upregulates B receptors
2. Transpression: prevents translation of the pro-inflammatory proteins

Question 11

How do inhaled drugs enter the systemic circulation?

Answer 11

Can enter the systemic circulation from the lungs
Some can be swallowed and metabolised through the liver.
At high doses drugs such as bleclomethasone and fluticasone can cause systemic side effects

Question 12

Which asthmatic patients respond better to oral inhaled steroids?

Answer 12

Eosinophilic asthma

Question 13

What checks need to be done before initiating a new drug treatment eg stepping up?

Answer 13

• check patients compliance
• check inhaler technique
• eliminate triggers

Question 14

List the classes of medications used for asthma in order

Answer 14

Give first: SABA eg salbutamol, terbutaline
Oral inhaled steroid (dose not increased as next step as majority of actions is at low doses)
LABA eg salmeterol, formoterol (must always be prescribed with a steroid because they are not anti-inflammatory)

Question 15

Why are LABA and inhaled corticosteroid steroids combined in one inhaler?

Answer 15

• simpler for patients
• compliance
• only 1 prescription to organise
• potentially cheaper
• SAFETY, cannot take LABA without steroid which would be DANGEROUS

Question 16

What are the options for stepping up from level 3 (LABA)?

Answer 16

• higher dose of inhaled corticosteroid
• leukotriene receptor antagonists
• theophylline
• tiotropium

Question 17

How do leukotriene receptor antagonists work?

How effective are they?

Answer 17

Leukotriene is released by mast cells and eosinophils and induces bronchoconstriction, mucus secretion and mucosal oedema. LRAs block the activity via blocking the receptor.
Effective in 15% of asthma patients - inhaled steroids much more effective

Question 18

What are the side effects and drug interactions of leukotriene receptor antagonists?

Answer 18

Side effects rarely a problem in clinical practice but can get angioedema, dry mouth, anaphylaxis, arthralgia, fever, gastric symptoms, nightmares.
There are no important drug interactions.

Question 19

What are methylxanthines, how do they work? Name some examples

Answer 19

Adenosine receptor antagonists - logically reduce cAMP due to low adenosine
eg theophylline, aminophylline

Question 20

What are the side effects and drug interactions of methylxanthines?

Answer 20

Side effects common - nausea, reflux, headache
Narrow therapeutic window so need to be careful, can have life-threatening complications eg arrhythmias and fits
Increased by cytochrome p450 so need to be careful with polypharmacy

Question 21

When are long acting anticholinergics used?

Answer 21

Licensed for severe asthma - level 4/5 (and COPD)

Question 22

Name a LAMA and outline the mechanism of action

What are the side effects?

Answer 22

Tiotropim bromide - Relatively selective for M3
Reduces rate of asthma and COPD exacerbations
Side effects: dry mouth, urinary retention, glaucoma

Question 23

How are step 5 asthmatics treated?

Answer 23

• oral steroids effective, usually need ~10mg od
• now more biological therapies available such as anti-IgE which prevents activation of mast cells (steroid sparing)
• Anti-IL5, prevents eosinophils growth, migration, activation. Reduce rate of asthma exacerbations(allow steroid tapering eg lowering dose)

Question 24

What are self-management plans for asthma?

Answer 24

Every patient should have an asthma action plan.
Gives advise (usually based on peak flow) which inhalers to use, when to start oral steroids etc
Leads to better disease control and outcome

Question 25

Which size particles deposit where when inhaled?

Which size particle is optimum?

Answer 25

Large particles (10um) deposit in mouth and oropharynx 
Medium particles (1-5um) are most effective as they settle in the small airways
Small particles (0.5um) are too small, they are inhaled and exhaled from the alveoli without being deposited

Question 26

What is defined as a severe exacerbation?

Answer 26

Need one of the following features:

1. Unable to complete sentences
2. Pulse greater than 110bpm
3. RR greater than 25/m
4. Peak flow 50% of predicted

Question 27

What features make an asthma exacerbation life threatening?

Answer 27

PEF 1/3 of predicted 
O2 sats <92%
pO2 <8%
pCO2 >4.5kPa (should be blowing it off)
Silent chest 
Cyanosis 
Feeble effort
Hypotension, bradycardia, arrhythmia 
Exhaustion, confusion, coma

Question 28

How are acute exacerbations treated?

Answer 28

• Give high flow oxygen to get sats to 94%
• Nebulised salbutamol
• Oral prednisolone as soon as possible
• If unaffective add nebulised atrovent
• IV aminophylline

Question 29

How does atrovent work?

Answer 29

Anticholinergic

Develops slow bronchodilation, so useful add on in exacerbations where therapy is not working