Pharmacology of Asthma

Question 1

Asthma is characterised by what features?

Answer 1

Mucosal oedema, bronchoconstriction, mucus plugging

= Overall obstruction of bronchioles

Question 2

Asthma pathophysiology is driven by which cells of the immune system?

Which Ig?

Answer 2

Eosinophils

Th2 Cells

IgE antibodies- activate mast cells

Question 3

What is the consequence of the inflammation that occurs in response to triggers in asthmatic patients?

Answer 3

Bronchial hyperrespnsiveness and remodelling

Question 4

How can the features if asthma be targeted by certain drugs?

Give examples of each

Answer 4

Smooth muscle contraction:

Relax: Short acting beta-agonist e.g. Salbutamol
Long acting beta-agonist e.g. Formoterol

Inflammation (immune response):

Dampen immune response: Steroids
Inhaled e.g. Budesonide
Oral e.g. Prednisolone

Question 5

Describe some of the desired features of “controlled” asthma

Answer 5

Minimal symptoms during day and night

Minimal need for reliever medication

No exacerbations

No limitation of physical activity

Normal lung function (FEV1 and or PEF >80% of predicted)

Question 6

What things should be done before initiating a new drug therapy for asthma?

Answer 6

Check compliance with existing techniques

Check inhaler technique

Eliminate trigger factors

Question 7

Following a diagnosis of asthma, what are the 5 steps involved in the evaluation stage of management?

Answer 7

Step 1- Infrequent, short-lived wheeze

Step 2- Low dose ICS

Step 3a- Initial add-on therapy
+LABA

Step 3b- Additional add-ons
STOP LABA
+ Increased ICS dose
or
continue LABA + medium dose ICS

Step 4- High dose therapy
High dose ICS
Addition of 4th drug
Refer to specialist

Step 5- Continuous or frequent use of oral steroids
+Daily steroid tablet
Maintain high dose ICS
Consider other treatments

SABA throughout all as a reliever, consider moving up a step if using three doses or more a week

Question 8

What is the predominant action of beta2-agonists?

What other effect may these have in the short and long term?

Answer 8

Relaxation of airway smooth muscle

Short term: inhibit mast cell degranulation

Long term: mast cell degranulation in response to allergen increases

Question 9

Describe the cellular events that take place once a beta2-agonist binds to beta2 adrenoceptors

Answer 9

Bind to beta2 adrenoceptor (G alpha S)

(remember: QISS QIQ)

Stimulates Adenylyl cyclase, increased cAMP, activation of PKA

Decreases Ca2+

Bronchodilation

Question 10

Salmeterol has a ______ and ______ duration

Answer 10

Slow

Long

Question 11

List some of the side effects of beta2 agonists

Answer 11

Adrenergic side effects: tachycardia, palpitations, tremor

Question 12

What are the molecular actions of inhaled steroids?

Answer 12

Increased GR translocation

Increased GRE binding

Increased anti- inflammatory effects

Question 13

Explain how ICSs are absorbed systemically and the clinical relevance of this

Answer 13

Inhaled: 1)Deposited in lungs
2)Swallowed fraction

1) Absorbed from lungs into systemic circulation
2) Absorbed from gut into GI tract: active drug to systemic circulation and some is inactivated by first pass metabolism

Question 14

Patients with ________ asthma have a better treatment response to ICS thN non-__________ patients

Answer 14

eosinophilic

Question 15

ICSs have a flat dose-response curve.

What is the relevance of this clinically in relation to dosing?

Answer 15

The maximum efficacy will usually be at lower doses, don’t increase the dose but add a LABA if ICS not controlling their symptoms

Question 17

What size of inhaled particle is the most effective in the treatment asthma? Why?

Answer 17

1-5 microns

They settle in the small airways

(10microns too big- are deposited in the mouth and oropharynx

0.5 microns too small- inhaled to alveoli and exhaled without deposition in the lungs)

Question 18

Name the 4 features which each individually would classify an adult as having ACUTE SEVERE asthma

Answer 18

1. Unable to complete sentences
2. Pulse > 110 bpm
3. Respiration >25 breaths pm
4. Peak flow 33-50% of best or predicted

Question 19

Give examples of some of the additional features (apart from the 4 features that can independently define acute severe asthma) that are classed as life threatening

Answer 19

PEF <33%

sPO2 <92%

PaO2< 8 kPa

PaCO2> 4.5 kPa

Silent chest

Cyanosis

Feeble respiratory effort

Confusion, coma

Question 20

Which value of PaCo2 is classed as near fatal and would require mechanical ventilation?

Answer 20

>6 kPa

Question 21

How is acute severe asthma treated?

Answer 21

1. Oxygen, high flow- aiming for 94-98% sat
2. Nebulised salbutamol- continuous if necessary
3. Oral prednisolone
4. • Nebulised ipratropium bromide if not responding to above
5. Consider IV aminophylline if not responding still BEWARE IF TAKING ORAL THEOPHYLLINE