Lecture 19: Respiratory pharmacology

Question 1

Describe the underlying causes of asthma symptoms:

Answer 1

• Inflam infiltrate of bronchial wall i.e mononuclear cells, eosinophils
• Hypertrophied smooth muscle
• Oedema of the bronchial wall intersitium
• Mucous plugs

Question 2

What does the inflammatory profile of the bronchial wall lead to which causes asthma symptoms?

Answer 2

• Inflammation
• Hyper-reactivity
• Airway obstruction

Question 3

How many phases of asthma are there, and some notes on them:

Answer 3

Dual phase:

Immediate phase i.e allergen or non-specific stimulus activates Mast cells-> spasmogens (induces bronchospasm) and chemokines (late phase response)

Late phase: Immune cell infiltrate i.e EOSINOPHILS, TH2, monocytes etc -> All release many factors which can cause airway inflammation, airway hyper-reactivity = Bronchospasm, wheezing, coughing (side note, some factors can actually cause epi damage)

Question 4

What are some classes of bronchodilators?

Answer 4

• Beta adrenoreceptor agonists
• Methylxanthines
• Muscunaric antagonists
• Leukotriene antagonists

Question 5

What causes smooth muscle contraction in the lung?

Answer 5

Acetylcholine
Adenosine
Leukotriene (i.e leukotriene antagonist)

Question 6

Write some notes on beta 2 agonists?

Answer 6

• They are agonists for the beta 2 receptors but function physiologically as an antagonist for contraction
• Activate cAMP dependant pathway which inhibits SM contraction (PKA)

i.e Salbuamol (SABA) Salmeterol (LABA)

Question 7

Compare SABA and LABA:

Answer 7

• SABA have fast onset but short duration of action
• LABA generally slower onset but long lasting

This difference is primarily due to lipid solubility i.e structurally long side chains increase solubility

Question 8

Describe in relation to the receptors where the beta agonists function:

Answer 8

SABA act on the EC surface of the receptor

LABA diffuse into the lipid bilayer and act on the sides of the receptor (long acting pathway)

Formoterol does a combo..

Question 9

What are the potential side effects of beta agonists?

Answer 9

Side effects are associated with system absoprtion

• Tremor
• Tachycardia (due to lack of selectivity i.e fenoterol)

Question 10

What are the methylxanthines? and how do they work?

Answer 10

Likely combo of effects:

• PDE inhibitor of smooth muscle and inflam cells (breaksdown cAMP which is inhibiting contraction via PKA)
• Possibly adenosine antagonist…

Question 11

What are some methylxanthines?

Answer 11

Theophylline

Aminophylline

Question 12

How do muscarinic antagonists function? and some examples

Answer 12

• Some inhibition of bronchoconstriction
• Inhibit mucous secretion
• No effect on inflam phase

i.e Ipratropium (SA) (POORLY absorbed), tiotropium (LA)

Question 13

What do glucocorticoids target?

Answer 13

The immune system

Question 14

What are some examples of glucocorticoids and what there effects are? and their side effects?

Answer 14

Budesonide, fluticasone

• Often in combo with LABA
• Side effects: Oropharyngeal candidiasis and sore throat
• Inhibits IgE production and mast cell/ eosinophil activation

Question 15

How do glucocorticoids work?

Answer 15

• Diffuse through membrane and can act via:
• Transactivation of GR receptor = GRE, increase Anti-inflam production
• Cis-repression of GR receptor = Side effects…
• Trans-repression of GR receptor = Decrease inflammation

Question 16

Describe the asthma interventions and where they target in the dual phase of asthma:

Answer 16

Immediate phase bronchospasm reversed by: Beta 2 agonists, Leukotriene antagonists, methylxanthines

Late phase and early phase is inhibited by glucocorticoids

Question 17

Describe the order of asthma treatments:

Answer 17

1. SABA i.e salbutamol
2. inhaled corticosteroids i.e beclometasone
3. LABA i.e slameterol
4. Methlxanthines i.e theophylline
5. Muscunaric anatagonists (LAMA)
6. Leukotriene antagonist i.e montelukast

Question 18

What are ICS and LABA recomended?

Answer 18

• To relieve when required
• Maintaince continually

But asthma treatment is a continuum and treatment follows accordingly

Question 19

Where do biologics fit in to asthma treatment?

Answer 19

Approx 5% patients dont respond to traditional treatments so biologics are used to target specific chemokines using antibody based therapy…

Can reduce need for corticosteroids

Question 20

What can biologics target in asthma?

Answer 20

• Allergen receptors
• Specific interleukins to prevent immune cell activation
• Antibodies

Question 21

What is COPD?

Answer 21

• Group of related disorders
• Underlying chronic airway inflammation
• Fibrosis of small airways, obstruction/destruction of alveoli and elastin fibres in parenchyma
• Not fully reversible

Question 22

What is COPD treatment?

Answer 22

• STOP Smoking
• Limited pharmacological treatments available
• Bronchodilators can provide some symptomatic relief, but not great
• Glucocorticoids do have small impact on quality of life, but do not slow disease progression
• OXYGEN therapy

Question 23

Why are glucocorticoids not that great?

Answer 23

A lot of COPD is related to smoking, and smoking decreases Histone Deacylation enzymes which ultimately means there are less targets for glucocortiocoids to work and change gene transcription

Question 24

How are macrolides used in COPD?

Answer 24

• They have antibacterial action via inhibition of protein synthesis usually but also immunomodulatory action at lower doses
• Mixed opinions
• I.e erythromycin

In essence used to decrease severity of COPD caused by the immune system

Question 25

Do we want to treat coughs? What is the purpose?

Answer 25

• Cough: Protective response to foreign particles or mucous secretions
• Useful vs useless cough i.e we want to treat the useless one

Question 26

What can be used to treat the useless coughs:

Answer 26

Antitussive agents

• Demulcents ile lozenges (wets back of throat in dry cough)
• Opiods i.e codiene, dextromethorphan (dirty, has side effects)
• Mucolytics (thins mucus) i.e carbocistiene