L15. Drugs Affecting Airway Structure and Function 2

Question 1

What is a a glucocorticosteroid?

Answer 1

Is a synthetically derived cortisol that acts as in many different pathways an anti-inflammatory mediator.

Question 2

What are the main aims of using glucocorticosteriods in asthma? [4]

Answer 2

1. Reduce production and persistence of eosinophil and T cell populations
2. Reduce mast cell activation (don’t affect mast cell degranulation)
3. Reduce cytokine production that facilitate the inflammatory environment (eg. IL-1, TNFalpha and IL-5 suppression). They don’t suppress IL-4
4. Reduce proliferation of SMCs, fibroblasts and epithelial cells which are a major source of inflammatory cytokines

Question 3

What is the overall effect of glucocorticosteroid use in asthma? [2]

Answer 3

1. Reduce the inflammatory cell numbers and activation

2. Reduce the probability and severity of asthma episodes

Question 4

Through what process does glucocorticosteroid act to decrease inflammation?

Answer 4

By transactivation and transrepression of anti-inflammatory and pro-inflammatory mediators and cytokines (respectively). They act to affect transcriptional events.

Question 5

How does the glucocorticosteroid enter the cell to cause its effects on the genome: transactivation and transrepression in the nucleus

Answer 5

It crosses the cell membrane (lipid soluble steroid), interacts with its cytosolic receptor (which dissociates its chaperone molecules) and translocates into the nucleus.

MONOMERIC form recruits histone deactylase-2 and chromatin which repacks the DNA of pro-inflammatory promotor regions. This prevents the NFkB promotor and polymerase action.

Receptor:Ligand complexes DIMERISE in the nucleus. These bind to promotor regions of anti-inflammatory genes causing their expression (upregulation).

Question 6

What is the normal process of the NFkB cytokine pathway?

Answer 6

Cytokine binding to the ligand increases the i kappa kinase (IKK) which phosphorlyates Inhibitor KappaBalpha (iKBa).
This phosphorylation causes ubiquitination which marks it for degradation.
This allows NFkB to dissociate from it to translocate to the nucleus and act
It binds to the kBRE promotor regions which upregulates proinflammatory genes

Question 7

What is the normal process of the AP-1 cytokine pathway?

Answer 7

Cytokine binding to the receptor causes phosphorylation of the Junk Kinase (JNK).
This activated kinase phosphorylates Jun
JunK forms a complex with itself or with Fos called AP-1
The AP1 translocates to the nucleus where it binds to TRE promotor regions
Upregulation of the expression of proinflammatory genes

Question 8

What are the three consequences of transactivation? - binding to positive GREs

Answer 8

1. Glucocorticoid-induced Leucine Zipper (GILZ)
2. MAPK Phosphatase-1 (MPK-1)
3. Inhibitor of the kBa (iKBa)

Question 9

Describe the pathways of GILZ, MKP-1 and iKBa

Answer 9

ANTI-INFLAMMATORY

iKBa:
Increases the binding to NFkB and prevents dissociation from it and its subsequent actions

GILZ:
Binds to NFkB and inhibits its translocation and action

MKP-1:
Prevents the phosphorylation of JNK

Question 10

Explain how glucocorticoid binding to negative GRE sites leads to broad anti-inflammatory effects. Give some examples of the repressed factors

Answer 10

TRANSREPRESSION:
The monomer binds to the histone deactylase-2 enzyme which is able to repack the chromatin around promotor regions.

Inhibits expression of: ITAM, COX-2, IL-8 and NOS2

Question 11

When are glucocorticosteroids used in asthma?

Answer 11

MILD PERSISTENT ASTHMA

When a person requires a B2-agonist for relief more than 3 times a week as a preventer medication.

Question 12

Give some examples of topical/inhaled glucocorticosteroids

Answer 12

Beclomethaosone diproprionate
Budesonide***
Flucticasone proprionate***
Momtasone 
Ciclosenide 

*** often used in combination with B2-agonists (LABA)

Question 13

What is important in starting a patient on inhaled GCS? Why is this so?

Answer 13

Must start at the effective dose and then step DOWN because the onset (and offset) of action is protracted.

Question 14

What are the adverse effects of inhaled glucocorticosteroids?

Answer 14

Inhaled glucocorticosteroids are generally well tolerated.

Dysphonia, Oral candidiasis, decreased serum cortisol (not clinically relevant by biochemically testable).
- oral mouthwash generally reduces the burden of this

Question 15

What is the major example of a systemic/oral GCS?

Answer 15

Prednisolone

Question 16

When are oral glucocorticosteroids used in asthma? [2]

Answer 16

Short term (2) days for acute exacerbations of asthma with large inflammation

Chronically as control drugs for severe asthma for the high ceiling effect of anti-inflammation (not commonly used due to the high risk of side effects)

Question 17

What are the adverse effects of oral glucocorticosteroids?

Answer 17

Dose and indication-limiting side effects

Osteoporosis, diabetes, muscle wasting, hypertension, growth suppression, suppression of the adrenal/pituitary/hypothalamus axis (adrenal crisis)

Question 18

Why is it important to wean people off glucocorticosteroid usage?

Answer 18

Because of the effects it has on the feedback loops of the CNS which synthesise and release endogenous cortisol.

Normally levels of hormone negatively feedbacks on the systems that lead to a decrease in the production of cortisol and ATCH. Chronic use of GCS leads to failure of the trophic hormones and adrenal gland atrophy.

Sudden cessation of the exogenous GCS without adequate time for the adrenal glands to recover leads to adrenal crisis.

Question 19

What other drugs are used in chronic respiratory diseases? [2] What are their major mechanisms and adverse effects?

Answer 19

1. Methylaxanthines: Thelophyline
PDE inhibition
Adensoine receptor antagonism
HDAC2 inhibition
But has a low therapeutic window: dose-limiting side effects: nausea, vomiting, diarrhoea, CNS stimulation, cardiostimulation (dysrhythmia)

2. Phosphodiesterase inhibitors: Roflumilast
   Smooth Muscle relaxation
   Currently approved for COPD usage

Question 20

What combinations of agents are used for the different severities of asthma? [5]

Answer 20

1. Mild - inhaled SABA
2. Mild persistent - + inhaled GCS
3. Moderate persistent - + inhaled LABA
4. Severe Persistent - + Increased daily GCS, maintained daily LABA (plus theophyline + oral GCS when needed)
5. Severe deteriorating - + oral prednisolone

Question 21

What are the characteristics of COPD, what makes it distinct from asthma (cells, mediators and effects)?

Answer 21

It is a chronic obstructive disease with a difference character of inflammation (macrophage mediated) with airway remodelling that involves fibrosis and is thus irreversible. Progressively deteriorating

Cells: neutrophils, CD8 T cells and macrophages
Mediators: LTB4, IL8, TNFalpha, ROS
Effects: Peripheral airways with fibrosis and squamous metaplasia

Question 22

What treatment is used for COPD?

Answer 22

1. B2 agonists
2. GCS
   Despite not having as effectiveness as they do with asthma but the rationale is to “give what is available”

Question 23

What are some of the major risk factors for COPD development

Answer 23

SMOKING

Age, gender, Respiratory infections, asthma and bronchial hypersensitivity, exposure to particles, genes

Question 24

Why don’t glucocorticosteroids work as well in COPD as they do in asthma?

Answer 24

The inflammatory process is different: inflammatory cell polymorphs involved in COPD are not inherently susceptible to GCS like eosinophils and mast cells are.

Question 25

Why don’t bronchodilators work as well in COPD as they do in asthma?

Answer 25

Only a small proportion of the obstructive airflow is due to bronchoconstriction. They are only used for symptomatic treatment.