PH2113 - Asthma 3 Flashcards
Give examples of preventer medication used to treat asthma
- corticosteroids
- cysteinyl leukotriene receptor antagonists
- chromones
- cromoglycate
- nedocromil
- biologics
- vaccination
What is the function of corticosteroids, cysteinyl leukotriene receptor antagonists, chromones and biologics to prevent asthma attacks?
Anti-inflammatories
- limit remodelling
- limit disease progression
- reduce severity and frequency of attacks
How do corticosteroids work as an asthma treatment?
Decrease rate of pro-inflammatory gene products
- COX-2
- iNOS
Increase rate of anti-inflammatory gene products
- IL-10
Do inhaled corticosteroids have lots of side effects and what are they ?
Corticosteroids are the mainstay of preventer treatment. Taken by inhalation, topical delivery to the lung abrogates much of the serious side-effects associated with taken these drugs orally. Unless patients are on high doses of inhaled corticosteroids, the worse side-effect they are likely to suffer from is a sore throat due to localised immune suppression. This can easily be avoided by rinsing the mouth out after taking the corticosteroid inhaler.
What is the benefit of corticosteroids being hydrophobic?
they can diffuse across the plasma membrane to access glucorticoid receptors inside the cell.
Why do corticosteroids need to be used regularly to become effective?
It takes time to transcribe genes and produce proteins
What is the mechanism of action for inhaled corticosteroids ?
The receptor for glucocorticoids is an intracellular receptor. Glucocorticoids are hydrophobic in nature so can diffuse across the plasma membrane to access glucorticoid receptors inside the cell. Once bound with glucocorticoid, the activated receptors dimerise and translocate to the nucleus where they influence the transcription of genes associated with inflammation. The activated dimerized receptors bind to glucocorticoid response elements in the DNA and increase the transcription rate of anti-inflammatory gene products, such as interleukin-10. They also reduce the transcription of pro-inflammatory gene products such as cyclo-oxygenase 2 and inducible nitric oxide synthase.
What effect do corticosteroids have on inflammatory cells?
Reduced numbers of
- eosinophils
- T-lymphocytes
- mast cells
- macrophage
- dendritic cells
What effect do corticosteroids have on structural cells?
Reduced numbers of - cytokines - mediators Reduced amount of leaking - less permeable = reduced oedema Increased numbers of - B2 receptors Decreased amounts of - mucus secretion
What are the adverse effects of glucocorticoids?
Adverse effects affect nearly every organ system.
- hyperglycemia
- poor wound healing
- decreased immune function
- increased risk of infection
- osteoporosis
- emotional labiality
- sodium and water retention
What two factors affect how effective glucocorticoids are?
Receptor binding affinity
- increased affinity = reduced drug concentrations needed
Lipophilicity
- need to cross membrane
- increased lipophilicity = increased difffusion = reduced drug concentrations needed
What is a steroid treatment card?
A warning card which states that a patient is on steroids which must not be stopped suddenly
Why is it important that high steroid doses are not stopped suddenly?
Exogenous steroids interfere with hypothalamic-pituitary axis (HPPA)
Hormone secretions are affected by treatment with synthetic steroids
Doses need to be tapered off to allow HPPA function to return to normal patterns
What are the symptoms associated with sudden withdrawal of high doses of steroids?
- weakness
- decreased appetite
- weight loss
- nausea/vomiting
- diarrhoea
- abdominal pain
- hypotension
- dizziness/syncope
- hypoglycaemia
- menstrual changes
How do leukotriene receptor antagonists work?
Block the cysteinyl leukotriene receptor
- CysLT1
This receptor mediates bronchial smooth muscle contraction in response to leukotriene C4 and D4. It is also implicated in inflammation-induced increased vascular permeability that leads to oedema and eosinophil chemotaxis. Both bronchial smooth muscle contraction and oedema contribute to the early and late phase bronchoconstriction associated with an asthma attack.
Give two examples of chromones
- chromoglycate
- nedocromil
Why are chromones preferred to corticosteroids in children?
Concerns that corticosteroids retard growth in children
How do chromones work?
Mast cell stabilisers
- reduces release of inflammatory mediators from mast cells
Why are chromones less effective than corticosteroids as an asthma treatment?
Chromones have no effect on epithelial cells, but they are involved in triggering an inflammatory response
When are biologics used to treat asthma patients?
When patients can’t be treated by corticosteroids
Give examples of biologics that are used to treat severe eosinophilic asthma where inhaled corticosteroids are insufficient
- omalizumab
- mepolizumab
- reslizumab
- benralizumab
How does omalizumab treat severe eosinophilic asthma?
This antibody targets IgE to block it from binding to the Fc receptor. This prevents antigen from cross-linking the receptors and limits mast cell degranulation.
How does mepolizumab treat severe eosinophilic asthma?
Targets interleukin-5
- reduces eosinophil number and activation
How does reslizumab treat severe eosinophilic asthma?
Targets interleukin-5
- reduces eosinophil number and activation
