Antiinflammatories Flashcards
The antiinflammatory compounds used in asthma are corticosteroids, and there are cromolyns.
What kind of corticosteroids are they, and provide an example of an inhaled version and oral version.
Also give a cromolyn example
Corticosteroids used in asthma are glucocorticoids. (There are two types of corticosteroids: glucocorticoids, and mineralocorticoids).
Inhaled: Fluticasone, beclomethasone
Oral: Prednisone
Cromolyns: Cromoglycate
Why do we use glucocorticoids?
And what are their primary action?
Glucocorticoids e.g. cortisol are highly effective at suppressing inflammatory cytokines and immune cells.
Their primary action is to regulate gene expression.
What is the mechanism of action of glucocroticoids?
Gluccorticoids binds to a intracellular receptor, and this receptor then complexes with DNA to regulate gene expression:
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Up regulates gene transcription of phospholipase inhibitors
- Lipocortin-1
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Up-regulates anti-inflammatory molecules
- IL-10 & IL-12 and IL-1 receptor antagonists
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Down regulates pro-inflammatory molecules
- IL-2, -3, -4, -5, -6, -11, -13, -15, TNF-a, GM-CSF, endothelial stimulating molecules, COX, phospholipase A2, iNOS, etc.
iNOS is a pro-inflammatory molecule released by macrophages
What do molecule do glucocorticoids increase the transcription of, and what does this inhibit?
What are the down stream affects of this.
Glucocorticoids increase lipcortin-1 expression, which inhibits phospholipase A2 (PLA2), and this decreases arachadonic acid production.
Due to reduced arachadonic acid decreasing, leuktriene and prostanoid synthesis is decreased
What effects do glucocorticoids have on asthma?
Is the airways remodelling reversible?
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Reduce recruitment/ number of inflammatory cells
- Which reduces damage to airways epithelium.
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Inhibits macrophage function
- reduces antigen response (reduces nitric oxide synthase acivity)
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Reduce vascular permeability
- Decrease histamine releae from basophils and mast cells
- Decrease histamine release
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No effect on bronchodilation (all we’re doing is reduce inflammation)
- But over time may decrease airways hyper-responsiveness
NB. Cannot reverse the airways remodelling in poorly managed asthma
What are the metabolic effects of glucocorticoids?
Metabolic effects
Carbohydrates
- Decrease uptake & glucose utilisation (elevates blood glucose)
- Increase gluconeogenesis (hepatic)
Proteins
- Increase catabolism
- Decrease anabolism
Fat
- Causes fat re-distribtuion
- so in essence it causes fat gain and muscle wastage
gluccocorticoids are not anabolic steroids
Descibe the HPA axis
How do glucocorticoids impact upon the HPA axis?
The hypothalamus releases CRH, this acts on anterior pituitary gland to release ACTH.
ACTH acts on adrenal cortex, which then releases cortisol (which is a glucocorticoid).
Cortisol negatively feeds back on hypothalamus (reduce CRH release) and ant. pituitary gland (reduce ACTH release). It also has metabolic effects.
So by giving glucocorticoids, it will have the same inhibitory affects as cortisol on the hypothalamus and ant. pituitary.
therefore high systemic doses of glucocorticoids leads to chronic negative feedback of HPA axis.
How do glucocorticoids effect
Osteoperosis
HPA axis
Inflammation and immune reactions
Osteoperosis
- Inhibits Vit D-mediated Ca2+ absorption
- Suppresses osteoblast function
Suppresses the HPA axis
- Switich off endogenous glucocorticoid production
- causing adrenal or HPA axis suppression
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Inflammation and immune reactions
- This decreaes chronic inflammation
- Causes immunosuppresion
- Decreases wound healing
What are the ADRs of oral corticosteroids?
What are the pharmokinetics of inhaled glucocorticoids?
When we inhale glucocorticoids we have immediate access to the target in the airways - this means we can use a much lower dose. We can allow delivery at ~1/100 of concentration need to achieve a similar systemic anti-inflammatory effect with oral drug.
Metered dose inhalers contain microcrystalline preparations e.g. fluticasone, beclomethasone
Fluticasome (but no beclomethasone) undergoes extensive 1st pass metabolism - very little reaches systemic circulation, reducing potential for ADRs.
Need to do 1-2 puffs once or twice daily depending on severity, choice of steroid, inhaler device etc.
What determines deposition of aerosols?
The size of the aerosol.
Asthma affects the lower airways, therefore we need to have aerosols small enough to get down to the bronchioles.
The best size are particles within 1-10um
How can incorrect delivery lead to increase systemic ADRs?
If the patient fails to follow correct procedure they increase their risk of systemic effects.
Only about 10% reaches the lungs, 90% gets swallowed
The portion that gets swalloed undergoes acidic degredation, and then the remainders from that enter portal circulation to undergo hepatic metabolism - only about 1% enters the systemic circulation.
So if they have incorrect technique time and time again they will the amount which reaches systemic circulation.
What can chronic high dose of inhaled glucocorticoids result in?
What are the systemic effects?
With chronic high dose use, enough drug may be absorbed from the GI tract and pulmonary epithelium to cause systemic effects. This can occur after long term inhalation of potent steroids (fluticasone).
Systemic effects:
- Infection and immunosuppresion
- Poor wound healing in trauma
- Osteoperosis
- Delayed growth in children (marginal effects associated with chronic inhaled steroids)
- Secondary adrenal insufficiency: Systemic presence in suppresion of endogenous glucocorticoids. Produces insufficient adrenal reserve to respond to stress on discontinuation of glucocorticoid.
What infection can glucocorticoids cause?
And how can it affect the voice?
How can we reduce these ADRs
An ADR of inhaled glucocorticoid use is oropharyngeal candidiasis. This is caused by local immunosuppresion in oral & pharyngeal mucosa allowing infection by candida albicans.
Another ADR is dysphonia, which is hoarse voice due to laryngeal deposition of drug particles.
How to reduce risk of these ADRs
- Rinse after use/gargle with antifungal mouth wash.
- Use a large volume spacer to reduce travel of large droplets
- Reduce dose frequency depending on pulmonary function tets and symptom presentation (and FENO)
How do you treat acute asthma exacerbations?
SOS
SOS
- Salbutamol
- Oxygen
- Steroids
Use high dose prednisone (40-60mg daily) for a short course (~5 days), the stop. For longer courses you need to titrate down.
