Lecture - Pharmacology (Anti-inflammatories) Flashcards
Alright, so anti-inflammatory compunds are ‘preventors’
-what is the class of the drug and give me an example of one that is inhaled vs oral
What’s another class that is covered in this lecture?
So they are corticosteroids and the inhaled one is called fluticasone and the oral is prednisone
Cromolyns are mentioned but will not be in the exam
Alright, how do steroids work?
They need to get into the nucleus and they increase transcription and translation and this will increase the protein it produces so alter the cellular function
What are the two types of corticosteroids and give examples of each type
Glucocorticoids eg cortisol
-it is part of the stress response produced by HPA axis and it impacts the renal cortex - it is an anti-inlam on its own and it regulates gene expression and glucose levels and formation. Also impacts phospholipid release and it reduces eosinophilic recruitment etc
Mineralcorticoids eg aldosterone (spironolactone is an aldosterone antagonist)
So glucocorticoids’ primary action is to regulate gene expression. What are they highly effective at suppressing?
Inflammatory cytokines and immune cells
What does cortisol control and how?
It controls carbohydrates, fat and protein metabolism and is anti-inflammatory
How: It prevents phospholipid release and decreases eosinophil recruitment and action
Glucocorticoid binds to intracellular receptor and then what happens? There are three things that happen - this had a red box around it so you should know this
It binds to the intracellular receptor and that complex interacts with DNA. This interaction will:
- Up-regulate gene transcription of phospholipase inhibitors: LIPOCORTIN-1
- Up-regulates anti-inflammaotry: IL-10, IL-12 and IL-1 receptor antagonist
- Down-regulates pro-inflammatory: IL2, 3, 4, 5, 6, 11, 13, 15, TNF-a, GM_CSF, endothelial adhesion molecules, COX, PHOSPHOLIPASE A1, iNOS etc
So note that phospholipase A2 will be downregulated by cortisol itself and also by lipocortin-1
Also note that iNOS is inducible NO synthase: contained by macrophages - in an inflam resp in lungs, they bring out lots of NO and this causes damage. If we can reduce it from an anti-inflam agent eg corticosteroids, it should be good
SO in this pathway, where will the glucocorticoids affect?
What are the 4 pertinent effects of glucocorticoids (eg fluticasone/prednisone) in asthma?
- Reduce the recruitment/number of inflammatory cells
- consequently reduce damage to airways epithelium
- because you reduce inflammatory cytokines that reduce other cells - Inhibit macrophages function:
- reduces antigen response
* -it reduces iNOS which is in the macrophages* - Reduce vascular permeability
- decrease histamine release from basophils and mast cells
- bc reduce the prostaglandins from the pathway too and they vasodilate - No effect on bronchodilation
- but overtime may decrease airways hyper-responsiveness
* -imp bc those inflam agents increase the responsiveness to Ach*
NB - cannot reverse airways remodelling in poorly managed asthma
-if airways are damaged, there is no going back so need to manage from the get-go
High dose/ow dose oral/inhaled steroids generally have systemic effects
High dose oral steroids - they travel around systemically after getting through the gut and the volume is larger so get everywhere in the body
What are the metabolic actions of the ORAL glucocorticoids?
-
Carbohydrates
- they decrease uptake and glucose utilisation
- they increase gluconeogenesis (hepatic)
- so using corticosteroids on diabetic people can compound the problem because get increased glucose in the plasma
2. Proteins
- increase catabolism
- decrease anabolism
- -so they don’t give you gainz*
3. Fat
- re-distribution
- cause fat gain and muscle wastage
- fat gain and musce wastage isn’t good
NB: glucocortecioids are not anabolic steroids
How do glucocorticoids affect the HPA axis?
Start off by explaining what the HPA axis even is
HPA axis: hypothalamus releases CRH on anterior pit and ACTH released and impacts on adrenal cortex to release cortisol. That cortisol is a glutocirodi (endogenous), it has negative feedback so reduces ACTH and on hypothalams so reduce CRH release.
It also has metabolic effects = impact glucose levels like increase glucose production. So we boost metabolic effects and reduce stress response
When we put a glucocorticoid inside system that resembles cortisol - it’s going to have same effect in that it will decrease the production of cortisol. If have acute release then will have a short term effect and reduce the stress response. But if high dose steroids for long time = downregulate the stress response so the body is no longer able to fight inflammation
So high systemic dose of glucocorticoids leads to chronic negative feedback of HPA axis
What are the regulatory actions of glucocorticoids?
-these are the other effects
-
Osteoporosis
- inhibits Vit D-mediated Ca2+ absorption
- suppresses osteobalst function
* -so yeah, this happens with high dose chornic use*
2. HPA axis suppression
-switch off endogenous glucocorticoud production aka adrenal or HPA axis suppression
3. Inflammation and immune reactions
- decrease chronic inflammation
- immunosuppression allowing eg pulmonary aspergilllosis
- decrease wound healing
- also reduce TH2 response - useful in asthma inflammation but if body is exposed to systemic infection then we will downgrade the response to that (immunosuppression) so it’s a problem giving chronic corticosteroids
Just appreciate this image of the effects chronic oral corticoisterouds have - the ADRs
And some more ADRs of chronic oral/systemic glucocorticoids
So you’ve seen the ADRs of chronic oral/systemic use of gluocorticoids - how do you minimise them collectively?
Inhalation route minimises ADRs
- Fluticasone propionate is an example of an inhaled glucocorticoid
- It can also be given as a combination inhaler (Seretide) with salmetereol (a LABA)