Block E - lecture 3 Flashcards
what do glucocorticoids do ?
These compounds are used in transplantation but not for long term use after surgery. They are used to keep the inflammatory actions supressed, to help with transplant rejection. They are non specific
what are glucocorticoids similar to ?
The basic structure of glucocorticoids is that they are a similar to cortisol which is normally produced by our body
why would glucocorticoids modified ?
The areas labelled A,B, C and D are the areas which can be modified to produce greater activity.
cortisol ?
The prototype compound is cortisol, which is a normal physiological mediator produced by your adrenal cortex. The hormone that we produce is cortisol.
dexamethasone ?
One of the most potent anti-inflammatory glucocorticoids is dexamethasone, a substitution at the 9 alpha position is what makes it so potent. The second ring has an F, which is a fluoryl substitution, a hydrogen is switched for a fluorine and leads to its potency. The pentane ring has a methyl substitution when compared to cortisol, which also increases potency.
how does inflammation occur ?
The stimulus in transplantation is trauma, this leads to an inflammatory response and you get the 2 phases of mediators produced, the first is cytokines such as TNF, IL-1, IL-2 and IFN gamma. These then go on to produce proteinoids and prostaglandins using the enzyme cyclooxygenase (COX), especially PGE2 which is involved in the symptomatic manifestations of inflammation such as swelling, pain and increased blood supply.
role of steroids in inhibiting inflammation ?
Steroids will inhibit the production of cytokines at the gene level upstream by acting on the steroid receptor, and cytokine induced prostaglandin release, they can inhibit inflammation at 2 stages. Steroids DO NOT INHIBIT COX. However, they can downregulate COX if the pathway is upregulated, what steroids do is they prevent the flow of substrates such as arachidonic acid that COX needs to produce PG.
Steroids will lead to the protein lipocortin which will inhibit the production of inflammatory cytokines and arachidonic so that there is a decrease in substrates for the COX pathway and PG production indirectly.
cortisol potency and prednisolone ?
Cortisol has a potency of 1, therefore prednisolone is 4x more potent than cortisol
alpha fluro cortisol ?
9 alpha Fluro cortisol is 10x more potent.
bethamethasone and dexamethasone ?
Betamethasone and dexamethasone are 25x more potent, they have a substitution of methyl group and fluoride.
receptors for steroids ?
Steroids are lipid soluble molecules and can cross the phospholipid bilayer and reach receptors which are commonly cytoplasmic. The receptors are always bound with a heat shock protein 90 (HSP90) which is a regulatory protein if there is no steroid in the binding site. If the steroid binds this allows the HSP 90 to disengage and a receptor steroid complex forms, this is a transcription factor which translocate to the nucleus and binds directly to those regulatory components of DNA.
