Whiteboard Style Discussion the steroid Dexamethasone or Decadron, the medication being studied in COVID-19. We will discuss the anti-inflammatory and immunomodulating properties of Dexamethasone that may be at play when being used for COVID-19, including cytokine modulation, decreased prostaglandin synthesis, and neutrophil migration alteration.
Hey everybody and welcome back to another video so in this video today i want to talk about the medication dexamethasone also known as decadron so i’ll just write that up there um depending when you see this video the reason i i figured this was timely is because uh cova 19 is coming around there was that recovery trial that was preliminarily published about the
Efficacy of dexamethasone 4 covet 19 so i thought it could be helpful to talk about this medication specifically it’s um kind of role in inflammation in the immune response so we’re just going to put over here it’s going to be decadron and it’s rolling inflammation and the immune response so this is not going to go over the um immune response the recovery trial we
Will put out a separate video right after this on that this is specifically going to talk about dexamethasone as a medication what it does how it works and how it affects the immune system and inflammation for more info on dexamethasone’s role enclosing 19 check out our next upcoming video on that recovery trial so dexamethasone is a steroid for those of you who
Are not uh in healthcare steroids come in a couple different groupings so when we talk about steroids there’s actually kind of two different functionalities of steroids one is the mineralocorticoid so the mineral corticoid functionality the other one which we’re going to draw way over here is the glucocorticoid functions and steroids in general have uh effects
In both of these with some exceptions so we’ll get into them but so that you guys can help categorize it dexamethasone which i’m going to abbreviate as dex actually has almost solely glucocorticoid functionality with very little mineralocorticoid and we’ll show you why that’s uh important here in a second so the mineralocorticoid functionality primarily focuses
On sodium retention and fluid retention so it modulates some of the signaling accesses to uh potentiate sodium retention which then also leads to fluid retention as fluid often follows sodium the glucocorticoid functions though are primarily anti-inflammatory in origin and immunomodulatory so the glucocorticoid functions are the portion of steroid functionality
That are important when we talk about its anti-inflammatory effects immunomodulation and there’s also some hyperglycemia so those who give steroids or take steroids are probably familiar with this and cause increased glucoses blood glucoses why is this important well as we talked about most steroids do both both mineralocorticoid and glucocor glucocorticoid
But sometimes we don’t want both functions right in patients who are critically ill who you’re trying to modulate their immune system with steroids you don’t necessarily want sodium retention fluid retention which is where dexamethasone becomes super helpful because dexamethasone has almost solely glucocorticoid function so it does not do the sodium retention
Or fluid retention which could be really helpful especially in patients who are sick with ards or septic shock or hypernatremia high sodium already um you might not want this sodium retention fluid retention so dexamethasone being primarily glucocorticoid can be really useful and we’ll go into why in kova 19 that might be the uh reason one of the reasons that
They’ve seen some beneficial results just kind of a something of note so the half-life so the t half which stands for half-life is about 36 to 48 hours for dexamethasone half-life means the time to which half the drug has been metabolized and is no longer present so in 36 to 48 hours the concentration of the drug in the body will be about half of what it started
As in addition to that dexamethasone specifically has better cns penetration so it can get into the central nervous system which can be theoretically helpful for things like hemophagocytic lymphohistiocytosis which we’ve talked about i can link the study or the video we did on it might have a secondary hlh type process going on in covid19 which again could be
One of the reasons that dexamethasone could be more helpful than some of these other steroids okay so what exactly does dexamethasone do i think that’s the question that you know people are all curious about we’ve seen these positive results in one of the trials so what exactly does i’m going to write it right here dexamethasone do well to do that we’re going to
Separate into a few different kind of pathways so the first pathway is one where it modulates and decreases pro-inflammatory cytokines so let’s try that out a little so here is a human cell membrane all right within each human cell membrane there is a nucleus we’re going to draw this as the nucleus and within the nucleus of the human cell there’s dna right and
This dna goes to dna goes into rna right which then goes into proteins and these proteins can be a many many many different things right proteins make up our body so there’s a obscenely large number of possible proteins in this case though some of these proteins are cytokines inflammatory cytokines things like interleukin-1 or interleukin 12 18 tumor necrosis
Factor cranioslant macrophage colony stimulating factor so these are all cytokines these are all inflammatory molecules they cause inflammation which can be helpful when fighting off an infection until unless they start to go haywire and cause more inflammation than they’re helpful for so dexamethasone as a protein or sorry as a fat a steroid a fat can actually
Get into through the cell membrane and into the nucleus and one of the things it can do is actually decrease the expression of these inflammatory cytokines so it actually modulates what dna turns to rna which turns the proteins and it decreases the level of these pro-inflammatory cytokines which means that you’re going to have decreased inflammation a decreased
Inflammatory response because it decreases the production of these pro-inflammatory cytokines all right another thing it does i’ll just use it down here is that through a similar kind of initial mechanism right we have our human cell we have our nucleus we’ve already talked about our dna which goes to our rna which then goes to proteins in the cytoplasm of the
Cell another thing steroids do is that again they go into the cell let me just get rid of the thickness of that they go into the nucleus and they also increase the production of a molecule called a nexin one a n n e x i n a nexin one so we have these increased levels of a nexin one and an x in one does a bunch of different things one is similar to actually the
Pathway for non-steroidal anti-inflammatory drugs nsaids so it modulates the production of prostaglandin i’m going to draw the pathway then we’ll talk about prostaglandin so arachidonic acid or a a gets converted into prostaglandin through cox cyclooxygenase enzymes and there’s one and two here well a nexin actually goes up and it inhibits the cox enzyme by
Doing so you’re going to get less prostaglandin now prostaglandin is actually an inflammatory marker that can lead to fevers and inflammation so by decreasing the production of prostaglandin we actually are causing less fevers so there’s an antipyretic pyretic being fevers response and you actually have some pain control as well an analgesic response in addition
To that you get an anti-inflammatory response this is actually what nsaids like motrin and ibuprofen do they inhibit so we could just add a little addendum there it’s like nsaids another thing though that an xn1 does is it actually inhibits circle with a cross through it something called pla and what pla does is it takes fatty acids fa and it converts them into
Arachidonic acid so it comes and inhibits this step so that you get less rechidonic acid produced and by such less prostaglandin which then obviously increases these antiportic analgesics and anti-inflammatory effects and xn1 though isn’t done yet so an xn1 also has a number of other different properties so dexamethasone by increasing the production of ednexin1
We’re just going to take this and we’re going to bring it over here so we have an x in one and dexamethasone increased the concentration of the nexa1 well next we’re going to talk about direct immunomodulatory effects so we’ve kind of seen here the decrease in pro-inflammatory cytokines we’ve seen the decreased production of prostaglandins which leads to less fevers
Less pain less inflammation but we also and you can check out our video on the immune system which i can link it also directly modulates immune cells so something that happens when there’s inflammation and i’ll tell you what i’m drawing here in a second so this here is a blood vessel so this is the endothelial lining and the blood flows through here with all these
Red blood cells right so we have blood flowing through and this is the outside tissue space so this is the tissue space let’s just use this this is the tissue space out here and what happens when there’s inflammation is some of these cytokines can come over here and cause the blood vessels to get leaky right so these this is an intact endothelial membrane in
A blood vessel this is what happens when some of these inflammatory cytokines attach to the blood cells they cause these gaps the reason they do that is because immune cells such as neutrophils this here can be a neutrophil will attach and then they’ll actually migrate through the gaps out into the tissues to fight different infections and this process takes a
Number of signaling molecules well a nexon one actually comes in here and inhibits this neutrophil migration through the inhibition of endothelial cell adherence so this neutrophil here has to bind to the endothelial cell then it has to start migrating through between the endothelial cells and out into the tissue an xn1 inhibits that endothelial cell adherence
Thus inhibiting neutrophil migration thus decreasing the number of neutrophils out in the tissue and neutrophils are inflammatory cells that release inflammatory markers right they have all these granules in their cell and they release all these markers into the cell that then cause inflammation and again that is meant to fight off bacteria and viruses and such
But in the case of cova-19 that increase inflammation can lead to problems so nexin one decreases the number of neutrophils that can adhere to the endothelial cells get out in the tissue and cause inflammation so those are the main anti-inflammatory and mutual modulating properties of dexamethasone right so as we talked about we get decreased and pro-inflammatory
Cytokine production through the direct modulation of dna to rna to proteins by dexamethasone you also get the increased production of venexa one with dexamethasone that inhibits cyclooxygenase enzyme leading to less prostaglandin it also inhibits pla which transitions fatty acids to arachidonic acid again decreasing prostaglandin and then through the increased
Production of nexo1 you get the inhibition of endothelial binding of neutrophils and other immune cells as well as decreased concentrations of neutrophils and immune cells in the interstitium the tissue spaces thus decrease inflammation in those tissue spaces so i know that’s complicated this is a simplistic version of what actually happens but it’s accurate
And i hope it kind of uh gets the the point of cross of the multifactorial mechanism of dexamethasone to modulate inflammation in the immune response and why it may have efficacy in a covalent 19. let us know what questions you have thoughts concerns check out our next video on the recovery trial which is decadron in covet 19. and we hope to see you soon thanks for watching
Transcribed from video
Dexamethasone/Decadron; How Does It Work And How May It Be Helpful In COVID-19? By Whiteboard Doctor
