medigocrazy-blog - Tumblr blog

[medigocrazy-blog]

Dexamethasone- The Wonder Drug or The Desperate Hope?

Despite all the desperate efforts to control the spread of the virus SARS-CoV2, wiz getting on nerves of us, humans, as a very, very, social ;sometimes; toxic, species 

Hello,          I am Arjun and this picture is not me. Its been like 6 months into this pandemic and I have been eating all this junk you can actually say that this picture is me.Gosh, I was so excited for 2020 because so many exciting things were about to happen. Elon Musk was actually going to complete that Neuralink trial thingy by the end of this year and I could finally end my never ending struggle to take care of my> oh my god> numerous organ systems? my weight ? and my metabolism? any my eyesight? and my everything? Who the h*ll does that? 

But no, its just not happening guys. I am pretty sure now because 2020 is just the worst year! let us just agree to that as a starter!

Can you guys like believe that we cannot go out for window shopping anymore?

I go out to buy milk and I have to wear this Halo master chief armored suit thingy.

Ordering from Starbucks is just a pandemic and one kidney away and I certainly cannot beat the Indian summer heat.

I am desperate, I am so desperate that Baba Ramdev doing Yoga at 4:30 in the morning actually makes sense somehow.

I am so desperate that my lockdown 3 AM anthem is :

Taoism talks about how you should go with the flow so thats what I am actually doing, I am finally going with the flow,

But it feels like this flow is actually going towards a falling waterfall and we all are almost on the edge now.

The International airlines are shut down You cannot travel to Ladakh or Goa with your friends and Emiway just featured Macklemore in his song? Like seriously? He went from worshiping M&M to MM? Half a million people have died due to the Coronavirus alone

Yemen is going through a civil war and one of the worst famines in modern history.

And for some reason Delhi is getting its ego drop by a series of Earthquakes.

Well,  Thank You 2020, UNESCO just declared you to be the most confused year in the history of mankind. Like seriously, please decide what you want man.

Now, lets talk medicine.

Lets talk about the scope Dexamethasone potentially has, against Covid-19,

There has been numerous claims in the recent past to have successfully found a potential cure for Covid-19, But I was like meh; BUT I am pretty excited for this one which Oxford just released a statement for I think last night maybe.

The World Health Organisation also applauded the initial results of the study.

It is really interesting, the excerpt said that they are trying to publish the data as soon as possible which basically makes it a more trustworthy of a claim.

The study was an attempt to potentially use Dexamethosone  (A long acting corticosteroid which can remain in the systemic circulation for as long as 3 days) as a DOC for the Covid19.

What are Steroids?

Steroids is a group of chemical compounds with extensive properties often used as a drug of choice for many life threatening diseases.

Some steroids ( Androgenic Steroids) are activated due to stress and leads to many anabolic processes inside your body for example "Muscle building", When you are like trying to get those gains so badly in the gym, what basically happens is you are stressing your muscular cells (also injuring) as a result of resistance training and then steroids are produced as a physiological response so that more and more protein is available for the muscle to repair (btw this is the reason why some bodybuilders using anabolic steroids, end up gaining exceptional gains over years of steroid use)

Some steroids (Glucocorticoids) can strongly suppress the immune system by either suppressing certain genes in various immune cells or by blocking the important enzyme activities. These steroids can act as Anti Inflammatory too which basically means these steroids counter any inflammatory response which can be physiological or pathological. This is the reason that if a steroid taken in the early phase of the Covid-19 disease (The mild symptomatic or Asymptomatic phase) can actually suppress the immunity to a certain point that the drug itself becomes counterproductive.

Some Steroids (Mineralocorticoids) maintain the mineral balance by salt retention, etc. Lets just skip this one.

Adrenal Gland produces Steroid. Them tiny glands you can see above the kidneys.

Now the immunity suppressing nature of Dexamethasone is also the reason why it cannot be taken as a mass prophylaxis drug,  unless the patient is in a state of severe immune response to the infection and requires ventilation or ICU.

The exudate formed in the lungs become an overwhelming immune response to fighting the virus and becomes fatal by causing the patient to stay in respiratory distress and finally succumbing to death.

The Trials done by the Oxford University aka RECOVERY trials, said that :

"1 death would be prevented by treatment of around 8 ventilated patients"

or

"around 25 patients requiring oxygen alone as of now"

*The prognosis may potentially increase as with other combinations in the future*

The study is really interesting because the study population was relatively large ( around 11,500) ; The Cohort population was around 2100 and Control was 4300 which is really exciting.

How does Dexamethasone work against SARS - CoV2?

Dexamethasone is a long acting Corticosteroid and mostly suppress the genes of immune expression

This is the Mechanism of Action of the drug if you are interested:  

Dexamethosone vs The Immune System :  

The goal of this drug is to just deactivate the immune system which has gone kinda crazy over this virus.

The immune system (IS) basically starts acting like its IS and terrorizes the whole body like its Iraq or Syria.

Jokes aside, This drug can really do some great damage to the hyper super- immune response which is kind of self destructive as the disease progress. Let's try to understand HOW

Only Within 6 hours of single dose of Dexamethasone:

There is a decreased availabilty of lymphocytes, eosinophils, basophils, monocytes,

These cells start redistributing and becomes less available and inactive for almost a day or two.

Also there is a decreased adhesion of these cells to blood vessel walls due to Dexamethasone, Actually the drug is not letting these immune cells to cross the wall of the vessel and go to the infection site (which is kinda cool cuz' no immune response no problem right? seriously why didnt evolution think of this?)

SECONDLY < there is a > decreased phagocytotic capacity of the immune cells so that they do not eat up the virus and form further exudates.

Finally leading to the decrease in respiratory burst (It is the area inside a phagocyte where we burn the pathogen inside the phagolysosome usually, in the case of Covid19,  later explodes and kills us, Dont worry the jokes' on evolution not us )

Now the first most remarkable thing Dexamethasone does is, that, it suppresses Macrophage activity.

Which is basically blocking the Arachidonic Acid Pathway, Prostaglandins, Leukotrienes, Interleukin 1, Interleukin 6 and TNF

Explaination :

IL-1 goes to the brain and causes fever and normally increases the production of steroids by stimulating the hypothalamus, but since we are giving Dexamethasone (which is a steroid) there's something called as a negative feedback and it decreases the natural physiological production of steroid, causing the person to be severely dependent on steroids; and if the person stops taking this steroid, he can eventually die due to acute adrenal insufficiency, thats the reason why we should always taper the dose when withdrawing a steroid.

Now,

The Interleukin 6 usually activates almost all other immune system actions (Remember that respiratory burst is also decreased and hence theres no signal from the MHC I and II to activate the immune system either)  but when it is suppressed by Dexamethoasone, it cannot activate the immune response like it normally would.

The second most important thing is that Dexamethasone down stimulates the cooperation between naive T cells and Interleukins

In Covid 19, Macrophage connects with the Naive T cells and there is a co-stimulation and can be two pathways. (depending on which interleukin is available for the naive T cell)

The first pathway:

In presence of Interleukin 4, these Naive T cells convert into T helper -1 cells which further increases Interleukin 4 and Interleukin 5 by positive feedback mechanism.

Finally causing the other cells of cell- mediated immunity, the "B-cells" to become active and produce antibodies which bind with the virus antigen and try to repeatedly neutralise it. (and kills us).

The Dexamethasone can potentially end all this suffering by attacking a gene known as GATA3 on the T helper 1 cell, (Remember Steroids suppress some immune genes it is just one of them) and hence GATA3 is suppressed, and therefore the chain is broken and there is no immune response ( yay, we alive now)

The second pathway :

If the naive t cell has Interleukin 12 available instead of Interleukin 4, it becomes T helper 2 cell, which produces Interleukin 2, which activates Cytotoxic T cells which produces some naughty proteins called perforins and granzymes.

These Perforin causes perforations in the infected cell and granzymes are then injected to that infected cell which makes the cell kind of commit suicide I guess ?. (and it kills us)

Dexamethasone acts on the T-bet gene on the T helper 2 cell which suppresses the further activation of immune response ( and hey we back to life again)

Now, ALL this information which just went over all of our heads is just the immune suppression of steroids, Lets not go in details with the EXTENSIVE collection of what Dexamethasone can actually achieve.

Please note the trials were done with Dexamethasone and not other corticosteroids mainly because of its wide availability, inexpensive nature, and most importantly because it is along acting Corticosteroid despite being the most potent among them

Dexamethasone also decreases inflammation

Explaination :

Our Cell membranes have a phospholipid bilayer, which is converted by PLA2( Phospholipase A2 ) enzyme to Arachidonic Acid. a) Arachidonic Acid is acted on By COXs ( Cyclooxygenases) to release PGE2F2, PGI2, Thromboxin A2 b) Arachidonic acid can be converted to Leukotrienes by LOXs (Lipooxygenase)

Dexamethasone can block the PLA2 enzyme and COX2 and COX1,  by producing Lipocortin 1, and therefore there's no formation of Arachidonic Acid in the first place, and the whole inflammatory system goes down. (Kudos to the structure of Dexamethasone)

Please, keep in mind that we do need the immune and inflammatory response in the early part of the disease but as their  actions overwhelm the healthy effects of the process, steroids can be used. Not too early, because it can actually worsen the disease if steroids are administered too early.

Some Side Effects which are to be kept in mind :

1. Withdrawl :

- Underlying disease which we were treating may rebound even stronger than before - Acute Adrenal Insufficiency - Pseudotumor Cerebri - Myalgias - Arthralgias - Malaise

2. Hyper use of steroid for long period :

- Fluid and electrolyte abnormalities - HTN ( more sodium retention) - Hyperglycemia ( gluconeogenesis) - Increased infection susceptibility (suppressed immune system) - Behavioral disturbances - Striae (fat redistribution)

While this is a serious concern for us as Indians, people are already stocking up Dexamethasone, price is most likely to spike up and things actually somehow do not work perfectly in India. Let's hope we learn from our mistakes in the past and just get this done and over with. PS - I will try to post more articles like this if I find something interesting regarding the pandemic. Thank you for the time. :)   Feel free to contact.

Source: Dexamethasone statement by WHO

https://www.who.int/news-room/detail/16-06-2020-who-welcomes-preliminary-results-about-dexamethasone-use-in-treating-critically-ill-covid-19-patients

Oxford Recovery Trial Statement

https://www.recoverytrial.net/files/recovery_dexamethasone_statement_160620_v2final.pdf