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Are Steroids really slow to act?



We all have those drugs in our medics, squads, or helicopters that sit and collect dust, right? The usual statement is something to the effect of, “We don’t give that medication too often because it takes a long time to take effect.” I heard this story with a few specific medications, but I wanted to zero in on a specific one – Steroids. Namely, Solumedrol and Dexamethasone (Decadron).


These steroids are undoubtedly part of the cocktail we reach for in patients presenting with acute asthma, allergic reactions, or anaphylaxis - and traditional clinical logic has taught us these drugs work to reduce inflammation in the airways and reduce bronchial mucus production. It has long been held that steroids take longer to activate, and as a result, administration of steroids tends to take a “back seat” and fall down the algorithm for many providers. My argument is that there is a short-acting benefit to these medications that has been hidden in the literature for a long time.


Here is the TL;DR version of this… Steroids have an important ancillary function besides reducing inflammation. They have a relatively unknown mechanism by which they help up-regulate beta receptors. They do this through various mechanisms, but in short, they help boost the availability of beta receptors to augment the function of our beta-agonists. This is especially useful in patients presenting with respiratory conditions and/or anaphylaxis!


1 - Let’s Get Some Definitions out of the way…

I know in the pre-hospital settings, we carry mainly Decadron or Solumedrol. These two medications are steroids, but we can get a bit more specific than that. We have the over-arching classification of corticosteroids. These corticosteroids are hormones produced by the adrenal glands. Under the corticosteroid umbrella, we have two sub-categories to focus on: Glucocorticoids and mineralocorticoids (technically 3, if you count sex hormones). Mind you, we produce these steroids both endogenously as well as get them exogenously (i.e. Decadron or Solumedrol).


The glucocorticoids' primary functions are immunological- reducing inflammation and metabolic- regulating glucose metabolism. On the other hand, mineralocorticoids regulate fluid and electrolyte balance primarily through the hormone aldosterone. Decadron and Solumedrol are almost solely glucocorticoids and have nearly zero mineralocorticoid function in the body. This is why we give these medications to help reduce inflammation in clinical situations such as allergic reactions, asthma, or COPD, to name a few.




2 - Decadron vs. Solumedrol

So, what exactly is the difference between the two of these medications? Why carry one over the other? Well, whoever oversees ordering at your agency probably likes Decadron because it is far cheaper than Solumedrol. 25 vials of Decadron will run your agency about $170 as opposed to $475 for 25 vials of Solumedrol.


But the real difference between the two… is really the strength of one over the other. Both medications are glucocorticoid receptor (GR) agonists, meaning the steroids pass through the cell membrane and attach to the GR receptor within the cell's cytosol. The main function of these receptors is to turn on or off gene transcription, which occurs in the cell's nucleus.


Once these steroids bind to the glucocorticoid receptor, it creates a complex known as “Glucocorticoid Response Elements”, or GRE’s for short. These GREs traverse from the GR location (the cytosol) and pass into the nucleus of the cell, and physically attach to DNA sequences that are flagged specifically for GREs. Once in the DNA, they turn on DNA sequences to express anti-inflammatory proteins and turn off DNA sequences that produce pro-inflammatory proteins (Timmermans et al., 2019). Administration of these medications then produce an overall anti-inflammatory state.




As for the real difference between Solumedrol and Decadron – Decadron is far more potent. In the steroid medication world, all steroids are compared to hydrocortisone. As for anti-inflammatory properties, Hydrocortisone is considered the baseline – so it gets 1 unit (or a score of 1) for its anti-inflammation ability. Solumedrol is worth 5 units (or a score of 5) for its anti-inflammatory ability, and Decadron is worth 30 units. This is also all relative to its equivalent dose, where Hydrocortisone is 1 unit at 20mg, Solumedrol is 5 units at 4mg, and then Decadron is 30 units at 0.75mg (Katzung, 2012).


All I want you to know is that Decadron is far more potent in smaller concentrations (and it’s cheaper).


3 - Steroids and Beta Receptor Regulation

This is the meat of the blog, and if you forget everything up to this point, I am honestly totally fine with that. The medics who told me steroids take too long to work are wrong. Steroids can have a short-acting effect on respiratory patients because they also regulate gene expression for beta receptors in addition to their anti-inflammatory properties. The same beta-2 receptors in our lungs facilitate bronchodilation.


The literature supporting this does not exactly exist in the emergency medicine FOAMed world but rather in clinical pharmacology. So, it is no wonder that this small detail has been left out of our mental framework of steroid use in the acute care setting. Glucocorticoids have a known ability to “upregulate beta receptors.” It does this via three mechanisms:


  • Rapid uncoupling of beta receptors: The beta agonist medications (albuterol) we give eventually must kick off the receptor once their job is complete. This “uncoupling” helps speed up that process and turn over the beta receptor faster to be available for the next albuterol or beta-agonist to attach (Taylor, 2000).


  • Upregulation of previously down-regulated beta receptors: Many patients with chronic respiratory conditions have de-sensitized beta receptors due to chronic albuterol or other beta-agonist use. Glucocorticoids can circumvent this issue by increasing gene transcription and producing more beta receptors (Taylor, 2000). If there are more beta receptors available, there is more potential for beta-agonists to attach and exert a physiological change (in this case, bronchodilation)


  • Increase GRE translocation into the Nucleus: Remember those GREs? The complexes of glucocorticoid medication + the glucocorticoid receptor… Exogenous steroids have been found to increase the speed at which they migrate into the nucleus. This increases the overall gene expression of the anti-inflammatory proteins and beta receptor expression (Barnes, 2010).


Recap

All the science is cool (to me, at least), but I always seek to answer the question: how does this affect my everyday practice? Here’s the scoop:


I found myself reaching for the steroids a little earlier in the treatment algorithm than I had before. Epi and albuterol are still my mainstay pharmacological treatments in severe asthma and anaphylaxis, but steroids are the next drug I reach for. Let me be clear: steroids should not come before these medications in the anaphylactic patient or severe respiratory patient.


However, if steroids upregulate the number of available adrenergic receptors (our alpha and beta’s) then theoretically it would have a synergistic effect with our first line agents of Epi and Albuterol as it makes available more sites for these agents to attach to. Once attached, steroids secondarily put these receptors in a high-affinity state, ready to receive the drugs in the acute setting.




References

Barnes, P. J. (2010). Inhaled Corticosteroids. Pharmaceuticals, 3(3), 514–540. https://doi.org/10.3390/ph3030514. Beta agonists synergistic effects with glucocorticoids (speeds up transcription processes).

Katzung, B. G. (2012). Basic & clinical pharmacology (12th ed.). Mcgraw-Hill Medical. relative activity of steroids compared to hydrocortisone.

Taylor, D. R. (2000). Interactions between corticosteroids and beta agonists. Thorax, 55(7), 595–602. https://doi.org/10.1136/thorax.55.7.595. Mechanism of glucocorticoids on beta receptors.

Timmermans, S., Souffriau, J., & Libert, C. (2019). A General Introduction to Glucocorticoid Biology. Frontiers in Immunology, 10(1545). https://doi.org/10.3389/fimmu.2019.01545. GRE’s .

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