Steroids and pancreatitis- what's the mechanism?

tech77

Hi.
Just a medical question that i can't get an answer on.
Steroids and NSAIDs are (obviously) antiinflammatory.
Yet they are listed as one of the causes of pancreatitis.

This appears counterintuitive (and no attempt at explanation appears to be given in medical texts).
Can anyone tell me the mechanism of this- and could you direct me to the info.
Thanks.

Traumadoc

Steroids and NSAIDs also predispose to stomach ulcers, It is probably a similar mechanism where prostaglandin production is inhibited so endothelial cells are more prone to damage from the digestive enzymes.

tech77

Traumadoc wrote: »

Steroids and NSAIDs also predispose to stomach ulcers, It is probably a similar mechanism where prostaglandin production is inhibited so endothelial cells are more prone to damage from the digestive enzymes.

Yeah, that's the only thing i could think of.
But wouldn't such an action on the endothelial lining imply that steroids/NSAIDs (when given PO) somehow make their way up the pancreatic duct to the pancreatic lining.
Does such retrograde movement of drugs actually occur? (Or do they act on something like the duodenal lining with an enteropancreatic reflex mediating it?).

BTW, IV steroids are also not indicated in pancreatitis (if i'm not mistaken)- so what's the mechanism here (i can't imagine iv steroids are acting on the pancreatic endothelial lining are they?).

Ihaveanopinion

tech77 wrote: »

BTW, IV steroids are also not indicated in pancreatitis (if i'm not mistaken)- so what's the mechanism here (i can't imagine iv steroids are acting on the pancreatic endothelial lining are they?).

They have a systemic effect, including but not limited to, endothelial lining

SomeDose

tech77 wrote: »

Yeah, that's the only thing i could think of.
But wouldn't such an action on the endothelial lining imply that steroids/NSAIDs (when given PO) somehow make their way up the pancreatic duct to the pancreatic lining.
Does such retrograde movement of drugs actually occur? (Or do they act on something like the duodenal lining with an enteropancreatic reflex mediating it?).

BTW, IV steroids are also not indicated in pancreatitis (if i'm not mistaken)- so what's the mechanism here (i can't imagine iv steroids are acting on the pancreatic endothelial lining are they?).

For steroids and NSAIDs, it's irrelevant whether they're given orally or parenterally - their effect is systemic (not local) regardless of the route of administration. This somewhat betrays the popular belief that NSAIDs must not be given on an empty stomach (partially true but not for the reasons most people think).

I imagine steroid-induced pancreatitis is probably quite a rare presentation, and I'm not aware of any firm evidence behind the mechanism of action. Mind you, it's not a topic I'm overly familiar with either. The thing is with steroids though, they have so many actions on such a wide range of mediators, hormones etc that its often very difficult to pin down individual effects. Even some of their most well-documented effects (e.g. in inflammation) are not completely understood.

tech77

Ihaveanopinion wrote: »

They have a systemic effect, including but not limited to, endothelial lining

I always thought the actions of steroids/NSAIDs on protective PG's (etc) in gastritis were mediated locally (this is wrong so?).

(ie steroids/NSAIDs directly -> decrease in PG synthesis -> no endothelial protection -> inflammation of pancreatic lining (pancreatitis)).
So such a direct action of NSAIDs/steroids on pancreas is wrong also?

By "systemic", i take it you mean both PO steroids and NSAIDs cause pancreatitis not via their direct effects on the gastrointestinal tract/pancreatic duct/pancreas but after entry into the bloodstream.

But what exactly is this systemic effect that is pro- rather than anti-inflammatory?

BTW with this systemic effect (which you say would include action on the endothelium), would you expect IV steroids to similarly aggravate a gastritis say?
But isn't it only oral steroids/NSAIDs (and not parenteral steroids/NSAIDs) that worsen gastritis (or am i again mistaken ).
What is specific to pancreatitis over gastritis that would account for this particular systemic effect of steroids/NSAIDs in pancreatitis.

Should i discount any possible local effects of steroids/NSAIDs in both gastritis/pancreatitis and just focus on the their systemic effects (i dunno, i always thought NSAIDs at least acted locally on the endothelium ).

Also, if there are any links to the exact mechanism, i'd really appreciate it.
Thanks.

tech77

For steroids and NSAIDs, it's irrelevant whether they're given orally or parenterally - their effect is systemic (not local) regardless of the route of administration. This somewhat betrays the popular belief that NSAIDs must not be given on an empty stomach (partially true but not for the reasons most people think).

Hi.
So is the action of NSAIDS and steroids in worsening pancreatitis attributable more to their systemic effects (whatever these are) than their local enteric effect ( NSAID/steroid-> mucosal PG reduction as occurs in gastritis).

Should i discount the enteric effect (necessitating a retrograde migration up the pancreas :P) altogether.

So just sticking with this systemic effect:
what happens to the potent systemic antiinflammatory effect of the steroid in all this?
It is an antinflammatory afterall.
Is it totally overridden by an even more potent reduction in synthesis of protective endothelial PG .

And if it is a "systemic" rather than enteric/direct effect, why don't parenteral (as opposed to oral) steroids/NSAIDs exacerbate gastritis in a similar way to oral steroids/NSAIDs.

The thing is with steroids though, they have so many actions on such a wide range of mediators, hormones etc that its often very difficult to pin down individual effects. Even some of their most well-documented effects (e.g. in inflammation) are not completely understood.

Yeah fair enough on the mysterious nature of steroids.
But NSAIDs are understood better IIRC.
Can you elaborate on the exact mechanism of these in causing pancreatitis?

Thanks.

Traumadoc

Parenteral NSAIDs can also cause gastric ulceration as can parenteral Steroids.

I was always under the impression that steroids acted to decrease the inflammatory response at a cellular level. Thats how they work in asthma to decrease the delayed inflammatory response.

But the inflammatory response is very important in protecting the body from injury.
There is a lot about the inflamatory response and cytokine cascade we still do not understand.

tech77

Parenteral NSAIDs can also cause gastric ulceration as can parenteral Steroids.

Thanks (yeah actually i wondered that after i posted tbh ).
So does this mean parenteral/(even inhaled) steroids for stuff like RA/colitis/asthma etc can cause/are contra-indicated in gastritis also?
Or something like IM diclofenac- can that cause/is that CI in gastritis.

I was always under the impression that steroids acted to decrease the inflammatory response at a cellular level. Thats how they work in asthma to decrease the delayed inflammatory response.

Right.
So i suppose i was just wondering what exactly the pro-inflammatory nature of steroids/NSAIDs was (in the context of causing pancreatitis at least).
And gastritis (presumably).
OK it's an endothelial PG depletion thing (primarily systemically mediated i guess?).
But how does this come to be more potent than their essentially antiinflammatory nature.
Edit: I appreciate now this is not completely answerable so i guess i'll stop asking.

There is a lot about the inflamatory response and cytokine cascade we still do not understand.

Yeah, fair enough.
It's just a pity standard medical texts never seem to make explicit this unknown vs known distinction when it comes to mechanisms.

SomeDose

tech77 wrote: »

Hi.
So is the action of NSAIDS and steroids in worsening pancreatitis attributable more to their systemic effects (whatever these are) than their local enteric effect ( NSAID/steroid-> mucosal PG reduction as occurs in gastritis).

Should i discount the enteric effect (necessitating a retrograde migration up the pancreas :P) altogether.

I'm not sure of your area of work/study so I apologise if I'm teaching you to suck lemons here Just so we're clear on the differentiation between local and systemic effects: a local effect is one where the drug acts directly on the surrounding tissue/organ where it it is delivered e.g. topical cream, inhaled bronchodilators etc, whereas a systemic effect occurs at a cellular level once the drug has been absorbed into the circulation and delivered throughout the body. You are correct in pointing out that inhibition of certain PGs can result in gastro damage by NSAIDs but this is never a "local" effect - it's always due to a systemic action via COX-1 inhibition as described above.

I should point out that I'm using only NSAIDs as an example here since, in my opinion (based on what I've read and from speaking to a couple of gastroenterologists), the association between steroids and gastro damage is weak.

tech77 wrote: »

And if it is a "systemic" rather than enteric/direct effect, why don't parenteral (as opposed to oral) steroids/NSAIDs exacerbate gastritis in a similar way to oral steroids/NSAIDs

I'd be interested to know what literature/texts say that parenteral steroids/NSAIDs do not cause or exacerbate gastritis. They do (or NSAIDs do, at least). The reason you won't see many reported incidences of this is because parenteral steroids/NSAIDs are used very rarely relative to their oral counterparts i.e. almost exclusively during hospital admissions for acute indications. That's purely a numbers thing.

tech77 wrote: »

Yeah fair enough on the mysterious nature of steroids.
But NSAIDs are understood better IIRC.
Can you elaborate on the exact mechanism of these in causing pancreatitis?

Thanks.

I wish I could elaborate! Again, as for steroids, I would guess that the incidence of NSAID-induced pancreatitis is quite low compared to the other causes of it. Are the associations strong or weak? Were there other confounding risk factors in these cases which might have influenced the risk of pancreatitis?

Although I know how the drugs work, I don't have anything more than a rudimentary understanding of the cellular events that underlie pancreatitis. Like Traumadoc pointed out, there's so much about inflammatory mechanisms we still don't understand...or maybe it's through another pathway entirely. Maybe steroids remove some of the protection against pancreatic enzymes, maybe they mess about with the hormonal control of the pancreas...just revel in the mysteriousness of it all!

EDIT: Just saw your previous post, you seem to have answered some of your questions already!

tech77

I'm not sure of your area of work/study so I apologise if I'm teaching you to suck lemons here Just so we're clear on the differentiation between local and systemic effects: a local effect is one where the drug acts directly on the surrounding tissue/organ where it it is delivered e.g. topical cream, inhaled bronchodilators etc, whereas a systemic effect occurs at a cellular level once the drug has been absorbed into the circulation and delivered throughout the body.

No i understand that, thanks.

You are correct in pointing out that inhibition of certain PGs can result in gastro damage by NSAIDs but this is never a "local" effect - it's always due to a systemic action via COX-1 inhibition as described above.

I'd be interested to know what literature/texts say that parenteral steroids/NSAIDs do not cause or exacerbate gastritis. They do (or NSAIDs do, at least). The reason you won't see many reported incidences of this is because parenteral steroids/NSAIDs are used very rarely relative to their oral counterparts i.e. almost exclusively during hospital admissions for acute indications. That's purely a numbers thing.

Fair enough.
This is actually something i overlooked before i posted so thanks (for some reason always thought it was (even partly) a local effect).
At least i learnt something useful.

Anyway, back to the main query:
(ie the exact pro-inflammatory nature of these anti-inflammatory drugs).
Which i now accept is not completely answerable.

I wish I could elaborate! Again, as for steroids, I would guess that the incidence of NSAID-induced pancreatitis is quite low compared to the other causes of it. Are the associations strong or weak? Were there other confounding risk factors in these cases which might have influenced the risk of pancreatitis?

Although I know how the drugs work, I don't have anything more than a rudimentary understanding of the cellular events that underlie pancreatitis. Like Traumadoc pointed out, there's so much about inflammatory mechanisms we still don't understand...or maybe it's through another pathway entirely. Maybe steroids remove some of the protection against pancreatic enzymes, maybe they mess about with the hormonal control of the pancreas...just revel in the mysteriousness of it all!

Fair enough, thanks.
Goddamn mysteriousness. :P :pac:
Just wish mysteriousness was less pervasive in medicine (and more explicitly acknowleged when present).

EDIT: Just saw your previous post, you seem to have answered some of your questions already!

Thanks.