Loperamide and MPTP dangers

[edzeppelin]

It looks like ill bengoing back to the suboxone dr and extend the time it will take to get my CDLs for my job. They dont let truck drivers if they are prescribed opiates. .

Buprenorphine/suboxone doesn't show up on a drug test for opiates, from what I've read on this site. Are you saying you are delaying getting a CDL(commercial drivers license) because of suboxone?

 

[serotonin2A]

And what is LPP exactly? It doesn't seem likely either that loperamide might be dehydrated in vivo to a metabolite that is MPTP-like.

Loperamide can be metabolized to a MPP-like metabolite:
http://www.ncbi.nlm.nih.gov/pubmed/15319335

 

[N0 W4RN1NG]

^^^Thank you for posting that, I was looking for this after Adder's reply, but did not find it.

The article in question mentions an interesting piece of information: Loperamide's metabolic conversion into LPP, from the first pass metabolism at least, seems to be mediated by CYP3A4.

Therefore, perhaps in the interest of harm reduction, we should be encouraging loperamide (ab)users (ESPECIALLY to those taking p-GP inhibitors) to co-administer P450 inhibitors? White grapefruit juice from concentrate, the cheaper the better (bergamottin and naringin[actives responsible for 3A4 inhibition] is rich only in the rind skin, which is not used as much in higher quality, and subsequently more expensive, products) for instance is practically as cheaply and readily available as loperamide itself.

This does not necessarily mean that lab clones with 3A4 knockout are incapable of producing LPP by some other mechanism. One should not lull themselves into a false sense of security. Loperamide, in these incredible doses, is revealing itself ever more to be a fairly dangerous drug, or at least has the potential to be one. I am not saying it is not possible to use it correctly; clearly Nagelfar has figured some way out, and I myself have used Loperamide succesfully many times to ease withdrawals, but only on a short term basis.

But it seems that the "average Joe", who has not been reading on substance forums for a decade, will not be as succesful as myself or Nagelfar. To them, I would recommend abstaining from loperamide entirely, although ironically enough they are the group which will never read this message.

For the rest of us, unless a Mod (or someone who is not a mod, but has clearly an impressive knowledge of pharmaco kinetics - like adder for instance) comes in and disagrees with me, I recommend all loperamide users administer the substance orally alongside a CYP3A4 inhibitor (like the grapefruit juice for instance) from now on.

EDIT: @EdZeppelin, I assure you that buprenorphine will not trigger a drug test for opiates, (or, as written on the test, "OPI") like you said. However, the test will come back conclusively for "SUB".

IT IS NOW VERY CUSTOMARY IN THE USA FOR EVEN REGULAR JOB SCREENS, LET ALONE PAROLE/CERTIFICATION ELIGIBILTY, TO TEST FOR BUPRENORPHINE.

This was not the case even 5 years ago, but it is strongly the case today in 2016, of this I am actually painfully aware of in a personal way.

 

[serotonin2A]

^^^Thank you for posting that, I was looking for this after Adder's reply, but did not find it.

The article in question mentions an interesting piece of information: Loperamide's metabolic conversion into LPP, from the first pass metabolism at least, seems to be mediated by CYP3A4.

Therefore, perhaps in the interest of harm reduction, we should be encouraging loperamide (ab)users (ESPECIALLY to those taking p-GP inhibitors) to co-administer P450 inhibitors?

I don't think that should be the recommendation without evidence. The downside is that CYP inhibitors could potentially increase loperamide blood levels, increasing the risk of cardiac problems.

 

[N0 W4RN1NG]

^^^Much agreed - we should all tread carefully on any given thing, sans evidence.

But the study posted by yourself, says that primary metabolites were produced by CYP2B6 pathway, not 3A4. White grapefruit juice affects almost exclusively 3A4. Major clearance of loperamide should not be affected by 3A4 inhibition/deactivation.

EDIT: And this was an exceptional study, especially for a niche of such obscurity, in that the findings were done in both rat AND human.

To me, this is evidence enough that selective inhibition of 3A4 is a beneficial thing, with no foreseeable drawbacks, and much potential benefit (in those who are going to use loperamide regardless, harm reduction must be a key mode of thought)

But, let the masses chime in, and therefore, come to a conclusion.

 

[serotonin2A]

^^^Much agreed - we should all tread carefully on any given thing, sans evidence.

But the study posted by yourself, says that primary metabolites were produced by CYP2B6 pathway, not 3A4. White grapefruit juice affects almost exclusively 3A4. Major clearance of loperamide should not be affected by 3A4 inhibition/deactivation.

Read it again -- it didn't say that.

"Recombinant P4503A4 catalyzed all of the loperamide biotransformation pathways in human liver microsomes"

"Loperamide depletion was markedly inhibited in human liver microsomes pretreated with 2 μM ketoconazole, a selective P4503A4 inhibitor"

3A4 is the primary isoenzyme that metabolizes loperamide and enzyme inhibition would almost certainly produce drug-drug interactions.

 

[N0 W4RN1NG]

You may have accidentally left off the end of that first point, I will remind you:

...Recombinant P4503A4 catalyzed all of the loperamide biotransformation pathways in human liver microsomes, whereas P4502B6 was only responsible for N-dealkylation and N-oxidation routes...

I concede that I did misread that portion of the study initially, and thought it said "ONLY 2B6 was responsible" instead of "2B6 was ONLY responsible"...Thank you for bringing that to my attention.

In light of that evidence, it seems on the surface that loperamide users who take substances which are 2B6 inhibitors should not take the 3A4 inhibitor also...but this is debatable.

Users of loperamide who take 2B6 inhibitors, WITHOUT 3A4 inhibitors, are likely to have a MARKED increase in LPP+ production in vivo, thanks to decreased clearance into the safer metabolites by 2B6...so it can be argued that loperamide users on 2B6 inhibitors *MUST* take 3A4 inhibitors, or risk increased cellular toxicity.

Yes, the dose of loperamide will have to be lowered accordingly, but since it is already such an impotent substance in the real world, I question whether an increase of, say, 25% of oral dose would actually have a very pronounced effect on cardiovascular health, especially if the most pertinent of the toxins being produced is cut by 75%.

All conjecture, of course. I am not a doctor, and I don't "play one on TV", but I do work in the medical profession - and while it would be terrible prescribing practice to suggest use of P450 inhibitors without respective reduction in substrate, I do think it still may be a safer route to take - especially if used as long-term ORT - than to simply allow LPP+ production unhindered.

Ideally, a loperamide user should take a lowered dosage than they usually do - alongside a CYP3A4 inhibitor - to mitigate health risks that they already assume upon themselves from ingesting loperamide regardless.

Or do you disagree with this train of thought? (Anyone?)

 

[serotonin2A]

You may have accidentally left off the end of that first point, I will remind you:

I concede that I did misread that portion of the study initially, and thought it said "ONLY 2B6 was responsible" instead of "2B6 was ONLY responsible"...Thank you for bringing that to my attention.

In light of that evidence, it seems on the surface that loperamide users who take substances which are 2B6 inhibitors should not take the 3A4 inhibitor also...but this is debatable.

I omitted the end of the quote on purpose. 2B6 can metabolize loperamide but its role is almost negligible compared with 3A4. That can be clearly seen from Fig. 8

Yes, the dose of loperamide will have to be lowered accordingly, but since it is already such an impotent substance in the real world, I question whether an increase of, say, 25% of oral dose would actually have a very pronounced effect on cardiovascular health, especially if the most pertinent of the toxins being produced is cut by 75%.

I think you are underestimating the potential severity of the interaction. You can't base any conclusions on the study we are discussing because it was conducted in vitro. One study that actually looked at the potential interaction in humans found that a 3A4 inhibitor increased peak loperamide plasma concentration almost 3-fold (from 0.62 ng/mL to 1.78 ng/mL). While a 25% increase may not be all that worrisome, a 300% increase is dangerous, especially given the fact that people are taking high doses. Until it is clear that there is actually a neurotoxicity risk, I don't think CYP inhibition should be recommended as a harm reduction strategy due to the potential for drug-drug interactions.

http://www.ncbi.nlm.nih.gov/pubmed/16758263

 

[N0 W4RN1NG]

^^^You are indeed correct, a 300% increase is a different matter entirely.

Perhaps it could be used as a potentiation method then...but now we are talking about a niche use, and not something to be recommended to all users...

It is also true that a clear risk of neurotoxicity has not been documented from LPP+.

But, MPP+ doesn't act purely as a neurotoxin, but as a mitochondrial poison...this is more relevant in the brain because neurons aren't exactly "replaceable on the fly"...but of course, all cells contain mitochondria, and rely on them heavily. Since loperamide induced arrhythmias dissapear after discontinuation, even after being switched onto methadone, for instance, perhaps loperamide's cardio toxicity is not based in QT elongation like most opioid, but actually a result of direct cardiovascular damage from LPP+...again, purely conjecture...but mitochondrial poisons are nasty things....

I still will personally be using loperamide with a CYP3A4 inhibitor in the future, along with a greatly reduced dose, should I ever find myself in a nasty withdrawal situation.

But you are correct, given the other study's benchmark of CYP3A4 inhibition increasing loperamide concentrations 3-fold, this is probably not something to be recommending to every loperamide user.

 

[Limpet_Chicken]

Serotonin2A-not necessarily, not its only a relatively small section of neurotoxins that actually cause permanent cell death, excitotoxins are the main kind.

But any toxin that exerts all or its main set of toxic activity/s via the CNS, PNS or, I suppose, the enteric nervous system could be and usually are, classed as neurotoxins.
You wouldn't argue the toss, I am sure, of the truth/falsity of a statement such as that cobra (although in this case the effects are a mixed bag, seeing as how many or even perhaps most cobras possess a not insignificant tissue affecting component), mamba, krait or for another family, many spider, let's say, Latrodectus (the true widow spiders) venoms are neurotoxins. They don't destroy nerves for a lot of the time. But the effects on nervous transmission are inimical to the maintenance of life or health.


Of course with something like LPP+ that doesn't apply, for the above reasons^

Is MAO-B required for the induction of biotoxification with loperamides metabolite LPP to LPP+? it is with MPTP.

 

[serotonin2A]

Serotonin2A-not necessarily, not its only a relatively small section of neurotoxins that actually cause permanent cell death, excitotoxins are the main kind.

But any toxin that exerts all or its main set of toxic activity/s via the CNS, PNS or, I suppose, the enteric nervous system could be and usually are, classed as neurotoxins.
You wouldn't argue the toss, I am sure, of the truth/falsity of a statement such as that cobra (although in this case the effects are a mixed bag, seeing as how many or even perhaps most cobras possess a not insignificant tissue affecting component), mamba, krait or for another family, many spider, let's say, Latrodectus (the true widow spiders) venoms are neurotoxins. They don't destroy nerves for a lot of the time. But the effects on nervous transmission are inimical to the maintenance of life or health.


Of course with something like LPP+ that doesn't apply, for the above reasons^

Is MAO-B required for the induction of biotoxification with loperamides metabolite LPP to LPP+? it is with MPTP.

You have to evaluate my answer in the context of the specific topic we are talking about, which is whether there are some opioids that are neurotoxic or have neurotoxic metabolites. It is true that some chemicals are defined as being neurotoxic by virtue of just deranging brain function, such as curare. However, using that as the definition for this discussion is meaningless because virtually all opioids would then be considered to be neurotoxic by virtue of the fact that they can derange breathing to the point that they produce fatal respiratory depression. Thebaine and normeperidine would also be considered to act as neurotoxins because they can cause seizures. However, in the context of a discussion about MPTP, it is meaningless to call thebaine or other opiates/opioids neurotoxic -- that isn't what the person who posted the question was asking about.

It is not just excitotoxins that cause cell death. Metabolic poisons like MPP can also cause neuronal death. Hexanes and arsenic can also cause neuronal death. Botulinum toxin can also cause neuronal death...

 

[Weltmeister]

If I remember correctly there have been cases of people with a defective blood brain barrier (either chronic or from a desease) who had very bad reactions to loperamide. The information in this thread would certainly explain why.

 

[paranoid android]

No other opioids are known to have neurotoxic metabolites.

Meperidine/Pethidne produces the rather toxic metabolite Norpethidine. (Dextro)Propoxyphene produces the really nasty metabolite Norpropoxyphene.

How the hell can anyone take 80mg's of Loperamide a day? The most i take at one time is 8mg's which works just fine to stop the D. I only take that much when i am really suffering. I couldn't imagine the constipation from 80mg's of the stuff.

 

[Limpet_Chicken]

Yeah appreciated serotonin2A.

I wasn't really placing my remarks in the context of opioids as such, aside from the observation about pethidine. I was just pointing out that your definition of neurotoxic seemed to be excessively narrow,to the point of classifying the vast majority of toxic principles with effects dependent upon the effects upon the nervous system entirely, or almost entirely (such as compounds also carcinogenic, mutagenic etc.)

I didn't think botulinum toxin caused cell death. Rather, it is first uptaken into the nerve terminals of cholinergic neurones and prevents association of/dissociates synaptobrevin, an intracellular protein required for acetylcholine exocytoxis from storage
vesicles, with its associated effector, a protein of the SNARE family which seem to be involved generally in controlling exocytosis of neurotransmitters. permanently inactivating the cholinergic synaptic terminal and requiring re-arborization and regrowth of new synapses. But it spares the cholinergic axons themselves and the soma. Unless removal of cholinergic input in and of itself then results in denervation, but in which case, wouldn't botox and botulism both be irrecoverable?


Paranoid android-isn't the mechanism of action of the toxic muck resulting from propoxyphene administration (not to imply however that the drug itself is not toxic muck, it is, its both toxic and an utterly, utterly garbage excuse for an opioid. Had it only once, and that was only because I happened to come across a box of the stuff whilst liberating a bunch of copper pipe and lead scrap from a skip, somebody had thrown out the box of D-propoxyphene. On trying it, because I was withdrawing at the time, I realized WHY they must have done so

Had I known from subjective experience, and had I also not being in opioid withdrawal at the time, I'd probably have returned it to the place from whence it came, for a dumpster is where indeed it is most in its rightful place

 

[Limpet_Chicken]

And 80mg bad? definitely. But just read that account of someone taking 1g!

That was truly shocking to say the least. I thought I'd seen, read, and heard it all. But fuck me diagonally with a rusty syphilitic mink and call me mother cunting well theresa, a gram of loperamide....fuc...fuck..fucking he....just...jesus twatting wept! there are no words for that, no words are suitable both to describe it, and to be written where the rest of the human race might read them. Whilst there are indeed a few things I'd have to say to describe quite how shocking reaching a state through opioid abuse
where a full gram of loperamide is required to prevent the person ingesting same from shitting themselves so hard that they can lace up their shoes using their trachea, I cannot here say them, for most of them are not only impolite, but they require the use of at LEAST my second fluent language. And given that its ASL sign language, the catalog of obscenities I have in mind cannot therefore be posted via the medium of a post here.

I shudder to even think about the tolerance level that must require. Because loperamide, peripherally is a pretty damn potent opioid. To put it into perspective I can myself easily shoot up a gram of morphine sulfate, assuming I am able to locate a syringe of suitable capacity to dissolve that quantity and use a butterfly, etc. to get around the physical solubility constraints, and one or two 12mg boxes of loperamide, orally is quite sufficient to deal with the GI issues were I to do so at that level of morphine abuse for a while and then stop cold turkey for long enough to provoke withdrawal at its subsequent maximal amplitude. I'd need some of my ondansetron too, but I need that anyway to deal with other GI trouble. And it doesn't stop the acute beshittendom resultant from sudden stoppage of high-level opioids, just the stomach cramps and vomiting.

 

[Nagelfar]

^technically; it was a gram and a quarter. 1,250mg. (4 seventy-two count boxes, within 24hrs later the next day, 4 ninety-six count boxes). Narcan'd 5 times, they wanted to do a sixth but I was conscious and didn't go out again since the last shot and was able to refuse it, before moving me from ICU.

(if someone is a medical historian for some junkie Guiness Record Book, I'd be glad to sign a release of info for you to get the hospital records on the incident; circa Nov./Dec. 2014, PeaceHeath, Vancouver WA)

 

[Limpet_Chicken]

!!!


^that
^is
^all


(one or two questions though), did the naloxone overpower that obscene dose of loperamide in totality, inducing precipitated withdrawal; or were there still opioid agonist effects present (and do you know what dose/s of naloxone used and how far apart?
it looks like p-glycoprotein does indeed operate with saturable kinetics, and despite the alleged not passing the BBB, well it obviously does, just either shat back out again as fast as it enters, at least in humans who have the usual degree and manner of functionality where their triple-B is concerned, efflux pumps etc. etc., but being of nothing special when it comes to the drugs inherent permeability, or its both crapped out and is relatively poor at getting in in the first place.

Has it been determined which option is correct? or were Big Pharma content to know that its very poorly centrally active when taken per os, in doses that are not completely and absolutely fucking stark raving insane?

Junkie world book of records?

Bugger the historian. You should be the one to write the first page mate. That and collate the further entries and records. you've earned the right to start the book!

 

[Nagelfar]

(one or two questions though), did the naloxone overpower that obscene dose of loperamide in totality, inducing precipitated withdrawal; or were there still opioid agonist effects present (and do you know what dose/s of naloxone used and how far apart?

As for the dose of naloxone, I do not know. I do know there were no other opioids/opiates/narcotics in my system, and though they may have done a blood draw to look for problems, I do not know whether they did a drug screen to substantiate me telling them that the sole drug I ingested within this span of time was loperamide. I do know this, just prior to the ambulance / EMT /paramedics being in the parking lot of the Dept. of Social Health Services (DSHS) building I was at when I 'collapsed' and getting me immediately (and the paramedic not believing what I took in what amount: "You'd be dead!") I had quite the nod before I left, didn't remember much but I didn't get hit with narcan until the hospital, where I came to from unconsciousness; the first shot was surprising and I thanked the nurses/doctor on duty, had that intense "need to urinate / painful erogenous forced-retrograde climax impending" from instant withdrawal, so yes, it was miserable. Felt like I was dunked in ice water but sweating and under an interrogation light that was in the process of giving me a sunburn on my skin at the same time. Second time (I think) I came back to consciousness after falling out again, I said, I know this feeling, why? ("because your breathing went down to three times a minute" to which I thanked them) third time I was with it enough to ask 'how long does this last?' they told me ten minutes, I watched the clock, sure enough, at the ten minute mark exactly I start feeling a million times better, then, I black out; no memory of how long I stayed conscious after the ten minute mark, but I'm guessing not long. This happened each subsequent time with each time feeling worse, and my body getting a hint on what was going on and giving me a wider, and larger awareness of how miserable the narcan was each time. The ten minutes seemed to get longer and longer, until I stabilized, was awake, and the nurse came in and said "we're moving you out of ICU, but I'm going to give you one final (6th) narcan" starts to screw it in the epidural; "no, no, don't do that, I don't want that!" '...well, if you can refuse, you have that right' (wipes forehead in relief)

 

[N0 W4RN1NG]

^^^Regarding how they determined that Naloxone was the correct choice to make:

It is common practice in emergency medicine to give Narcan to an unconsious / semiconscious patient with bradycardia and constricted pupils which do not constrict further when exposed to a flashlight, even after lifting eyelids up and practically shoving the light in there.

This is sometimes done even before a blood test is performed, even if there are no witnesses present to say what the patient took, and the patient does not respond to questions.

The only thing they will look for, before administering Narcan, after determining shallow breathing/unconsciousness/unalterable miosis/bradycardia combination, is a "DNR" card in the pocket or wallet.

...where a full gram of loperamide is required to prevent the person ingesting same from shitting themselves so hard that they can lace up their shoes using their trachea...

Holy LOL. Thank you for that. Seriously.

 

[Limpet_Chicken]

Makes me glad as hell the other shit I'm rx'd pretty much ensures no miosis, my pupils don't pin unless the dose of opioid is HUGE (760-1g morphine sulfate, I.V does, but not very much, even with a fair few oxy IRs tossed in the shot wI get the opposite, people have in the past, asked me if I'm
on something like amphetamines or MDxx, although I wasn't), thanks to some antimuscarinics, tizanidine (and by extension I figure clonidine probably plays a part although I've not taken it, and nothing else whatsoever that could cause either meiosis or mydriasis, the two are close enough, though to assume one will do more or less anything the other does) etc.


Fly agaric can do though, although its unpredictable in that respect,