Blood-Brain Barrier compartmentalizes / dampens overdose effects in > binary manner?

[Nagelfar]

Blood-Brain Barrier compartmentalizes / dampens overdose effects in > binary manner?

By this I mean, if it is possible (which as a loperamide addict for years, I am quite sure that it is) to "rush the gate" and get p-glyco-protein overwhelmed to get drug effects from high doses, is there a differing concentration in areas of the brain or in depth of penetration of the brain of said p-glyco-protein which make deeper drug penetration (to the automatic nervous system, breathing, heart rate, etc.) less than to the conscious / subjective cortex that would lead to a subjective "high"?

I ask this, because I just did a 45 day sentence in county jail and kicked a 200mg a day loperamide habit of about two years straight. Within one week (blood serum level lowering to the point of BBB complete impasse?) I felt fine again, much quicker than a non-p-G-protein affinity opioid, but it was an *extremely* taxing detox. I lost 45 lbs in six days, couldn't eat or get food down or drink a thing at all (got very dehydrated due to it, but amazingly, didn't get much even in the way of diarrhea on account of it, some, but maybe one time) which is like a third of my body weight, went from over 150 lbs to 113 lbs (at five foot eight inches height), in under a week. Possibly a dangerous amount of weight loss.

Now my question comes up because, when I got out of jail this past weekend, after three days I wondered what would happen if I did the same amount as before I went in (which is about what I jumped to when I got of prison two years ago from doing it sporadically), one hundred pills or 200mg in one go.

Now normally, going back to the same amount of opioid as you had been maintenancing on is easily fatal, easily something one would overdose on in one capacity or another; even if just "nodding out", well, having taken eight bottles in 48 hrs with low tolerance and only overdosing on lope at that point, I figured going back to 200mg might be safe; all that happened, was I got an extremely euphoric opiate high, e.g. my pupils were pinned, I didn't have a bowel movement for one day (had four the next day), got very 'energized but relaxed', didn't so much as nod out, and definitely didn't feel as if I was "overdosing"

Might the BBB affinity for loperamide be able to regulate it in more than an "either/or" (1 or 0, binary) manner of it "just gets into the brain" or it "just doesn't"? Might areas of the brain, the deeper, reptilian-brain ones, more necessary to the automatic functions of survival, be more likely to filter it out (more scaffolding of p-G-protein between which) than the seat of consciousness that dictates subjective experience of high?

If so, might megadoses of p-G-protein affinity opioids be largely *SAFER* than opioids that have no such affinity for that reason? My own colloquial experimenting on myself, though I admit very much original research, seems to indicate as much to me (I know how often this kind of thing is brought up by laymen, but the discussion I wish to elicit is the nature of the BBB and whether any academic research shows that this aspect of the BBB may be more complex than it is simplified and explained as)

Also, good to be back, I think this thread topic will explain where I have been for the past month and a half as well.

 

[sekio]

I think this thread topic will explain where I have been for the past month and a half as well.

it does beg the question of why an upstanding scientist like you would be in and out of jail!

Loperamide is just a really strange drug. As there obviously hasn't been an extensive study on ultra high dosage use you are kind of playing with fire here.

The BBB is all or nothing, though, you can't have a drug that magically isolates itself from the respiratory centers that way. But loperamide could have some activity at another type of receptors (viz. BIMU-8 ) that make it a mild respiratory stimulant or counteract some of its depressant effects.

I think you got lucky and your tolerance just didn't drop to the point where the normal dose of lope would make you sick. I'm certain people have had regular old opioid OD's with loperamide, and its lack of predictable "lower opioid effects level" makes using it more, not less risky. I think it actually also causes long QT syndrome, so please be careful...

 

[Cotcha Yankinov]

Welcome back Nagel! Glad to see you're okay

I remember seeing some information on some drugs remaining closer to the arteries and not diffusing too well, which might mean that the regions that are very well supplied with vascularity such as the Default Mode Network might have some differing pharmacokinetics. The other thing is that there are some areas of the brain that are not guarded by the BBB very well/well at all, see for example https://en.wikipedia.org/wiki/Subfornical_organ and the AV3V region.

Hope this was somewhat helpful lol, and I hope you'll start putting on weight soon, toodles

 

[Nagelfar]

The BBB is all or nothing, though, you can't have a drug that magically isolates itself from the respiratory centers that way.

The other thing is that there are some areas of the brain that are not guarded by the BBB very well/well at all, see for example https://en.wikipedia.org/wiki/Subfornical_organ and the AV3V region.

OK, well this is not a matter of consensus between two members I respect, then. I thank you for the reference on your end Cotcha.

I am well aware of the risks and have been for some time. Ironically, I was arrested for begging a doctor to admit me to a hospital, the ER doctor, and in Washington State, got charged with "Interference With Person Performing Official Duties" (RCW [Revised Code of Washington #] 69.25.155[1]), which is a felony. They wanted to give me twenty months originally, but I explained I was trying to get clean and had been without a possession charge for the last several years (thanks to Imodium addiction)

 

[sekio]

There are indeed some areas of the brain that lack a BBB - i.e. chemoreceptor trigger zone - however, the respiratory centers of the brain and other critical stuff like that is most certainly behind the BBB. The lack of a barrier in the circumventricular organs does not expose the remainder of the brain. I don't think drugs can diffuse fast enough into the other parts of the brain via the small gaps - there's not necessarily transporters to move the drugs around.

Shitty deal about the docs. Hope you're doing better.

 

[Cotcha Yankinov]

Sorry guys I just read the full thread and processed the real query lol - there is research suggesting that the BBB is not exactly static because the supporting cells that help maintain the BBB such as astrocytes can increase permeability of the BBB in times of stress. This is typically during times of infection/inflammation but BBB dysfunction is implicated in different pathologies. It might be a way for the brain to allow increased access to the central nervous system for the immune system to deal with infections (although I heard that about the nerve blood barrier specifically) or it might just be plain old dysfunction and there's no huge evolutionary advantage I suppose.

Neuropathic pain like complex regional pain syndrome is an example of where there can be very bad nerve blood barrier dysfunction and where that really contributes to the pathology of the disease, but I remember reading about other conditions where there was pathology of the astrocytes maintaining the BBB, I believe there was some BBB dysfunction implicated in neurodegenerative disease and such.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4068281/

On the other end, there is talk of being able to make non CNS endothelial cells express P-glycoprotein if they're in the presences of astrocytes.

But yeah basically I think a possibility is that you were under such stress that your BBB was not running at 100%.

Almost 20 months though? Wow.

 

[Nagelfar]

Sorry guys I just read the full thread and processed the real query lol - there is research suggesting that the BBB is not exactly static because the supporting cells that help maintain the BBB such as astrocytes can increase permeability of the BBB in times of stress. This is typically during times of infection/inflammation but BBB dysfunction is implicated in different pathologies. It might be a way for the brain to allow increased access to the central nervous system for the immune system to deal with infections (although I heard that about the nerve blood barrier specifically) or it might just be plain old dysfunction and there's no huge evolutionary advantage I suppose.

Neuropathic pain like complex regional pain syndrome is an example of where there can be very bad nerve blood barrier dysfunction and where that really contributes to the pathology of the disease, but I remember reading about other conditions where there was pathology of the astrocytes maintaining the BBB, I believe there was some BBB dysfunction implicated in neurodegenerative disease and such.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4068281/

On the other end, there is talk of being able to make non CNS endothelial cells express P-glycoprotein if they're in the presences of astrocytes.

But yeah basically I think a possibility is that you were under such stress that your BBB was not running at 100%.

Almost 20 months though? Wow.

Well on the other end, the kind of molecule involved in affinity with p-glycoprotein, I have read (though cannot now cite where), can have differing amounts of affinity for it depending on the conformation of the molecule, it's not 100% associative with it or 0%, can anyone verify this?

 

[DotChem]

Glad see you back @Nagelfar (thought you landed psych ward long term?).
But does the concentration of P-GP really matter much since it is more kinetically than thermodynamically controlled. I mean it works like a pump: the drug is able to freely get in (because it is not hydrophilic, clogP > 2) but is pumped back out at a rate exceeding the diffusion(entry) rate so that in balance there is more drug out than in the brain. The binding affinity of the drug to the glycoprotein is not so much important as the rate of "unbinding" so to speak; K(on) rate <<< K(off) rate so that more is pumped out?

 

[Limpet_Chicken]

I have to say, I am disgusted by pigs trying to press charges, and for that matter, the fact that medics asked for somebody to be arrested for begging for assistance to get clean. They clearly, assuming you were not 'kicking off' so to speak, but simply being persistent/desparate, have little regard for the hippocratic oath. Haven't those bastards got thieves, killers, rapists, arab suicide bombers and nonces to arrest and innocent people to beat on, tazer and murder?

 

[Nagelfar]

Glad see you back @Nagelfar (thought you landed psych ward long term?).

Almost did! Lawyer said I could be sent to Western State mental hospital, but on a felony I'd have to do 5 years (after I got out they said that's B.S., because it costs the state $500 a day to keep me there, I should have said *yes* and then I'd be further on my way to getting SSDI)

But does the concentration of P-GP really matter much since it is more kinetically than thermodynamically controlled. I mean it works like a pump: the drug is able to freely get in (because it is not hydrophilic, clogP > 2) but is pumped back out at a rate exceeding the diffusion(entry) rate so that in balance there is more drug out than in the brain. The binding affinity of the drug to the glycoprotein is not so much important as the rate of "unbinding" so to speak; K(on) rate <<< K(off) rate so that more is pumped out?

Interesting question, anyone?

I have to say, I am disgusted by pigs trying to press charges, and for that matter, the fact that medics asked for somebody to be arrested for begging for assistance to get clean. They clearly, assuming you were not 'kicking off' so to speak, but simply being persistent/desparate, have little regard for the hippocratic oath. Haven't those bastards got thieves, killers, rapists, arab suicide bombers and nonces to arrest and innocent people to beat on, tazer and murder?

I appreciate the commiseration, but I am not too worried about it; I mean, didn't I ultimately get what I want? ~30 days clean off of lope? I mean, no detox place would have kept me that long. Providence works in mysterious ways.

 

[serotonin2A]

Glad see you back @Nagelfar (thought you landed psych ward long term?).
But does the concentration of P-GP really matter much since it is more kinetically than thermodynamically controlled. I mean it works like a pump: the drug is able to freely get in (because it is not hydrophilic, clogP > 2) but is pumped back out at a rate exceeding the diffusion(entry) rate so that in balance there is more drug out than in the brain. The binding affinity of the drug to the glycoprotein is not so much important as the rate of "unbinding" so to speak; K(on) rate <<< K(off) rate so that more is pumped out?

You are correct that it wouldn't be the ratio (ie, affinity) that is most important. But you also wouldn't want Kon rate << Koff rate, because then there would be a bottleneck at the association stage. What you really want is for both Kon and Koff rates to be very fast.

 

[Limpet_Chicken]

Nagelfar, Its just that I have been been abused SO badly by those fucking shiteating whorespawned gutterborn ratbastard pieces of shit, shat from the diseased twat of mothers who really are kidding themselves they EVER had a tight pussy. When in reality the repulsive cheese-fermentation tanks they were defaecated forth from as neonates is in actual fact, just a supernumerary mouth that didn't develop properly. Its a sewer, with obese, overstuffed rats feeding on the lake of refried cheesy pinto beans they swim about in.

I would be more than disgusted at the treatment you received from both the medicks (I guess their field speciality must have been in autoproctology), the living matrilineal C.albicans burritos, and just generally the fucking injustice of it all. Did it actually hold up in court, and if so, HOW for the love of shitting bejesus H Styx on a unicycle-riding bloody well uni-the-fucking-hades-corn? surely not in front of a jury?

But given quite what I myself have (repeatedly) suffered at the hands of those justice-despising, contemptible, loathesome gutterspawned ambulant sewage-gobbets, I have absolutely ZERO sympathy, support or anything whatsoever bar utter contempt and the most searing, furious, acidic, vitriolic hatred for the pigs. I managed to get rid of the last bunch to turn up here though for once without them doing damage, by pretty much telling them don't even BOTHER looking for a chemistry/biotyech lab, yes, I've got one, despite what YOU lot have done to damage it in the past. You lot already KNOW the fact that I am indeed a chemist, and despite the things you have broken, illegally seized and stolen, I rebuilt it each and every time, so don't even fucking try, because the pork already know I have one, and you will not stop me, not now, and not EVER. Damage my shit another time and I will take you all to court, and regardless of anythign you could do, I'll be right back in operation as fast as replacement equipment can arrive. So go, there is nothing to see here.

 

[sekio]

can we limit the imagery plz: we get that you don't like state doctors but it's not productive to be going off like that

 

[Nagelfar]

Nagelfar, Its just that I have been been abused SO badly by those fucking shiteating whorespawned gutterborn ratbastard pieces of shit, shat from the diseased twat of mothers who really are kidding themselves they EVER had a tight pussy. When in reality the repulsive cheese-fermentation tanks they were defaecated forth from as neonates is in actual fact, just a supernumerary mouth that didn't develop properly. Its a sewer, with obese, overstuffed rats feeding on the lake of refried cheesy pinto beans they swim about in.

Wow. I (am glad I) didn't even mention the fact that four hospital security guards put the boots to me for touching the doctor until I defecated myself (*ahem*, acute lope WD) and a police officer there who was getting an X-ray for a work injury joined them. (I remember distinctly saying "you're hurting me!" and them answering sardonically "I know.")

But I was laughing about it not long after, I mean, I got to punch a doctor who was wrinkling his nose at me and thought himself high above my plight.

45 day sentence? For me who has been in prison? Worth it.

 

[Limpet_Chicken]

Lol i can one up you there.

I was WDing hardcore, and i had had nothing offered me to eat, nor anything to drink for days. Maybe longer, i can't be sure. End of it I snatched a pig's can of coke, ran for it, gulped it down then ripped the can in half, tried to ghost one of the porkers with the sharp edged metal like a garotte

And it isn't doctors i dislike. Its the filth.

 

[Weltmeister]

How is it even legal to deny people in withdrawl their medication. In germany these doctors would get sued into oblivion and lose their license