• Neuroscience & Pharmacology Discussion Welcome Guest
    Posting Rules Bluelight Rules
    Recent Journal Articles Chemistry Mega-Thread
    FREE Chemistry Databases! Self-Education Guide

  • N&PD Moderators: Skorpio

Liver & Kidney toxicity

Solipsis

Solipsis

Bluelight Crew
Joined
Mar 12, 2007
Messages
15,503
Location
NL
What are examples of drugs (or their metabolites) that can do significant and lasting damage to internal organs - here more specifically interested and liver and kidneys.

I read in a recent trip report of 3-MeO-PCMo the claim that PCP is not easy on the liver / kidneys, but then had a hard time finding studies on actual direct toxicity. Is it just assumed, because in some extreme cases the rhabdo causes renal failure?

That got me thinking: while predictions for novel RC type drugs are usually quite hard (though we can have concerns looking at closely related chem species), what are some type of recreational psychoactive compounds - broadly speaking - that are pretty sure to damage your liver or kidneys?
Also, how does that usually happen? I guess organic damage (terrible oxidative onslaught e.g.?), but also messing with enzyme activity? How do you measure strain on kidneys (or liver), the fact that a drug is metabolized and excreted extensively alone is not strain, is it? Just a lot of work for these organs.
 
For the kidneys damage can be done through many mechanisms. Toxicity can cause changes in hemodynamics of the kidney, inflammation, direct damage to microtubules and epithelial cells or via rhabdomyolysis. Traditional markers of kidney problems would be decreased GFR and creatinine clearance and increased BUN and serum creatinine but these changes usually occur when much damage has been done. There may be more specific markers of acute damage, primarily elevations in things like albumin, transferrin and other proteins but do not know how often they are checked for clinically. Cocaine, methamphetamine, and alcohol come to mind immediately as nephrotoxic drugs of abuse with rhabdo being the primary damage.

Not too sure about the liver but imagine many more drugs can be involved and elevation of AST and ALT would be some markers of damage.
 
@Sekio: Good to see you think the same :)

@Kittycat: Thanks, great info! I would absolutely love to hear about examples of inflammation or damage to microtubules, just case studies would even be fine - if they illustrate something about the array of known common rec drugs.
I realize the liver is a pretty complex organ, I myself have chronic surprising CK levels but have also learned that this is just a natural state for some people. I entertained the idea for a while that chronic use of various drugs (incl abuse in different seperate not too long phases) has caused induction or hyperexpression of a lot of enzymes.. But that is probably just an unfounded fantasy. The enzyme population does not exist like GI flora, but is genetically expressed. Still, I wonder about if it gets upregulated in reaction to chronic hyperactivity of the enzymes.
 
http://m.cjasn.asnjournals.org/content/8/4/523.full

Case study investigating synthetic cannabinoids and neprhotoxicity in four patients. They presented with ischemic acute tubular necrosis in many ways but werent hypovolemic. Authors also speculate it may be an adulterant such as a heavy metal rather than the cannabinoid itself.

http://www.ncbi.nlm.nih.gov/pubmed/9794581?dopt=Abstract&holding=npg

Free full text available. Multiple organ involvement in this one but nephrotoxic effects may again be from ischemia or rhabdo.

http://www.ncbi.nlm.nih.gov/pubmed/7170290?dopt=Abstract&holding=npg

Old but interesting. I didnt mention uricemia as a cause of renal failure because didnt think drugs of abuse would cause it. Here is a case study showing PCP may very well do it.

http://m.cjasn.asnjournals.org/content/1/4/655.long?view=long&pmid=17699270

And finally a review of cocaine and heroin associated kidney problems. Cocaine is pretty well known to cause kidney disease but the evidence for heroin is less convincing.

It seems none of these drugs are direct nephrotoxins like aminoglycosides or cyclophosphamide but rather decrease blood flow, cause rhabdomyolysis or secondary effects of the drug lead to kidney disease (PCP case). I will keep looking though.
 
Last edited:
"Role of metabolites in MDMA (ecstasy)-induced nephrotoxicity: an in vitro study using rat and human renal proximal tubular cells."
http://www.ncbi.nlm.nih.gov/pubmed/12373454
-" it appears that toxicity induced by thioether metabolites of ecstasy at the apical membrane of renal proximal tubular cells is the result of extracellular events, presumably redox cycling."
A lot of the damage to both the liver and kidneys seem to be from ischemia, but the liver damage from psychostimulants is typically from hepatitis then resulting cell death/cirrhosis.

If the some of organ damage is from ischemia/vasoconstriction then I would guess a betablocker something like Propranolol or even Clonidine towards the tail end up the trip might help if its a very adrenaliny RC but who knows, that's assuming its more a diabetic nephropathy type scenario involving blood pressure. I found myself with low blood pressure after some methy trips so a beta blocker might not have helped with organ blood perfusion but hard to say. Something to cut adrenaline could help with sleep and recovery too which would be beneficial for organs but just a warning for readers beta-blockers can give people problems sleeping because they hinder melatonin production so take some melatonin with them if you're gonna try it :)
 
Excellent, very educative thank you. :)

I wonder if it is very hard for each user to apply to themselves, and try to figure out whether much damage has been done. Or better yet: if most damage via ischemia occurs acutely, and not so much chronically. I guess that chronic damage is always incredibly hard to tie causally. Esp in polyusers and when not doing a huge study.
 
One critical variable is whether you have multiple medications metabolized by the same liver enzyme substrate. Cytochrome P450 has many substrates. CYP2D6, one substrate, seems to metabilize multiple psychotripics. For example a lot of people are given bupropion (wellbutrin, xyban) as an adjunct to fluoxetine. It is used because, though not understood, it has a different mechanism of action than SSRI's like fluoxetine. It also helps some people with SSRI caused sexual dysfunction.

However, both drugs are metabolized by the CYP2D6 substrate, so long term use of them can effect liver function of some people. ALT and AST may become elevated and/or some 5-10% of the population, the precise number not even close to being known, has a defect in that gene expression, further interfering with metabolism of psychotropics if more than one is using the same substrate. In this case, elevated liver enzymes from multiple drugs using the same substrate, limiting alcohol and fatty foods, both which cause systemic effects to the entire liver, could be wise. Don
 
I thought about CYP-inhibiting drugs possibly being more dangerous than currently said, if it was that these enzymes were here for a reason and inhibiting them would lead to accumulation of some yet-to-be-identificated small molecule toxins / waste products / etc .. with fluoxetine being a potent example..?
 
You must log in or register to reply here.
Top