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Acetaminophen as cannabinoid pro-drug

Well codeine is a bad example, since it needs to be metablized first, and then it's metabolized into morphine. We're considering what happens in the brain, and codeine + morphine really just equals morphine in the brain. So A + B = A, not the sum of A plus B.

Morphine plus Hydromorphone doesn't potentiate, though, they synergise. Or maybe they don't synergise, they might just be additive.

BTW- Does anyone have an opinion about the question I posed above (I think) that synergy is just where A + B is more than the literal sum of the two parts, but more like A x B, and that where A + B = A + B you have something else?
 
What? Its a fine example.

Codeine and morphine both work on the same receptors (you know what I fucking meandoes taking one make the other drug more potent? You get higher but thats only because you're feeling the effects of two drugs instead of one...

Its like saying you can potentiate this morphine with another dose of morphine. That makes no sense.



Yes, I would say thats what synergy is.
 
Codeine and morphine do not work on the same receptors. Codeine is a pro-drug for morphine, and so using codeine and morphine together means that you have morphine and morphine working on the same receptor.

That's why it's a bad example.
 
Its still a good example.

Taking codeine does not make the morphine you took stronger in any way other than having more opiates in your system.
 
How is using a unique case that can't be generalized at all a good example? Synergy is multiple drugs working on the same receptor- that's not what happens with morphine and codeine. You have one drug working on one receptor.

It isn't synergy, but it's not potentiation either.
 
Not quite, morphine isnt codeines mainly active metabolite.
 
It isn't? I can't find a mention of any other active metabolites. I don't doubt that there are some, but with 10% converted, I don't see how it isn't.

refs?
 
Codeine analgesia is due to codeine-6-glucuronide, not morphine.
Vree TB, van Dongen RT, Koopman-Kimenai PM.

Institute for Anaesthesiology, Academic Hospital St Radboud, Nijmegen, The Netherlands.

Eighty per cent of codeine is conjugated with glucuronic acid to codeine-6-glucuronide. Only 5% of the dose is O-demethylated to morphine, which in turn is immediately glucuronidated at the 3- and 6-position and excreted renally. Based on the structural requirement of the opiate molecule for interaction with the mu-receptor to result in analgesia, codeine-6-glucuronide in analogy to morphine-6-glucuronide must be the active constituent of codeine. Poor metabolisers of codeine, those who lack the CYP450 2D6 isoenzyme for the O-demethylation to morphine, experience analgesia from codeine-6-glucuronide. Analgesia of codeine does not depend on the formation of morphine and the metaboliser phenotype.
 
Anything beyond conjecture, though? I can't any human or animal research indicating that what they postulate is true, though they word it so convincingly.
 
Ham-milton said:
Anything beyond conjecture, though? I can't any human or animal research indicating that what they postulate is true, though they word it so convincingly.
Click to expand...

Its been found.

Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication

Pharmacogenomics Journal 7 (4), pp. 257-265

Codeine is an analgesic drug acting on μ-opiate receptors predominantly via its metabolite morphine, which is formed almost exclusively by the genetically polymorphic enzyme cytochrome P450 2D6 (CYP2D6). Whereas it is known that individuals lacking CYP2D6 activity (poor metabolizers, PM) suffer from poor analgesia from codeine, ultra-fast metabolizers (UM) due to the CYP2D6 gene duplication may experience exaggerated and even potentially dangerous opioidergic effects and no systematical study has been performed so far on this question. A single dose of 30mg codeine was administered to 12 UM of CYP2D6 substrates carrying a CYP2D6 gene duplication, 11 extensive metabolizers (EM) and three PM. Genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism methods and a single-base primer extension method for characterization of the gene-duplication alleles. Pharmacokinetics was measured over 24h after drug intake and codeine and its metabolites in plasma and urine were analyzed by liquid chromatography with tandem mass spectrometry. Significant differences between the EM and UM groups were detected in areas under the plasma concentration versus time curves (AUCs) of morphine with a median (range) AUC of 11 (5-17)μ hI-1 in EMs and 16 (10-24) μ hl-1 in UM (P=0.02). In urine collected over 12h, the metabolic ratios of the codeine+codeine-6-glucuronide divided by the sum of morphine + its glucuronides metabolites were 11 (6-17) in EMs and 9 (6-16) in UM (P=0.05). Ten of the 11 CYP2D6 UMs felt sedation (91%) compared to six (50%) of the 12 EMs (P=0.03). CYP2D6 genotypes predicting ultrarapid metabolism resulted in about 50% higher plasma concentrations of morphine and its glucuronides compared with the EM. No severe adverse effects were seen in the UMs in our study most likely because we used for safety reasons a low dose of only 30mg. It might be good if physicians would know about the CYP2D6 duplication genotype of their patients before administering codeine.
 
I suppose its activity is still somewhat disputed, though.
 
Yeah, I don't doubt that codeine-6-gluconuride is the major metabolite, but is there any evidence that it provides the majority of the analgesia, or if it's an active opiate at all?

I assume the sunglass smilies were accidental? ;)
 
one may assume potentiation in the sense that instead of psychoactive cannabinoids binding to the "pain relief receptor" subset, they would be forced to find a home at the psychoactive receptors, and thus increase the effective potency...

this is pure speculation on my part, and my technical use of the term potentiation is probably not up to snuff with the semantics lesson above, but the point should still be valid.

also, i realize the rediculous bowl of terpenoid soup that is a smoked bowl and the diverse interactions of said molecules, but if one were injecting pure delta-9 + APAP the case i present may be true
 
^ and that even would be different than someone popping Marinols and Tylenols. The human body is as diverse as the world is full of them, and the way any given drug metabolizes in one person varies as greatly in another person as it would another time of day or day of the week or with what foods, vitamins, industrial solvents (probably food-bourne, but equally likely to be in the atmosphere) are consumed and how in said person.
 
mulberryman said:
^ and that even would be different than someone popping Marinols and Tylenols. The human body is as diverse as the world is full of them, and the way any given drug metabolizes in one person varies as greatly in another person as it would another time of day or day of the week or with what foods, vitamins, industrial solvents (probably food-bourne, but equally likely to be in the atmosphere) are consumed and how in said person.
Click to expand...

Wait, how would that be different than marinol + apap? (pure thc + apap)
 
Ham-milton said:
Wait, how would that be different than marinol + apap? (pure thc + apap)
Click to expand...

only that oral vs IV can have signigficantly different effect in many cases.

This thread's kinda giving me a headache though. It'd be nice to have a joint, but Tylenol have will do. :)
 
^ you're telling me. 2 weeks and nary a bud in sight.

I see what you mean now. I thought it was something deeper than ROA differences. I was digging for gold when Fort Knox was next door.
 
yea, they both seem to work better than the gabapentin, ime, but neither are as good as the opiates. Oh, and, the blunts in the mail, as they say/ :D
 
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