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Something is not adding up, can someone please explain (opiates & their receptors)

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NSXR

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Something is not adding up, can someone please explain (opiates & their receptors)

I have more of a technical/scientific question about opiates and their receptors...

Talking hypothetically here, lets say a person is addicted to opiates. The person needs at least 30mg of oxycodone to curb their withdrawals, or 4mg of bupe to curb their withdrawals. We all know if you take bupe too soon after taking another opiate, the bupe knocks the other opiate off the receptors and puts you into a precipitated withdrawal, so heres where my question comes in...

Say the opiate addict is in withdrawal, then takes 30mg of oxycodone. He feels better, and soon gets his hands on 4mg of bupe but takes it too soon and ends up in precipitated withdrawal. How is this even possible? 30mg of any opiate would take up X amount of receptors, so 4mg would obviously take up 4/30 the amount of receptors, so wouldnt 4mg of bupe only be able to knock off 4mg of the oxy? I feel like the whole concept breaks some sort of law of physics, its not like the bupe can multiply itself, what happen to the other 26mg of oxy?

And the question goes beyond the whole precipitated withdrawal thing. What about potency/dosage in general? You can OD off 1mg of fentanyl, so whats the deal with that? Does the 1mg of fentanyl activate a very small amount of receptors, but so strongly that its enough to kill you? Is there a ceiling dose for weaker opiates like codeine, simply because there are no receptors left to occupy?
 
The suboxone causes pwd with its high binding affinity..

Fentanl od is caused by its high efficacy..



Binding affinity is a measure of how strongly a compound binds to an enzyme.



Efficacy is a measure of the effect on some biological property
 
I think OP is also confused about opiate conversion rates.

1Mg of morphine does not = one mg of fentanyl. This is why you need more of one to achieve the same effects as the other.. And why a heroin withdrawal will never be satiated with codeine (or even morphine IME)

Not all the drugs fill receptor sites at the same dosages. At all. And different opiates last longer than others.. Such as suboxone an methadone. Each opiate is really a unique drug in its own right, the commonality being that they stimulate the same receptors. Even then different opiates work on difference types of opiate receptors. The main one that creates euphoria is the my receptors while the kappa are associated with negative and physical effects.. Dysphoria, respiratory depression etc.

Its a pretty basic question actually. It sounds like you know about receptors but not at all how opiates work on them.
 
Bupe is what's called a partial agonist, this means that it binds to the opoid receptor but it doesn't activate them with 100% "efficacy" like a regular opiate, so maybe bupe only activates the mu opoid receptor (MOR) 50% of the way. Bupe is competing with the oxycodone for access to the MOR - as the bupe concentration rises, there will be less oxycodone binding and activating the MOR 100% of the way and more and more bupe binding and only activating the receptor 50% of the way and blocking a 100% drug like oxycodone from binding.

On the other end of 100% efficacy (a full agonist) you have antagonists, which bind to the receptor and block it. But in between 100% efficacy (full agonist) and 0% efficacy (antagonist) you have partial agonists.

The point is that if a weak efficacy partial agonist has high affinity for a target, it can compete competitively with a higher efficacy ligand and reduce the amount of full agonists binding.

This means that when endogenous receptor activation is low, bupe can increase overall MOR response, but as receptor activation rises with a full agonist, bupe won't get you even higher because it's competing with the full agonist and every time bupe binds and only activates a receptor half way, that means an opiate could have bound there instead and activated it 100%.
 
I'm sure someone has pointed this out but 4mg of bupe is way, way more than 30mg oxy in terms of its binding affinity and potency
 
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