At what point do receptor sites get fully saturated?

[RoboRobot]

So, I have a question, trying to understand the pharmacodynamics and pharmacokinetics (would it be a case of both?) of opiate receptor sites..

I take methadone. I am on MMT, a methadone maintenance program for opiate addiction. Ive been dropping my dose, and at an all-time low of 55mg! (Though, not of my own volition- I missed too many days). Since it was a 23mg drop (I was on 78mg, dropped to 55mg), I am actually feeling slight withdrawals before my next day's dose, usually in the morning/late at night. I am used to having my receptor sites completely saturated and being able to miss a day or two and be okay.

Anyway, today is Sunday, the day I have my take home dose of 55mg. I haven't taken my 55mg dose in over 24 hours, approaching like 36 hours right now. I just took 20mg of oxycodone. And it has me thinking...I know buprenorphine has such a strong binding affinity that it will compete for receptor site activity and cause precipitated withdrawals (when addicted and under the influence of another opiate). Methadone does not do this, and the opiate-blocking effect it causes, to my understanding, is just due to a complete saturation of the receptor sites after a certain dose (most say `80mg+ after daily dosing for awhile). When I was on 80 mg (and esp, when I was all the way up to 150mg of methadone), I felt I couldnt get high off of opiates. I did a half gram shot of heroin when I was on 80mg a month or so ago and hardly felt it at all (or didnt actually really feel it, even though others confirmed it was good), which was crazy. For harm reduction sake I *DID* do a small test shot first, as well. And I've had similar experiences like that multiple times, being on 80+mg of methadone and then using IV heroin and it not having any effect. Once I missed those three days at my methadone clinic recently, I was able to get high off of heroin. I took 30mg of methadone I had saved after missing one day, then waited over 24 hours and was able to use a .2 of some really good tar and get a good rush via IV and a high that lasted.

Even when they bumped me down to 55mg and I felt it wasnt fulllly holding me 24hrs, later on in the night Ive done a .1 shot and still felt it. Which leads me to believe my receptor sites are not fully saturated anymore (as well as a drop in tolerance). It's been about a week and Im starting to get acclimated to my lower dose a bit, but now Im gettiing ahead of myself.

So, I took this 20mg of oxycodone. If I take any of my methadone (been 40min dont feel anything from the oxy haha, as expected, oh well), will it compete for receptor site activity? I looked up binding affinities and it seems methadone has a stronger binding affinity than oxycodone (as expected), but its not at the level bupe (suboxone) is, where it will compete for receptor site activity and displace any of the drug.

But once methadone (or any opiate/opioid) is metabolized, does it just randomly take place into receptor sites, possibly overtaking some of the oxycodone that is at the receptor site since the methadone has a stronger binding affinity? Or will it only bind to open receptors, without reducing (removing) any of the oxycodone? Since it has a higher binding affinity, it would make sense it would displace it, but I would also like to think that would only happen once all receptor sites are saturated...

So that is where my question arises, if I didnt make it too convoluted.. Do opiates (and all drugs) randomly bind to receptor sites? Or do they only bind to open receptors, and once they are all saturated then do you have to take the binding affinity into account?

 

[serotonin2A]

Methadone maintenance does not completely saturate MOR. This study shows occupation ranges from 19-32%. Methadone works by inducing a moderate level of occupation in combination with a good deal of tolerance.


http://jpet.aspetjournals.org/content/295/3/1070.long

The fact that the occupation level is that high is actually evidence of substantial tolerance. In nontolerant individuals, full agonists induce analgesia at negligable occupation levels, and anesthesia occurs at approximately 25% occupation. Normally (ie, in non-tolerant individuals), there is actually a pretty big MOR receptor reserve, meaning that for full agonists you can get large effects from even low levels of occupation. The trade off is that there is a ceiling to the effects, so responses max out way below the point where receptors are saturated.

So methadone is not saturating receptors, but with the methadone on board there isn't much "room to move" for another agonist to increase MOR signaling. Adding heroin to methadone will increase the level of MOR occupation but that doesn't translate into much of an increase in G protein activation over what the methadone produces by itself.

But it should be obvious that 80 mg methadone is not saturating MOR -- otherwise no one would ever take more than 80 mg of methadone.

But once methadone (or any opiate/opioid) is metabolized, does it just randomly take place into receptor sites, possibly overtaking some of the oxycodone that is at the receptor site since the methadone has a stronger binding affinity? Or will it only bind to open receptors, without reducing (removing) any of the oxycodone? Since it has a higher binding affinity, it would make sense it would displace it, but I would also like to think that would only happen once all receptor sites are saturated...

When pharmacologists talk about displacement, that doesn't mean that one ligand can "remove" another ligand from a binding site. What really happens is that a ligand will go through repeated cycles of binding to and then unbinding from a receptor. Different ligands will exhibit different rates of association (binding) and dissociation (unbinding). Say you have two different ligands present adjacent to a receptor, and ligand A tends to bind at a faster rate than ligand B. In that situation, once ligand A unbinds, there is a good chance that ligand B will bind before ligand A is able reattach to the receptor. As long as ligand B does not immediately unbind (which would allow ligand A to reattach) then ligand B will gradually replace ligand A in the binding sites. That phenomenon is what pharmacologists mean by displacement.