resorcinol
11-21-2008, 10:04 PM
nd it.
This was a response to a question by a friend on AIM that got out of hand due to me having a touch of speed in my system.
Agonists, Antagonists, and Partial Agonists
+++What I typed Like a Madman+++
buprenorphine does have a high binding affinity and potency, I'll give it that. buprenorphine is a far stronger analgesic in opioid naive individuals than methadone is (buperenorphine is quite a potent euphorien in opioid naive people too), by far (the EXACT OPPOSITE is true in opioid tolerant patients... then methadone is the superior analgesic).
At low doses (i'm talking like 50 to 1000 mcg), buprenorphine's actions are pretty much indistinguishable from that of a full agonist opioid. However partial agonist drugs are subject to a ceiling effect of a different kind than drugs like codeine. The ceiling effect that bupe has occurs because it begins to lose its agonist properties as dose increases. In fact, if around 20 mg (official literature says 32 mg but I don't agree) won't hold an addict out of w/d fully b/c their habit is too large, buprenorphine cannot be used to maintain them unless they're willing to taper, using a full agonist, their tolerance down a bit.
I'm going to explain why buprenorphine looses its agonist properties to a degree as the dosage increases; this is important. First, lets understand what a full agonist actually does. A full agonist doesn't attach to a receptor and stay exactly put with the receptor in the ON position like a switch.... it doesn't work that way. Rather, a drug (which I'll call a ligand from now on) needs to be able to repeatedly "activiate" the mu receptor... the mu receptor is more like one of those button switches where when you apply pressure it turns on, but bounces back to off when pressure is taken off. Also, if locked into "on" by being continuously pressed down... the light also goes off. So using this analogy, a full agonist needs to be able to turn it on, let it turn off, but rapidly turn it back on yet again.... repeat ad nauseum. Full mu agonists do this by seating in the receptor in such a way that they "bounce" between two different conformations. Mu receptors are a protein, and proteins "fold"... you may remember from biology. The ligand and the mu receptor form something called a ligand-receptor complex. A full agonist ligand needs to attach, turn the folding of the mu receptor into the position that starts its signal transduction (turns it on to signal its message to the nerve cell) and then "bounce" into another conformation that turns the receptor off, but then rapidly "bounce" back into the folded position that sends another signal. A full agonist acts on the mu receptor like someone pressing a button at rapidfire pace repeatedly since the receptor can't STAY on from being activated once. Full agonists accomplish this by being able to bind to the receptor in two conformations: the one that sends the signal / turns it on, and another conformation that is "off"... sends no signal (but the "off" conformation with an full agonist bound doesn't need to be the same conformation as the completely unbound receptor... in fact, it isn't ever).
An ANTagonist at the mu receptor is such a ligand that it can only bind to the mu receptor in one conformation and it STAYS there... so even drugs that at first turn mu "ON" and take that conformation... they're still antagonists if they can't switch to another conformation briefly in order to "reset" the receptor to let it be turned on again and again.
A partial agonist acts much like an agonist at low plasma concentrations, but it has DIFFICULTY locking itself into the second, "off" confomation, and tends to lock up after awhile and not be able to witch back and forth. But, at the low concetrations in plasma, the partial agonist more often leaves the receptor, opening it up for another molecule of the ligand to bind, and struggle to switch between the two conformations. So even though they struggle, because blood levels are low, the partial agonist ligand frequently leaves any one mu receptor totally to allow a new partial agonist ligand molecule to attach...so it recreates the full agonist effect in a crude way. But, as blood conc of the ligand increases, there is more pressure for each partial agonist ligand to stay bound to its receptor. This is called Le Chatelier's Principle in equilibrium chemistry. So the bound partial agonists ligands get locked up from time to time and act briefly as antagonists at some of the receptors. Sometims they escape the lockjaw and agonize again... this is why partial agonists don't become antagonists at high doses, but the amount of agonism is limited to a ceiling... and that ceiling is how often the partial agonist can unlock itself out of one conformation... since the receptors are all saturated with the partial agonist because there's lots in your blood (Le Chatelier's). This means that above a certain dose, agonist effects of mu will not increase with a partial agonist.
Buprenorphine is a partial agonist. At the low doses where its effects are quite indistinguishable from those of an full agonist, the physical dependence potential is the same. However, when it hits the ceiling of agonism, withdrawal from understimulation of mu is pretty easy to hold back with just the occasional unlocking of bupe from its stuck conformation. Not all partial agonists are created equally either, they lie on a spectrum of how tough it is for them to unlock from the stuck conformation. Stuff like butorphanol or nalbuphine... nasty stuff... have a REALLY tough time unlocking at their ceiling doses... they can ALMOST act like antagonists at those doses. Bupe has a bit of a struggle with it, but unlocks and activates mu frequently enough to prevent w/d and to a degree, cravings, up to 20 mg for the average person. However, the amount it unlocks to reactivate mu enough to cause euphoria and analgesia... the more desirable effects .... stops becoming enough after only like 1 or 2 mg. This is why bupe is “less is more” with euphoria and hard to get off on for people with a big tolerance.
+++End of What I Typed like a Madman+++
If my understanding is plain wrong, or just a bit off, let me know.
This was a response to a question by a friend on AIM that got out of hand due to me having a touch of speed in my system.
Agonists, Antagonists, and Partial Agonists
+++What I typed Like a Madman+++
buprenorphine does have a high binding affinity and potency, I'll give it that. buprenorphine is a far stronger analgesic in opioid naive individuals than methadone is (buperenorphine is quite a potent euphorien in opioid naive people too), by far (the EXACT OPPOSITE is true in opioid tolerant patients... then methadone is the superior analgesic).
At low doses (i'm talking like 50 to 1000 mcg), buprenorphine's actions are pretty much indistinguishable from that of a full agonist opioid. However partial agonist drugs are subject to a ceiling effect of a different kind than drugs like codeine. The ceiling effect that bupe has occurs because it begins to lose its agonist properties as dose increases. In fact, if around 20 mg (official literature says 32 mg but I don't agree) won't hold an addict out of w/d fully b/c their habit is too large, buprenorphine cannot be used to maintain them unless they're willing to taper, using a full agonist, their tolerance down a bit.
I'm going to explain why buprenorphine looses its agonist properties to a degree as the dosage increases; this is important. First, lets understand what a full agonist actually does. A full agonist doesn't attach to a receptor and stay exactly put with the receptor in the ON position like a switch.... it doesn't work that way. Rather, a drug (which I'll call a ligand from now on) needs to be able to repeatedly "activiate" the mu receptor... the mu receptor is more like one of those button switches where when you apply pressure it turns on, but bounces back to off when pressure is taken off. Also, if locked into "on" by being continuously pressed down... the light also goes off. So using this analogy, a full agonist needs to be able to turn it on, let it turn off, but rapidly turn it back on yet again.... repeat ad nauseum. Full mu agonists do this by seating in the receptor in such a way that they "bounce" between two different conformations. Mu receptors are a protein, and proteins "fold"... you may remember from biology. The ligand and the mu receptor form something called a ligand-receptor complex. A full agonist ligand needs to attach, turn the folding of the mu receptor into the position that starts its signal transduction (turns it on to signal its message to the nerve cell) and then "bounce" into another conformation that turns the receptor off, but then rapidly "bounce" back into the folded position that sends another signal. A full agonist acts on the mu receptor like someone pressing a button at rapidfire pace repeatedly since the receptor can't STAY on from being activated once. Full agonists accomplish this by being able to bind to the receptor in two conformations: the one that sends the signal / turns it on, and another conformation that is "off"... sends no signal (but the "off" conformation with an full agonist bound doesn't need to be the same conformation as the completely unbound receptor... in fact, it isn't ever).
An ANTagonist at the mu receptor is such a ligand that it can only bind to the mu receptor in one conformation and it STAYS there... so even drugs that at first turn mu "ON" and take that conformation... they're still antagonists if they can't switch to another conformation briefly in order to "reset" the receptor to let it be turned on again and again.
A partial agonist acts much like an agonist at low plasma concentrations, but it has DIFFICULTY locking itself into the second, "off" confomation, and tends to lock up after awhile and not be able to witch back and forth. But, at the low concetrations in plasma, the partial agonist more often leaves the receptor, opening it up for another molecule of the ligand to bind, and struggle to switch between the two conformations. So even though they struggle, because blood levels are low, the partial agonist ligand frequently leaves any one mu receptor totally to allow a new partial agonist ligand molecule to attach...so it recreates the full agonist effect in a crude way. But, as blood conc of the ligand increases, there is more pressure for each partial agonist ligand to stay bound to its receptor. This is called Le Chatelier's Principle in equilibrium chemistry. So the bound partial agonists ligands get locked up from time to time and act briefly as antagonists at some of the receptors. Sometims they escape the lockjaw and agonize again... this is why partial agonists don't become antagonists at high doses, but the amount of agonism is limited to a ceiling... and that ceiling is how often the partial agonist can unlock itself out of one conformation... since the receptors are all saturated with the partial agonist because there's lots in your blood (Le Chatelier's). This means that above a certain dose, agonist effects of mu will not increase with a partial agonist.
Buprenorphine is a partial agonist. At the low doses where its effects are quite indistinguishable from those of an full agonist, the physical dependence potential is the same. However, when it hits the ceiling of agonism, withdrawal from understimulation of mu is pretty easy to hold back with just the occasional unlocking of bupe from its stuck conformation. Not all partial agonists are created equally either, they lie on a spectrum of how tough it is for them to unlock from the stuck conformation. Stuff like butorphanol or nalbuphine... nasty stuff... have a REALLY tough time unlocking at their ceiling doses... they can ALMOST act like antagonists at those doses. Bupe has a bit of a struggle with it, but unlocks and activates mu frequently enough to prevent w/d and to a degree, cravings, up to 20 mg for the average person. However, the amount it unlocks to reactivate mu enough to cause euphoria and analgesia... the more desirable effects .... stops becoming enough after only like 1 or 2 mg. This is why bupe is “less is more” with euphoria and hard to get off on for people with a big tolerance.
+++End of What I Typed like a Madman+++
If my understanding is plain wrong, or just a bit off, let me know.