The disconnect between half life and effects

[Pegasus]

Okay, so I know all the half lives of all the drugs I use and in some cases, it makes sense. Oxycodone's half life: 3 - 4.5 hours. That seems pretty much in line with what the effects I receive tell me.


But now onto the drugs with very long half lives that I do not understand. For example, clonazepam has a minimum half-life of 18 hours, but it certainly does not take 18 hours for the majority of the effects to go away. However, if I took a dose halfway through the 18 hours (9 hours) of half of the amount I originally took, I would not be at the same level of effects that I originally was when I took the full dose.

So, here is the issue. What exactly is the relationship between half life and the effects a person receives? I am on a drug with a pretty long supposed half life (phenazepam) and the effects certainly do not take any number of days to diminish by one half. However, I am warned that this long half-life would help build addiction more easily because unlike a short-acting benzo like alprazolam which half would excrete in 4-6 hours or so, the drug will accumulate in my system. However, if I take the same dose of phenazepam every day, I would get the exact same effects every single day, exactly like if I was taking the same dose of alprazolam once a day. This doesn't seem to add up. Can someone please explain this?

Similarly, with these longer acting drugs, why doesn't the amount of drug in the system accumulate to extremely high levels after only a few dosages? It would seem that after taking three days worth of a drug that has a half life of three days, on the third day you would have like 216% of the amount of the original dose in your system, but would only be receiving effects as if you were taking it on the first day. Please, someone help me understand this!

 

[vecktor]

receptor down regulation etc also influence duration.

 

[Pegasus]

^After one use? That helps explain the long term accumulation (which I appreciate), but what about the three day test I proposed above?

 

[vecktor]

yep,
in many systems down regulation and receptor internalisation happen almost immediately, this desensitization is super fast with some systems, for example the serotonin 5ht2a system.

 

[forensic bob]

I know this does not answer your question, but it might help you understant half lives a little bit better. Marijuana has a half life of 1.6-59 hours, but only has significant psychoactive effects for approx. an hour. Why is that?...i dont know.

 

[Damien]

^ That's the very question he's asking.

 

[forensic bob]

^ That's the very question he's asking.

I know, but sometimes the best way to answer a question is to look at the subject at hand in a different light.

There has been much more open, "non-biased by the multibillion dollar pharm machine" research done on marijuana than on the drug at hand.

Considering most of the information people obtain regarding halflifes and what not somehow stem from wikipedia, a site that Pharmaceutical company employees have complete access too, looking into the half life cycle of marijuana just might be more reliable and informative than that of rx drugs.

Make sense? (if it doesnt, im open to the idea of me being naive)

 

[forensic bob]

However, I am warned that this long half-life would help build addiction more easily because unlike a short-acting benzo like alprazolam which half would excrete in 4-6 hours or so, the drug will accumulate in my system. However, if I take the same dose of phenazepam every day, I would get the exact same effects every single day, exactly like if I was taking the same dose of alprazolam once a day. This doesn't seem to add up. Can someone please explain this?

QUOTE]

I would have to disagree with whoever told you that benzos with long half lifes are more addictive than benzos with short half lifes (alprozolam).

In laymans terms,please correct me if im wrong, the difference between the two is this:

Alprozom (short half life benzo):
Quickly enters your blood stream, attatches to those benzo receptors in your brain (which it has an exceptionaly high affinity for), and makes you feel good. In a few hours, however, instead of gradualy detatching from these receptors or being metabolized into highly active metabolites (Alprozolams metabolite, α-hydroxyalprazolam, is only slightly active) that rebind to the receptors, xanex tells your brain to go fuck itself, rips itself from the receptors, and hitch-hikes towards the kidneys, then though the woods, til out of your bladder it goes. This quick change of your bodies GABA receptors from Fully activated to not active at all will cause your body to make drastic changes to maintain equilibrium and get its much needed anxiety back on track.

Valium (long half life benzo):
-very soluable in fat...im not exactly sure if this is one of the factors that give it an extrordinarily long half life, but-seeing as marijuana is fat soluable and has a comparably long half life-it is something that should be considered. Furthermore, according to my past research many scientists believe that THC's long half is at least partly responsible for the relatively small risk of psychological and physical addiction.

aaannnyywayss...When diazepam decided it had enough with your brain and wants to leave, your body doesnt metabolize it into unactive bullcrap or kick it out. Instead, those valium chemicals, upon leaving, are turned into more Benzos, temazepam (halflife:8–20 hours) and oxazepam(halflife:4-14 hours), which also have long half lives. Notice, please, that oxazepam will be eliminated roughly 6 hours before temazepam. This results in a gradual release of benzo from your gaba receptors, a phenomina that gives your body time to make subtle chemical changes in response to its activation of GABA.

Remember folks, your body has two purposes: 1)reproduction 2) the protection of life. When you use drugs that make your body less prone to fulfill either of these obligation, the consequences will be swift and unenjoyable-to say the least. Pain and anxiety, although unpleasent, are the two most effective weapons in your biological arsenal that keep you from death. Without the two, you would not be disturbed by the comingof a lion and you would be indifferent to his biting off of your nuts. If you fuck with your bodies evolutionary defense mechanisms(i.e. Opioid and benzo abuse) in an uninformed or uncautious manner, you will lose.

..that is, until we make better drugs.

Peace, forensic bob

 

[Pegasus]

^What I meant was that the longer lasting ones were more easy to become addicted to because the drug lingers for so long after the effects of the drug wear off, that by using, say, three times a week, you will never completely excrete the benzo with the longer half life while you will with the one with the shorter half life. Kind of a pain in the ass if you're just trying to take benzos on an as-needed basis...

 

[forensic bob]

I could be wrong, but since longer acting benzos are gradual in their increase and decrease in your bloodstream while short acting ones hit you hard then just leave, the short acting would be more addictive.

Crack vs. Coke

IV vs Snort (heroin)

Xanex vs. Valium

Comparisons not meant to be completely accurate (i.v. heroine hits harder and lasts longer), but you get the picture.

Maybe if your talking about psychological dependence i can kind of see your point, but with physical addiction and the psychological urge to redose short acting benzos, such as xanex, are the worst.

 

[fastandbulbous]

I know this does not answer your question, but it might help you understant half lives a little bit better. Marijuana has a half life of 1.6-59 hours, but only has significant psychoactive effects for approx. an hour. Why is that?...i dont know.

That's because it''s a mixture of cannabinols that all metabolize at different rates. In some cases the 'active' drug eg THC is metabolized into a more active (11-hydroxy-THC) drug, whos level builds as the THC is metabolized. Other inactive cannabinoids can last a lot longer & while not getting you stoned are indicative of cannabis use.

Same thing with benzos, some are metabolized into other active drugs eg valium is metabolized ionto nordiazepam, temazepam & oxazepam, all of which are active, but have differing half lives. Just because all of the original benzo taken is gone from your system doesn't mean there are no benzos in your system (clonazepam is another of those with active metabolites I believe)

Explained enough?

 

[dread]

Short acting benzos are definitely the worst.

I will never forget the 2 month wd:s I went through after my midazolam addiction.

 

[Pegasus]

That's because it''s a mixture of cannabinols that all metabolize at different rates. In some cases the 'active' drug eg THC is metabolized into a more active (11-hydroxy-THC) drug, whos level builds as the THC is metabolized. Other inactive cannabinoids can last a lot longer & while not getting you stoned are indicative of cannabis use.

Same thing with benzos, some are metabolized into other active drugs eg valium is metabolized ionto nordiazepam, temazepam & oxazepam, all of which are active, but have differing half lives. Just because all of the original benzo taken is gone from your system doesn't mean there are no benzos in your system (clonazepam is another of those with active metabolites I believe)

Explained enough?

So then, the amount of drug in your plasma does directly correlate to effects you receive, but does not completely explain the effects...? The quick receptor down regulation explained above would then come into play and also explain how you only feel the effects of a drug for the first small fraction of the total half life? (in addition to the metabolization to other drugs)

If this is the case, how does addiction play into this? Does your body get accustomed to the amount you have in plasma, or the amount that is actually bound to receptors? Is there a difference between the two? (Like, considering down regulation happens so fast, much of the drug that is in plasma is actually just floating around and not binding?)

Thanks for all of your help, guys!

 

[Pegasus]

Ok, another question related to my above one... Let's say you're taking a drug with a long half-life (phenazepam) and it binds to a bunch of receptors on that day and that dose. The next day, there will still be some of the drug (or maybe by this time its metabolites) bound to receptors... I have two questions from this point...


1) In general, is the idea correct that the amount of drug (and its metabolites) that is bound to receptors is not forever increasing when daily dosing with a drug with a long half life? If this is true and due to down regulation, how is it that taking more of the drug would result in more effects? Does the increased saturation in plasma from the larger dose make more bind than the brain had adapted to allow to bind by the original down-regulation, which occurred in response to the lower, daily dose concentration?

2) Do the metabolites from the first dose block some of the same metabolites from the second dose from binding, due to receptor down regulation? How correct is this, if it is at all?


Again, I'm still early in my schooling, so any help in explaining these concepts is greatly appreciated!

 

[Pegasus]

... Did I phrase this too confusingly for you guys? I am really trying my hardest to understand this with my limited schooling, so if there is an error in something I am saying, or if you can help point out anything to me at all, I really would appreciate it. It's kind of hard to give the best advice to the people who come into OD when I am not completely understanding the mechanisms between the actions commonly discussed.

Please help me guys. If there's any part that is so off base that you don't know where to start, at least say that so I have some clue! Please!?

 

[forensic bob]

Ok, another question related to my above one... Let's say you're taking a drug with a long half-life (phenazepam) and it binds to a bunch of receptors on that day and that dose. The next day, there will still be some of the drug (or maybe by this time its metabolites) bound to receptors... I have two questions from this point...


1) In general, is the idea correct that the amount of drug (and its metabolites) that is bound to receptors is not forever increasing when daily dosing with a drug with a long half life? If this is true and due to down regulation, how is it that taking more of the drug would result in more effects? Does the increased saturation in plasma from the larger dose make more bind than the brain had adapted to allow to bind by the original down-regulation, which occurred in response to the lower, daily dose concentration?

2) Do the metabolites from the first dose block some of the same metabolites from the second dose from binding, due to receptor down regulation? How correct is this, if it is at all?


Again, I'm still early in my schooling, so any help in explaining these concepts is greatly appreciated!

I wish i could answer that.

I wonder if the metabolites compete with each other for the receptors?

Perhaps, even though a down regulation in receptors occur, the metabolites are in a constant state of attaching and reattaching for as long as they are in the bloodstream (No one benzo molecule attaches to one receptor for 4 hours to produce a constant effect, but instead the 4 hour duration is a result of a bunch of molecules is a constant state of attach, detach, repeat) Even if a down regulation of receptors occur, an increased dose would mean that the molecules have a higher chance of hitting those receptors in the brief time interval after the previous molecule left it.

WHat is say is not fact though, so dont take it as truth. I dont know whats true, just what seems logical and plausible

 

[cegli]

Ok, another question related to my above one... Let's say you're taking a drug with a long half-life (phenazepam) and it binds to a bunch of receptors on that day and that dose. The next day, there will still be some of the drug (or maybe by this time its metabolites) bound to receptors... I have two questions from this point...


1) In general, is the idea correct that the amount of drug (and its metabolites) that is bound to receptors is not forever increasing when daily dosing with a drug with a long half life? If this is true and due to down regulation, how is it that taking more of the drug would result in more effects? Does the increased saturation in plasma from the larger dose make more bind than the brain had adapted to allow to bind by the original down-regulation, which occurred in response to the lower, daily dose concentration?

2) Do the metabolites from the first dose block some of the same metabolites from the second dose from binding, due to receptor down regulation? How correct is this, if it is at all?


Again, I'm still early in my schooling, so any help in explaining these concepts is greatly appreciated!

Alright, I can't answer your in-depth pharmacology questions, but I can help you with one misunderstanding I believe your having.

No matter the drug's half life, it will eventually hit a steady state if the dosage is kept constant.

Lets say, for simplicity, the drug has a one day half life and you are taking 1mg a day. At first thought, you may think that it would build up every day you take it because only 50% is removed per 24 hours, and you're dosing 100%. Consider this though:

-Start of Day -- End of Day

Day 1 - 1.00 -- 0.5
Day 2 - 1.50 -- 0.75
Day 3 - 1.75 -- 0.87
Day 4 - 1.88 -- 0.93
Day 5 - 1.93 -- 0.96
Day 6 - 1.96 -- 0.98
Day 7 - 1.98 -- 0.99
Day 8 - 1.99 -- 0.99
Day 9 - 2.00 -- 1.00
Day 10-2.00 -- 1.00

By day 3 you're close to a steady plasma level and by day 9 you are at a steady plasma level. Combine that with down-regulation, maybe your enzyme's that break the drug down up-regulate and other pharmacological things, and that's the start of your answer.

 

[Pegasus]

Thanks for the starts to the answers answers on that you guys provided (very much appreciated), guys, and really, all of the help that has been given so far.

Does anyone know where I can go to teach myself this information, because I'm very interested in the answers, and my freshman biology class is only touching on organic chemistry. So, I'd like to get some answers, but I would like maybe some direction as to where to go to start teaching myself this type of information? Google searches do not really work, at least not the way I am phrasing them...

 

[cegli]

I think starting here would be a good place:

http://ocw.mit.edu/OcwWeb/Chemistry/index.htm

It's most of MITs chemistry courses, fully available for free.

 

[vortex30]

I could be wrong, but since longer acting benzos are gradual in their increase and decrease in your bloodstream while short acting ones hit you hard then just leave, the short acting would be more addictive.

Crack vs. Coke

IV vs Snort (heroin)

Xanex vs. Valium

Comparisons not meant to be completely accurate (i.v. heroine hits harder and lasts longer), but you get the picture.

Maybe if your talking about psychological dependence i can kind of see your point, but with physical addiction and the psychological urge to redose short acting benzos, such as xanex, are the worst.

I think you figured things out for yourself by the end there, but maybe I can shed some light on this. Diazepam and Clonazepam, are not necessarily more ADDICTIVE than say Temazepam or Alprazolam, but they do have a much simpler time creating DEPENDENCY (but most would agree, in recreational terms, Diazepam and Clonazepam have just as much appeal). For example, I can not take a single dose of Diazepam, without a mini taper, to avoid rebound anxiety and insomnia a few days later. I can take a single dose of Alprazolam, in fact, several single doses, and be completely fine. This is different from the idea of a dependency already being in place, and needing to come off the drugs. Naturally, it is ludicrous to taper, or cold-turkey with Alprazolam, off an Alprazolam dependency. That goes without saying. And obviously a cold-turkey off Diazepam will be a bit more gradual, though if the dependency is bad enough a cold turkey withdrawal is still going to be BRUTAL. But when no dependency yet exists, it is a lot easier for a Diazepam habit to spiral into dependency than an Alprazolam habit, but of course if no self-control is practiced, the end result will be the same for both.