Benzo half life vs effect life

[BurritoJimmy]

Do benzos exert an effect on GABA even after the noticeable therapeutic effect? I usually take ativan for panic attack and I notice its effect for approx 10 hours but read that it takes 2.5 days for it to completely leave your system. Does that mean it is exerting an effect on GABA for that whole timeframe even if it is too small for me to notice? I ask because I drink too and want to know a good time between the two. Thanks.

 

[Kaden_Nite]

The half-life doesn't necessarily reflect the duration of noticeable effects. Diazepam has quite a long half-life but the effects don't seem to last much longer than any other benzo in my opinion. I think effects can linger in the background for quite a while after though, as in it's having an effect but too subtle to notice.

If you take a modest dose of benzos then get some sleep, should be all right to drink by the next day.

 

[justtakethat]

If you take Clonazepam you can expect to feel it the next day. It's not like when you first took it but it's definitely noticeable. Any benzos with a long half life you can expect to feel it a bit the next day.

 

[GirlWithBlueHair]

The time it takes to leave your system is it's half life. This has to do with it's occupancy in your bloodstream and not at your receptors. By the time you're describing, the drug has already dissociated from the receptors and is being metabolized and is just circulating through the body and being eliminated; that is why, as Kaden_Night said, hald life doesn't necessarily correspond to clinical effects.

 

[razordesignz]

The idea of feeling ativan for ten hours is interesting. Possibly partially placebo. Ativan is longer then xanax, still it remains a weak little brother of xanax. Then valium although huge half life. And konopin huge half life, it's effects last longer then the first 3 I listed and librium is around kolopin although weaker

 

[Keif' Richards]

While there are going to be correlations between the half-life of certain drugs and their duration of effect, they are not directly bound. For instance, Diazepam can take weeks to be eliminated fully from the body, but it's effects are much shorter.

 

[Slow_Mobius]

The time it takes to leave your system is it's half life. This has to do with it's occupancy in your bloodstream and not at your receptors. By the time you're describing, the drug has already dissociated from the receptors and is being metabolized and is just circulating through the body and being eliminated; that is why, as Kaden_Night said, hald life doesn't necessarily correspond to clinical effects.

So does the tissue distribution change? I've been trying figure out a biochemical/molecular explanation to OP's question and haven't found much outside of speculation.

 

[GirlWithBlueHair]

So does the tissue distribution change? I've been trying figure out a biochemical/molecular explanation to OP's question and haven't found much outside of speculation.

I would think so. As each drug would have a different rate of exposure and distribution to different tissue - such as skin, or muscle, fat etc. And a different percentage of rate of elimination from each tissue. Would you agree? But I don't think it is studied with this specificity. Just at a general elimination rate from which they can detect it from the blood.

 

[GirlWithBlueHair]

It would still be having an effect on GABA as it would still be binding to GABA A receptors in the brain - just at a very small, unnoticeable amount, as the blood level would be too low. But there would still be biointeraction, just not enough to be perceivable.

Just like 8 hours after taking a temazepam 30mg capsule you generally wouldn't feel it, but you'd still have around 15mgs in you, which is a typical dosage and enough to interact with receptors and cause an effect.

 

[Gorillaboy21]

I think there are many reasons: receptor affinity, the way you took the drug (pathway of absorption), how often did you take the drug before? (if you stacked the drug in your bloodstream over a long time), empty or not empty stomach, etc.
But Ive always wanted to know what the half life really means in correlation with how long its in your bloodstream, your body, and withdrawal affects.
Pharmacokinetics are confusing

 

[T. Calderone]

You want to be careful not to drink too much on the days you take Ativan. (I'm going to move this to NPS)

 

[Solipsis]

I think there are many reasons: receptor affinity, the way you took the drug (pathway of absorption), how often did you take the drug before? (if you stacked the drug in your bloodstream over a long time), empty or not empty stomach, etc.
But Ive always wanted to know what the half life really means in correlation with how long its in your bloodstream, your body, and withdrawal affects.
Pharmacokinetics are confusing

I don't think so. Diazepam is often mentioned for having relatively short therapeutic duration while lasting in the body very long. If it just wasn't efficacious at the receptors it would just have low potency instead and the other suggested factors can't be the explanation if you compare to other benzos taken the exact same way.

The time it takes to leave your system is it's half life. This has to do with it's occupancy in your bloodstream and not at your receptors. By the time you're describing, the drug has already dissociated from the receptors and is being metabolized and is just circulating through the body and being eliminated; that is why, as Kaden_Night said, hald life doesn't necessarily correspond to clinical effects.

Not disagreeing here but my question is why would the drug (well diazepam / nordazepam) dissociate from the receptors and just circulate through the body (and not partially circling back to those receptors?) more than other benzos? Metabolized? Well both diazepam and nordazepam have extremely long half lives?
Are they just relatively lipophilic and just sticking to your fatty tissues like crazy which keeps it from being around the receptors for very long? That would certainly explain the half lives and everything else.
But it would be a sidenote to your explanation as less lipophilic benzos would also dissociate from the receptors (I don't think association and dissociation rates are relatively quick and are not all that relevant compared to absorption and distribution over various tissues over time) and circulating through the body, only it wouldn't get stuck everywhere I guess.
If it gets stuck in fatty tissue I don't understand why the half life wouldn't show it as if it's cleared from the blood though?

Why are there benzos with a longer clinical duration but not longer half life, wouldn't the concentrations be rather low as it is just circulating in the blood? I think clonazepam qualifies... phenazepam also lasts very very long in my experience. Do they somehow require lower concentrations to still have a pronounced effect while diazepam cannot?

And it's amazing cannabinoids in edibles lasts as long as they do with all this in mind.

@gorillaboy: the half life exactly reflects concentrations in the blood. Withdrawals are due to receptor decoupling and upregulation among other things, but I think that requires activation as well so the question is how much activation is there over all that time while the diazepam / nordazepam is in your blood?

 

[Cotcha Yankinov]

The differences between half life and timeline of effects between different drugs could be due to homeostatic compensation at or near the receptor itself occurring differentially across different GABA-A subtypes, and depending upon what cells are downstream of the affected cells expressing the various GABA-A receptors and what role they actually play functionally, you could see faster or slower downstream compensation to that upstream inhibition.

 

[Solipsis]

The differences between half life and timeline of effects between different drugs could be due to homeostatic compensation at or near the receptor itself occurring differentially across different GABA-A subtypes, and depending upon what cells are downstream of the affected cells expressing the various GABA-A receptors and what role they actually play functionally, you could see faster or slower downstream compensation to that upstream inhibition.

Interesting, would then diazepam being such an 'all round' benzo have anything to do with it possibly? If so balanced perhaps that makes this homeostatic compensation easier? I think that wouldn't preclude from binding and activating so I don't see why there should necessarily be less tolerance and potential withdrawal development during this ineffective period trailing with diazepam. (@gorillaboy's question)

 

[RandomClean3]

Metabolism. Diazepam metobolizes to oxazepam, nordazepam and temazepam, all 3 are considerably less potent. Since it's highly lipophilic, it will be stored in fatty tissue and metabolize to less potent benzos. Lorazepam is the complete opposite, it's relatively water soluble and more importantly it doesn't metabolize, it's excreted as the same drug. That's why lorazepam lasts longer when treating a seizure even tho it has a much shorter half life. The active effects last the majority of the half life, while in the case of diazepam, it leaves the bloodstream and is metabolized to low potency drugs. Which are themselves easily excreted (temazepam and oxazepam are the same as lorazepam in that sense, that's why those 3 drugs are given to people with renal/hepatic issues)

 

[Solipsis]

Diazepam itself still has longer duration than say lorazepam so that includes metabolism to active metabolites regardless if they are less potent... You are talking like diazepam's half life includes formation of its metabolites and their metabolism.
It being stored in fatty tissue should make for a much longer half life though, although I wonder how linear that is esp initially compared to later.

 

[Slow_Mobius]

I've tried to find some legit info on this topic, and I'm inclined to believe that we don't know the answer. I'm just seeing a lot of speculation from people. If anyone has any sources, I'd be ecstatic

 

[Cotcha Yankinov]

Interesting, would then diazepam being such an 'all round' benzo have anything to do with it possibly? If so balanced perhaps that makes this homeostatic compensation easier? I think that wouldn't preclude from binding and activating so I don't see why there should necessarily be less tolerance and potential withdrawal development during this ineffective period trailing with diazepam. (@gorillaboy's question)

I see other people talking about the PK factors, I suppose those are pertinent to mention when comparing drug to drug. I believe haloperidol for example is known to really build up in the brain.

But as far as a drug in isolation that has i.e. a 24 hour half life while only really having effects for 6 hours, I think we could chalk that up to homeostatic effects occurring in that timespan rather than PK issues (other than if a metabolite of a drug activates a GABA-A subtype that tends to diminish the effects of activation of another GABA-A subtype that would normally occur due to the parent drug, in which case we would expect to see diminshed effect of the parent drug as the metabolite builds up).

Differences in homeostatic effects induced by benzos with different affinities for different subunit containing channels might not involve altered subunit composition type stuff which is thought to occur with chronic benzo use, but I get the feeling that if it can occur with long term use, maybe its occurring to some degree with short term use. Maybe some GABA-A channels are more vulnerable to this effect.

There is also stuff like downstream Glutamate receptor upregulation - maybe a particular benzo tends to inhibit Glutamate release in a part of the brain that readily upregulates because it is only 1 synapse away.

Another benzo may have a roundabout way of inhibiting Glutamate (i.e. an Inhibitory neuron inhibits a principle neuron, which decreases serotonin release another neuron down, which then decrease glutamate release from astrocytes), and maybe with more synapses in between, homeostatic effects don't occur as rapidly.

 

[Gorillaboy21]

I don't need your input buddy if you're gonna put words into my mouth and try to be mr. Know it all . I never fixated on one reason I listed a bunch of reasons, and what you replied to me with was clearly stated before.
Looking at your comments it seems like you came here to prove everyone wrong and show how smart you are we don't need that

 

[Kdem]

'Not disagreeing here but my question is why would the drug (well diazepam / nordazepam) dissociate from the receptors and just circulate through the body (and not partially circling back to those receptors?) more than other benzos? Metabolized? Well both diazepam and nordazepam have extremely long half lives?
Are they just relatively lipophilic and just sticking to your fatty tissues like crazy which keeps it from being around the receptors for very long? That would certainly explain the half lives and everything else.
But it would be a sidenote to your explanation as less lipophilic benzos would also dissociate from the receptors (I don't think association and dissociation rates are relatively quick and are not all that relevant compared to absorption and distribution over various tissues over time) and circulating through the body, only it wouldn't get stuck everywhere I guess.
If it gets stuck in fatty tissue I don't understand why the half life wouldn't show it as if it's cleared from the blood though?

Why are there benzos with a longer clinical duration but not longer half life, wouldn't the concentrations be rather low as it is just circulating in the blood? I think clonazepam qualifies... phenazepam also lasts very very long in my experience. Do they somehow require lower concentrations to still have a pronounced effect while diazepam cannot?'

Because it is so lipophilic and is absorbed quickly and binds tightly to plasma proteins, diazepam will quickly redistribute to fatty tissues after the 'duration of action'. From a practical point of view, we'll consider the 'duration of action' here as the 'duration of action of a single dose'.

So it will do nothing to very little the next day, unless you take a large dose or happen to have zero tolerance.

Once the diazepam has accumulated, the diazepam will gradually be released fromt he (fat) cells into the bloodstream, and that will do *something*. Also, the only really active metabolite desmethyldiazepam will start to build up and exert an effect. It's a complicated drug.

Re: Ashton and her statement that diazepam is 'long acting', her talk about half lives and her complete dismissal of the concept 'duration of action' is something that annoys me. It may work for some drugs , individuals and mild dependencies.
Her statement that blood levels are in equilibrium with with tissue is too simple. If you take a dose of diazepam it will peak in the brain and do a lot more than just maintain an 'equilibrium'. Also, that a drug is present in the blood does not necessarily mean it will rapidly cross the blood brain barrier. That's complicated, I don't know much about it.

I'm not sure about diazepam's effective 'half life' after accumulation. Isn't the diazepam going to move from cell to cell ... ?

Re: lorazepam: in my experience, it will do *something* after the duration of action, it is just much weaker.

And '
Why are there benzos with a longer clinical duration but not longer half life, wouldn't the concentrations be rather low as it is just circulating in the blood? I think clonazepam qualifies... phenazepam also lasts very very long in my experience. Do they somehow require lower concentrations to still have a pronounced effect while diazepam cannot?''
Clonazepam is possibly the least lipophilic benzo. It enters the brain less rapidly, and the 'duration of action' (12 hours, 15 hours, 24 hours?) is therefore longer. Clonazepam does have a long half life, 1-2 days although this varies.

Especially after long term use, benzodiazepines do a lot more than affect GABA. This source: https://www.hindawi.com/journals/aps/2012/416864/ is not even complete !