'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 !