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Long acting benzodiazepines (not 'half life'), suitable for tapering

K

Kdem

Bluelighter
Joined
Mar 14, 2015
Messages
334
Given my issues, I want to give this question another go.

Obviously, there is a difference between 'duration of action' and 'half life'. While diazepam has a very long half life, I would need to dose 3 x a day to 'cover' one dose of clonazepam. For me, clonazepam lasts a full day.
In my experience it seems I'm a 'duration of action' type of guy, once that is over it is not doing much.

Benzodiazepines other than clonazepam, that have a long duration of action (>11 hours). Once, I followed a foolish suggestion of my doc to switch to lorazepam. Taking it twice a day worked well, till I developed tolerance to and dependence on the drug, making it fairly short/medium acting (peaks and vallleys).

I don't want to take a research chemical, maybe I can import something (legally) if it can work.
I have this list from wikipedia: https://en.wikipedia.org/wiki/List_of_benzodiazepines which unfortunately doesn't say anything about the 'duration of action'.
Obviously such a drug would need to meet certain criteria, for example a strong hypnotic would not be suitable.

Anyone ?
 
Didn't Librium used to be the drug of choice for this at at one point? Not sure if it's still available though.
 
Yeah, diazepam and chlordiazepoxide are the gold standard for this kind of stuff.
 
If you want to import something legally, then it most definitely will have to be a research chemical. I'm pretty sure conventional and well-researched benzos are all scheduled.

Can anyone explain why diazepam is said to have quite a short duration of action despite its fairly long half-life and that of its active metabolite?
 
A single dose of Librium is short/medium acting. Diazepam, about the same.
I have a source (not in English) that for therapeutic purposes, Librium should be dosed three to four times a day, diazepam two to three times a day.
In my experience, a dose of diazepam is relatively short acting. The duration of action is a bit variable. Dosing would be required at least twice daily, with a smaller dose in between to prevent the worst of interdose withdrawal.

I'm quite familiar with the 'Ashton manual'. What most people don't know, is that prof Ashton started her career as an addiction doctor. Hence the use of words like 'addict' in her manual. And switching someone from a short acting to a long acting drug, is a bit like switching someone from heroin to methadone. Why she completely ignores the concept 'duration of action' and focuses on 'half life' only is unknown.
With diazepam, some people can rely on half life. For others once the 'duration of action' is over it is pretty much over.
While clonazepam has a 1-2 day half life, for me the duration of action is about 24 hours, for other people it is 8-12 hours.

Diazepam has a faily short duration of action because of the following (and now I'm quoting from an article from the defunct benzowithdrawal.org) 'Valium is 98% bound to plasma proteins. It rapidly crosses the blood-brain barrier and peaks within 2 hours following administration. Following the peak, the initial distribution phase in the brain is one hour. Since Valium is highly bound to plasma proteins, the drug is rapidly redistributed to adipose (fat) tissue. It is stored there, and slowly eliminated over a period of 4 days (or one month for prolonged use). Given that it is redistributed throughout the body, the duration of action following a single dose is 6-8 hours (average 6). The actual half-life of the drug (which is 30-100 hours) means very little.'

There are other articles that use somewhat different words and numbers, but this is pretty much it.
How effective desmethyldiazepam/nordiazepam is, and at what level it is in the bloodstream, I don't know.

In other words, diazepam sits in the fat cells and doesn't do much. It accumulates to 5-8 times of a daily dose after chronic dosing. Not the best replacement for an ultra-potent benzo with a long duration of action.
 
So basically you're saying that with chronic use, diazepam elimination doesn't follow the usual first-order kinetics, but something like 2nd or even higher order - each dose raises the drug's blood concentration, which then rapidly, within hours, falls close to the "baseline" (of the chronic use) and from then on starts further, but way more slowly, being eliminated. In that case, yes, the use of half-life is not very useful, because half-lives only apply to first-order kinetic processes. I assume this behavior is a function of lipophilicity (THC and other cannabinoids do the same, don't they?), but I don't have log P values on hand - any other benzos that behave in this way to a significant extent?

E: in case this confuses someone, I meant to say that constant half-lives only apply to processes described by first-order kinetics, other forms of kinetics don't have constant half-lives - it either is a function of concentration or the speed of elimination is constant (zero order, like alcohol).
 
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I'd say an important thing to consider here is the concentration of benzodiazepine required to gain relief from withdrawal.

A drug with a long half life in the body only means it takes a long time to eliminate from the body. That doesn't mean that it is to have an effect. With a lot of drugs and just things in general, one requires a threshold dose for sufficient relief from withdrawal, I would suggest. What I mean by this is that if the concentration of diazepam in the blood is only slightly below a certain value, then a dependent patient will experience discomfort. This gives an explanation for why Valium has a long half life but short duration of action: once it reaches peak concentrations one gets relief/anxiolysis but after a while when the concentration drops past a certain value (this value might even be say 85-90% of original value, and let's assume that it is) then no more relief is provided. Taking the assumption I asserted before, only after way less than one half life is the drug no more effective. It's still in high concentrations, but it's not doing anything. So it still has a high "half life" and will still take ages for it to be eliminated, but it has no or minimal CNS effects in this time.

My suggestion would be the following: to achieve a constant concentration of benzodiazepine in the blood, probably by some time release mechanism. Or to increase the dose although that is not really an option as you're trying to taper.

This is only my thoughts on why Valium has a short duration but long half life; it'd be interesting to hear others' thoughts. I couldn't really make sense of the plasma protein theory either.
 
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belligerent drunk,

You got me there. First order kinetics, second, third order ... I tried looking it up, without much success. I never followed a full course in pharmacokinetics or pharmacodynamics. Could you give a brief explanation ?
I think the idea is that because diazepam is highly bound to plasma proteins, very lipophilic, has a long half life it will be in the blood and per Ashton it will have at least some effect on the CNS. And of course, there is accumulation, in theory diazepam would be released from fat cells, the liver, all the time. For some reason, it has been stated that it doesn't stick around in the brain very long, at least not in high concentrations.
Again, could you explain how first/2nd,3rd order kinetics applies in this case ?
 
Following intravenous administration, a drug follows x order kinetics if the rate at which it's eliminated is proportional to the concentration of the drug raised to the power of x. You need to read about differential equations if you wish to understand more about this.

This results in a first order kinetic drug exponentially decreasing in concentration ( concentration of drug at time t = initial concentration*e^(-kt) where k is a constant to be determined, mainly dependant on the individual's liver)
A second order kinetic drug would decrease in an inversely proportional manner ( concentration of drug at time t = 1/(kt +(1/initial concentration)) where k is another constant to be determined)
A third order kinetic drug would decrease in an inversely square rooted proportional manner ( concentration of drug at time t = sqrt( 1/(kt + (1/(initial concentration)^2)) where k is another constant to be determined)
 
aced126,

I'll give it more time to understand tomorrow ... It has been a very long time since I had to solve differential equations.
I'll just ask this straight up now, what kind (first order ...) of drug is diazepam ?
 
I'll spare you the lecture, just some basics. Basically the higher the order, the more strongly dependent the speed of the process is on the concentration of "something" - a drug in this case. The more dependent it is, the more rapidly the speed decreases at first, but also the slower it decreases later on. If you remember anything about functions, then for example first-order kinetic equation could be v = k*c, where v is speed, k is a constant and c is concentration, second-order could be v = k*c^2; now the derivative of speed is analogous to acceleration (e.g the rate at which the speed changes), so in the case of first-order the derivative will be a = k, second-order a = 2k*c (a - acceleration, for simplicity sake). As you can see, in the case of first-order the acceleration is just constant, so that means the rate of the process changes at a constant speed independent of the concentration, in the case of second-order the acceleration itself depends on the concentration (so at higher concentrations it changes faster than at lower). This is why only processes following first-order kinetics can be described using half-lives regardless of the dosage (acceleration independent of concentration). Now, whether the theory applies in reality is another question, of course; as you can see, it doesn't always work that way.

aced: that's what I thought as well, but I noticed some non-dependent benzo users say the same - that diazepam doesn't last long at all. And in that case it wouldn't make sense that dependent users, like Kdem, feel clonazepam significantly longer than diazepam either.
 
Kdem said:
Ozle, per #1, 2 mg clonazepam a day, single dose.
Click to expand...

Why not try tapering using clonazepam itself, if that's the one that lasts longest for you and gives you least desire to redose?
 
It must vary wildly from person to person - not speaking from a scientific perspective, I personally will feel the effects of any benzo for greater than 24 hrs (sometimes 2-3 days at a time) at a certain dose (2-3mgs alprazolam, clonazepam, lorazepam, clonazolam etc. or 20+ diazepam) but only feel the effects for a few hours at a smaller threshold dose (0.5-1mg of lower dose benzos, < 20 mg diazepam) I typically do not take them more than few times a month though. This definitely follows a first order model of kinetics, and also possibly explains why non-dependent benzo users still experience the short duration - if they were to take a larger dose it is highly likely that they would feel the effects longer, as intolerant individuals still might be affected through a full half life of the chemical.

It seems that while you may not continue to feel the drugs effects for the full half life, if you are trying to taper, as long as you are not experiencing profound withdrawal symptoms, you may just have to do your best to cope with some anxiety issues (as do virtually all who have had to taper from benzos, myself included, though it was 7 years ago). Is there a reason you cannot just go back to taking clonazepam if it was working better? It is a decent taper med, if not as highly used as diazepam.
 
Kdem said:
Given my issues, I want to give this question another go.

Obviously, there is a difference between 'duration of action' and 'half life'. While diazepam has a very long half life, I would need to dose 3 x a day to 'cover' one dose of clonazepam. For me, clonazepam lasts a full day.
In my experience it seems I'm a 'duration of action' type of guy, once that is over it is not doing much.

Benzodiazepines other than clonazepam, that have a long duration of action (>11 hours). Once, I followed a foolish suggestion of my doc to switch to lorazepam. Taking it twice a day worked well, till I developed tolerance to and dependence on the drug, making it fairly short/medium acting (peaks and vallleys).

I don't want to take a research chemical, maybe I can import something (legally) if it can work.
I have this list from wikipedia: https://en.wikipedia.org/wiki/List_of_benzodiazepines which unfortunately doesn't say anything about the 'duration of action'.
Obviously such a drug would need to meet certain criteria, for example a strong hypnotic would not be suitable.

Anyone ?
Click to expand...

Does the half life not correlate with the duration of action at a high ratio? I always thought half life is the approximate equivalent to the duration of action. What more pharmacokinetic parameters should be have in mind to properly calculate the duration of action? Volume of distribution, binding to plasma protein, lipid solubility? Maybe there are some extremely large differences in distribution of the drug, and the plasma drug concentration is not the good equivalent to the concentration of a drug at the target receptors?
 
belligerent drunk,

Are you-we not looking at this in the wrong way ? Diazepam is a first order kinetics drug ?
After sufficient accumulation, blood levels of diazepam in the blood are relatively stable. Of course, this takes time. Given enough time, diazepam accumulates to 5-8 times the daily dose.

The effect in the CNS is what matters. As stated after dosing the drug rapidly distributes to the CNS, then most of it goes ´elsewhere´.

Again, from a practical perspective - a lot of people can rely on half llife with diazepam. For others, once the ´duration of action´ is over, it´s mostly over.
 
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Renald,

Have you read the PDF in mentioned in #9 ?
I´m not sure how to properly explain it, it´s complicated.

´What more pharmacokinetic parameters should be have in mind to properly calculate the duration of action? Volume of distribution, binding to plasma protein, lipid solubility?´
LogP, plasma protein binding, acid-base environments (PH), more ... I think that the duration of action is mostly related to the distribution phase of the drug, possibly I´m wrong.

´I always thought half life is the approximate equivalent to the duration of action.´ For both benzodiazepines and barbiturates this is often not the case.


And if anyone has any suggestions per the title of this thread ...
Pharmacokinetics is hard ...
 
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Wouldn't phenazepam be good to taper? Or is it's distribution inferior even if it has high lipid solubility?
 
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