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

[Kdem]

Slow_Mobius and all,

I would appreciate your comments, especially to post #50.
Decisions, decisions ...

 

[Solipsis]

Is it perhaps a better explanation that part of the population - that would include you - has considerable difference in enzyme expression... some have deficiency and others have overactive / larger concentrations? Since benzos are not all metabolized the same way some benzos can offer a solution for those that experience problems with other benzos...

You could see if Tranxene works better for you, like the time-release nordazepam it's supposed to be.

Bromazepam had a pretty short duration of action for me, not suitable in any case imo... Flunitrazepam is way too heavy, it's like trying to taper with heroin if you have a tramadol dependency, and yea its hypnotic and has relatively quick metabolism. Then again clonazepam itself is certainly not light, but still.
I've never really heard of clobazam but it has a long half-life though could have the exact same issues for you as diazepam.

I can only imagine what a doc would do, or care they would withhold from you, if having taken an RC is a problem. In a reasonable and professional atmosphere it would change nothing about the fact that you are benzo dependent.

Other than that, if incomplete cross-tolerance is an issue switching to another benzo and/or if you have enzyme issues that give you problems with short duration of action with some... just tapering with clonazepam while not ideal might be the least bad option? Just dosing twice a day would suffice?

I take it this is familiar?: http://www.benzobuddies.org/forum/index.php?topic=130713.10

 

[Slow_Mobius]

Slow_Mobius and all,

I would appreciate your comments, especially to post #50.
Decisions, decisions ...

I wanted to scour PubMed a bit to find some info specifically related to diazepam. I looked at some studies that analyzed plasma concetrations with alternative routes of administration, and I'm thinking that the half lives commonly referred to are indeed plasma concentration half lives. Solpisis is correct to mention that the individual's biochemistry is going to have a huge impact on how the individual metabolizes the drug. As a result, plasma concentration half lives are going to vary greatly between individuals. I didn't see any studies that cited kinetic parameters, nor half lives to describe plasma concentrations. However, hey did mention steady state plasma concentrations following drug accumulation. This is not to be confused with steady state kinetics. So it looks like diazepam doesn't accumulate indefinitely, but instead it reaches something more like a maximum plasma concentration that is maintained with periodic dosing.

 

[Kdem]

Slow_Mobius,

Thanks for that.
Did you find anything like a dose/plasma correlation, in the sense that (after sufficient accumulation) if a person is on 40 mg diazepam, the plasma level will drop to half of that once he is on 20 mg ?

It appears that a lot is guesswork.

´terminal half life´ I´m not sure how that relates to biological half life or plasma half life.

 

[Kdem]

Additional question about half life.
Re: clonazepam I have read that (after the initial distribution phase?) the unbound fraction is responsible for clinical effects.

Diazepam is highly protein bound. So that would mean that the unbound fraction is very low. How is what is left as the 'half life' effective ? Is that not an issue unlike with clonazepam, because diazepam is more lipophilic ?
I'm trying to understand. I get that pharmacokinetics can be very complicated, and perhaps I ask for too much ...

 

[clubcard]

Look at the updated wiki page on diclazepam. All referenced.

 

[Kdem]

clubcard,

Thanks. Of course, no information about the 'duration of action'. And it's still a RC, which has disadvantages that I mentioned previously, in this thread or elsewhere. I would need it for quite some time ...

What I just noted, is that it appears that it isn't such a 'clean' drug. Delorazepam in particular has a long half life, the same goes for other metabolites. I just wonder if it is a drug that accumulates the way diazepam does (in fatty tissues, up to 5-8 times the daily dose).

 

[clubcard]

I know from personal experience that getting down from 24mg to 2mg took 13 months. It was taken orally BID and to replace with diazepam requires 10mg TID. You have to be careful to stabilize because of all the metabolites. Doctors just say x10 so 20mg diazepam BID, but that doesn't work. If you get a habit with this stuff (which is about to be banned) then you have an addiction that makes diazepam look like a Pepsi habit. Take 3 weeks to stabilize while the metabolites drain out of the body but keep the diazepam at the bare minimum - you start, need more and then drop back. YMMV.

PS I suffer ultra-rapid bipolar disorder that was refractive to all other medication so now I have to take neuroleptics to stop the mania and suffer the depressions. Easy to see why I abused it so much.

 

[Kdem]

This 'to be banned' doesn't so good. But you didn't say where.

'If you get a habit with this stuff (which is about to be banned) then you have an addiction that makes diazepam look like a Pepsi habit.' So, it is physically more addictive ?

'Take 3 weeks to stabilize while the metabolites drain out of the body but keep the diazepam at the bare minimum - you start, need more and then drop back. YMMV.'
So I guess it takes a long time to stabilize on diclazepam. But how does the diazepam factor in ? I'm confused.

 

[clubcard]

Banned? The UK - where it is made. Yes, it's causes a vastly stronger dependence like ORLAAM compared to methadone (without the long-QT). You go to your doctor with a copy of the papers CC diclazepam & ask for help. Trust me on this one - your only alternative is about 2 bottles of vodka per day. I've never heard of anyone with a decent habit with this stuff get clean without swapping to diazepam. if you are taking 2mg BID, you need 30mg diazepam [TID] to cover it.... and after a few days, 30mg isn't enough so you hang out for a couple of weeks to get all of the diclazepam & metabolites out of your GABA receptors and reduce with a weaker compound. Read The Ashton Manual.

Of course, plasma levels ≠ brain levels but, for long-term usage, it's more like 30x diazepam. I found out the hard way (seizures and so on) and you WILL reach the point when only a doctor can help. Forget cold turkey - this is frozen raven.

 

[Kdem]

Clubcard,

Diclazepam doesn't sound that good as an option the way you describe it ... of course, clonazepam isn't exactly a picnic either. And having to procure a large quantity because it will be banned ...

You had seizures ? Would you mind saying what kind ?
I've had what I'd call 'half absence seizures'. 'half' because I didn't fully lose consciousness/connection with my environment.

 

[Kdem]

Solipsis,

According to the equivalency charts 2 mg clonazepam equals 4 mg flunitrazepam. But in my experience, clonazepam is even stronger. I took flunitrazepam for a few days a long time ago (1 mg), it was mostly like an ordinary hypnotic except for some minor respiratory depression.

Anyway, clonazepam is way, way heavier. You don't want to be there when full tolerance and dependence has set in and you're having other health issues as well ...

 

[clubcard]

All of the 7-nitro benzos are about twice as toxic as 7-halogens. A study in Sweden found that the vast number of suicides were achieved with very high doses. It doesn't mention any co-administration of other sedatives. On the plus side, the nitro does give the body another way for the body to metabolize it. Interesting that pyrazolam is excreted unchanged but it's LogP isn't as high so I guess protein binding gives something for the kidneys to work with.

 

[Kittycat5]

Half live in PK nearly always means plasma half live. It is dependent on Clearance which is defined as the amount of drug removed from plasma by all means per unit time as well as Vd.

Formulas. Elim rate constant= Clearance/Vd. T1/2= ln2 (natural log 2 or .693)/Elim rate constant = .693/CL/Vd.

 

[Kdem]

Kittycat5,

Question: sources give a half life for diazepam of about 1-2 days. However, diazepam accumulates up to 5-8 times the daily dose. What does half life mean in that situation ? From what I get, it is slowly released from the fat cells and other parts of the body.

What I mean is, half of the diazepam won't be eliminated in two days. Is there a phrase for that particular type of 'half life' ?

 

[clubcard]

Kittycat5,

Question: sources give a half life for diazepam of about 1-2 days. However, diazepam accumulates up to 5-8 times the daily dose. What does half life mean in that situation ? From what I get, it is slowly released from the fat cells and other parts of the body.

What I mean is, half of the diazepam won't be eliminated in two days. Is there a phrase for that particular type of 'half life' ?

Diazepam seems to bind to the 4 'diazepam sensative' subtypes of receptor (α1,α2,α3 & α5) of β3γ2 roughly equally. Hypnotics favour α1 & α5, Z-drugs specifically α1. Whatever benzo you became dependant on, diazepam will act as a replacement (though 2-3 weeks to stabilize). That's why pyrazolam is more active at α2,α3 (affinity ≠ efficacy) so only has hypnotic effects at very high doses (>10mg). Shame nobody can patent it because it's a less abusable drug than all other benzos and only helps with GAD or such. The MOST dependence-forming benzo is diclazepam by a country mile. Since all of it's metabolites are also x10 diazepam, it makes diazepam seem like Halcion, in relative terms of duration. It's the very WORST of a dangerous class of drugs.

 

[Kittycat5]

Yes, there are what is called compartment modeling for PK. I wrote a whole post and my phone decided to hate me and it vanished. I will redo soon.

 

[Kittycat5]

Ok, lets start again. As I mentioned, pharmacokineticists will model the body into compartments with the single compartment model the most basic. In this model, the drug is absorbed, distributed, exerts its effects, is metabolized and is eliminated from one ideal physiological "box."

But in reality, this model is too simple to explain various PK and PD effects of benzos and many other drugs. A multi-compartment (usually 2 or 3) model is a far better tool when trying to understand PK of a drug.

Valium can be modeled as a 2 or 3 compartment system. I should probably say here, that this info generally pertains to IV administration but I believe oral Triazolam follows similar patterns. As I said before, the distribution phase is usually for IV ROA. A concentration v time graph of IV diazepam will show an initial rapid climb to Cmax, followed by a shorter but still quick distribution phase where levels drop sharply followed by a slower, steadier decrease in plasma levels in the elimination phase. This corresponds to the 2 or 3 compartments. The rapid climb in the first phase would be the central compartment and the distribution and elimination phases can be thought of either together as the second compartment or separate as compartment 2 and 3. As drugs distribute to various tissues, they leave the plasma at a rate very much like the terminal elimination half life, albeit much faster. This is often called the distribution t1/2. Again, I must state this all applies to IV admin and the decrease in drug levels is in the blood, not tissue.

After distribution into the various tissues or compartments occurs, the drug will start to redistribute back into the circulation and the slow steady decline of elimination occurs who's rate is called the elimination half life. It should be noted this rate is the same for IV and oral routes.

I know I didnt fully answer your question yet, Kdem but I am getting there. I am making a new post as I lost some of this one again. It is cursed.

 

[aced126]

Ok, lets start again. As I mentioned, pharmacokineticists will model the body into compartments with the single compartment model the most basic. In this model, the drug is absorbed, distributed, exerts its effects, is metabolized and is eliminated from one ideal physiological "box."

But in reality, this model is too simple to explain various PK and PD effects of benzos and many other drugs. A multi-compartment (usually 2 or 3) model is a far better tool when trying to understand PK of a drug.

Valium can be modeled as a 2 or 3 compartment system. I should probably say here, that this info generally pertains to IV administration but I believe oral Triazolam follows similar patterns. As I said before, the distribution phase is usually for IV ROA. A concentration v time graph of IV diazepam will show an initial rapid climb to Cmax, followed by a shorter but still quick distribution phase where levels drop sharply followed by a slower, steadier decrease in plasma levels in the elimination phase. This corresponds to the 2 or 3 compartments. The rapid climb in the first phase would be the central compartment and the distribution and elimination phases can be thought of either together as the second compartment or separate as compartment 2 and 3. As drugs distribute to various tissues, they leave the plasma at a rate very much like the terminal elimination half life, albeit much faster. This is often called the distribution t1/2. Again, I must state this all applies to IV admin and the decrease in drug levels is in the blood, not tissue.

After distribution into the various tissues or compartments occurs, the drug will start to redistribute back into the circulation and the slow steady decline of elimination occurs who's rate is called the elimination half life. It should be noted this rate is the same for IV and oral routes.

I know I didnt fully answer your question yet, Kdem but I am getting there. I am making a new post as I lost some of this one again. It is cursed.

What location of the drug is this concentration time graph referring to? If we are dealing with blood concentration, then surely at t=0 (assuming IV administration) the concentration is at a maximum, and then it exponentially decays?

 

[Kdem]

Kittycat5,

I would appreciate that !