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

[Kdem]

Clubcard,

So much for diclazepam ... I'm not that comfortable with flubromazepam or whatever RC chemical either. If I would have to contact a doc (health issues ! I once got cardiac arrythmia while trying to taper clonazepam) it would get tricky to explain that I took a RC chemical that they don't know a thing about, and the whole clonazepam story (prescribed!) as well ... Supply issues ...

Clonazepam is just a unique drug. For me, period. It seems that in practice many people have difficulty switching from clonazepam (in particular) to diazepam. It is said that 'clonazepam binds to (benzodiazepine?) receptors other benzodiazepines do not bind to', various sources, but I haven't been able to figure out what those receptors are ... Even the Ashton manual says 'binding of clonazepam to receptors that do not bind to other benzodiazepines and action on sodium channel conductors are relevant to anticonvulsant effects, not tranquillising effects. '
(http://www.benzo.org.uk/ashvtaper.htm)
Then there are important secondary effects on serotonin, acetylcholine etc.

 

[clubcard]

Go to the doctor - 2mg diclazepam [BID] = 30mg diazepam [TID] because, when taken for a long time, you end up with lorazepam, delorazepam, chlordiazepam. It takes 14 days to cross over and you will to need to print out the Wiki page to explain that although it's x10 diazepam, but so are all of the metabolites. Frankly, you cannot do down 0.1mg of diclazepam. You need blues, yellws & white. Fess up to doctor, bring a print of diclazepam and the Ashton manual. I got down from 24 to 2mg of diclazepam over 12 months but you need diazepam or try

Hi CC! Sorry I'm not too good with chemistry, are you implying that MPP+ might be formed with shoddy synthesis of various amphetamines?

I've always wondered what toxic byproducts might be present in a shoddy synthesis, and whether or not they might be contributing to addicts residual effects/neurotoxicity, do you think that toxic byproducts leftover from amphetamine/cathinone synthesis might be playing a role in neurotoxicity? And if yes, are there any chemicals in particular?

No - MDMA breaks down to an ortho phenol which is not lipophilic so exits the body FAST as it breaks down. I merely pointed out some new Knowledge that proves that sloppy work in the RC manufacturers lab. I've seen CB1 agonists that were contaminated with dimers, trimers & even polymers. Since they contain nitrogen, these compounds won't vapourize - they will burn releasing god knows what. As a guide - don't touch anything without a GC-MS as the number of NMR peaks would be HARD to work out with dozens of chemicals in them. 1 peak proves 1 chemical. I've counted 22 in one sample.

I've gone down from 24mg to 2 over a year but you have to fess up and you Will need to fess up. Print Ashton manual & wiki on compound. There are other hypnotics/sedative that are [POM] but possession is legal - whatever you need to get off the stuff.

 

[Kdem]

clubcard,

I never took diclazepam ... I'm on that horrendous clonazepam.

 

[Kittycat5]

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?

Yes, saying rapid initial rise was a bad choice. Although in reality is does take from a fraction of a second to minute for drug to mix with blood, there is no practical way to measure this so at t(0) the concentration is at its max. Sorry for that confusion.

I wrote more to answer your question, Kdem but again my phone hates me and I lost it. Will try to recreate it in a bit.

 

[Kittycat5]

So I should say that in PK compartmental modeling, the compartments do not necessarily have to correspond to an exact organ. For instance, the central compartment often is said to be the blood and all organ that receive a lot of blood flow. For diazepam, the three compartment model to describe its kinetics, the central compartment is the blood, the second compartment are organ with high blood perfusion (especially the brain but also the liver and kidneys) , often called the shallow compartment, and the third, or deep compartment, parts of the body like adipose tissue and skeletal muscle that receive less blood flow.

This model works best to describe diazepam's short duration of action despite a long biological half life. As I said, the initial rapid decline in plasma levels is called the distribution phase. This would be the time when diazepam is moving out of the blood and into the various tissues. Distribution into the brain is very rapid as distribution is determined by the physiochemical properties of the drug (lipophilicity being most important for benzos), amount of blood perfusion in the tissue, and any barriers to drug entry such as the BBB. Despite the robustness of the BBB at keeping drugs out of the CNS, diazepam's high lipohilicity and the high level of perfusion to the brain (1/6 of cardiac output), diazepam is quickly able to penetrate into the brain. This correlates to the initial sharp drop in plasma levels I mentioned as much of the drug leaves the blood and goes into the brain and other tissues. But equilibrium between tissue and blood in the shallow compartment also occurs quicker, as drug also redistributes out of the tissue and back into the blood until distribution=elimination. This ends the distribution phase. In the deep compartment, diazepam is also being distrubuted, albeit slower. Even though adipose tissue makes up much of the deep compartment and diazepam is lipophilic, the perfusion is more rate limiting and drug enters fatty tissue less quickly than the shallow compartment. But eventually an equilibrium will occur in the deep compartment, and now all drug being redistributed out of the deep compartment is subject to metabolism and excretion and the elimination phase begins. This would be the slower drop in plasma levels I spoke about that will continue to decline until all is eliminated.

So this explains the short duration and quick onset of diazepam as well as its long biological half life. Distribution into the shallow compartment is rapid, but equilbrium is also reached quickly. But distribution and equilbrium of the deep compartment both take longer to occur. So basically drug quickly reaches and leaves its site of action, but trickles out of those tissues where it exerts no effect. It also should be noted that while the rate of distribution into adipose tissue is less than the brain, the extent is greater which will also lead to a longer half life without affecting duration of action.

This three compartment model is describing the kinetics of a single IV bolus, and while still valid for multiple doses, it does not consider accumlation of drug. When trying to determine the amount or frequency of multiple doses, you must consider how much residual drug is remaining in the body as not to exceed toxic levels. This, Kdem, is what you were asking about. And oral administration of benzos is similar to multiple IV doses in terms of factoring in accumlation. In oral administration, the rate of absorption is what determines the rate of distribution (for most drugs) and there is no distribution phase as I just described. This doesnt mean drug isnt being distributed to tissues in the same manner (quicker to the brain, slower to the fat) just that distribution is considered to occur simultaneously with absorption and plasma levels are determined by things like bioavailability and absorption rate constant. But once it does absorb, it will certainly accumulate, especially in adipose tissue. But remember that it slowly leaves fat tissue as well, and with normal doses, this does not lead to huge increases in plasma levels. For drugs that have a narrow therapeutic index (toxic level close to therapeutic), such as digoxin or theophylline, accounting for accumulation is critical. But diazepam is not a narrow therapeutic index drug, so while it certainly is possible to calculate the amount of drug to be given after the first, or any, dose factoring in accumulation, it is not always necessary.

I hope this helps more than it confuses you. PK is indeed a difficult subject.

 

[Kdem]

Kittycat5,

Thank you ! That is an excellent explanation. I will reflect on this a bit more later. May I ask how you got to learn about all this ?

'long biological half life' I presume you mean plasma half life ? If we are talking about effects, a drug can have (therapeutic) effects after it has left the body completely.

Edit: I thought I had understood this. Then I reread the last paragraph. 'In oral administration, the rate of absorption is what determines the rate of distribution (for most drugs)' I have a source that states that the absorption half life for clonazepam is 24 minutes. I have always found that strange, since the 'duration of action' and the distribution phase is so long.
Anyway, both with clonazepam and diazepam (I haven't tried the latter for long) I'm very much a 'duration of action' person, and once that is over it won't do much.
Note: now I get it, that was for IV only. Still, it seems odd.

'In oral administration, the rate of absorption is what determines the rate of distribution (for most drugs) and there is no distribution phase as I just described. This doesnt mean drug isnt being distributed to tissues in the same manner (quicker to the brain, slower to the fat) just that distribution is considered to occur simultaneously with absorption and plasma levels are determined by things like bioavailability and absorption rate constant.'
I may even get that (in part), although it is complicated.

Would you say that for a drug like diazepam after continuous dosing there would be a relative shift from the central compartment to the second compartment and, especially, the deep compartment ? As in, the ratio of drug present in the body shifts to the deep compartment, if that makes sense.

 

[Kdem]

It's just bad that there is no other drug that has a medium to long duration of action like clonazepam, and that is not as messy ('dirty') like diazepam. Well, there is Tranxene/desmethyldiazepam but I suspect that there are issues as well, like different drug, duration of action (?), partial agonist, 'weaker' than diazepam/clonazepam, accumulation although less (?) than with diazepam.

 

[Kittycat5]

Kittycat5,

Thank you ! That is an excellent explanation. I will reflect on this a bit more later. May I ask how you got to learn about all this ?

'long biological half life' I presume you mean plasma half life ? If we are talking about effects, a drug can have (therapeutic) effects after it has left the body completely.

Edit: I thought I had understood this. Then I reread the last paragraph. 'In oral administration, the rate of absorption is what determines the rate of distribution (for most drugs)' I have a source that states that the absorption half life for clonazepam is 24 minutes. I have always found that strange, since the 'duration of action' and the distribution phase is so long.
Anyway, both with clonazepam and diazepam (I haven't tried the latter for long) I'm very much a 'duration of action' person, and once that is over it won't do much.
Note: now I get it, that was for IV only. Still, it seems odd.

'In oral administration, the rate of absorption is what determines the rate of distribution (for most drugs) and there is no distribution phase as I just described. This doesnt mean drug isnt being distributed to tissues in the same manner (quicker to the brain, slower to the fat) just that distribution is considered to occur simultaneously with absorption and plasma levels are determined by things like bioavailability and absorption rate constant.'
I may even get that (in part), although it is complicated.

Would you say that for a drug like diazepam after continuous dosing there would be a relative shift from the central compartment to the second compartment and, especially, the deep compartment ? As in, the ratio of drug present in the body shifts to the deep compartment, if that makes sense.

I learned in pharmacy school and through a curious mind.

For oral admin, it is usually simplest to assume a single compartment. Drug in=absorption, single compartment is where drug goes to exert its action (it is assumed that distribution is thorough and instantaneous in this model) and drug out=elimination. So that is why I say absorption and distribution occur at the same time. Remember, this is just modeling, not real physiologic organs, so it is a way for the kineticists to mathematically understand how a drug moves throughout the body while there probably is a phase where distribution occurs after absorption. And even though the one compartment model for oral admin is easiest and widely used, multicompartments still need to be utilized for many oral drugs.

And diazepam is a drug who fits a two compartment model for oral dosing.

This is an equation that describes plasma levels based on things like rate of transfer between compartments and "hybrid" dist and elim constants. We can say that the central compartment is the blood and richly perfused organs and the second is the adipose and muscle tissue etc.

Here is a picture describing it so you get a visual idea of whats happening.

 

[clubcard]

clubcard,

I never took diclazepam ... I'm on that horrendous clonazepam.

Well, why and how much could make the doc swapping you to clobazam.

 

[Kdem]

Well, why and how much could make the doc swapping you to clobazam.

Were you on some drug while typing that ... I'm trying to understand the sentence !

I actually asked the doc to switch me to clobazam. He didn't know it under that name, but he knew it as Frisium. When discussing equivalent doses, he said 'that's a lot of Frisium'. He had a problem with that. He preferred lorazepam. Followed by failed taper.
Later when I wanted to try diazepam he said 'that's a lot of diazepam !' That bastard ! (apologies for that comment, but it just had to be said)

Clobazam is less sedating than clonazepam, lorazepam and diazepam. It would have to 'carry the weight' of both the lorazepam and the clonazepam withdrawal.
It seems there is an issue with substituting 1,4 benzodiazepine by 1,5 benzodiazepines or vice versa. Impossible ? I'm not sure. At that time, at the worst clobazam might have been ineffective (early 2015!). I'm more vulnerable now.
I'm not sure about the 'duration of action' either.

 

[Kdem]

Kittycat5,

I don't think I'll be learning that equation any time soon, but thanks

 

[Kittycat5]

That wasnt my point, no one knows that equation except the 4 actual pharmacokineticists in the world and computers, I was in the middle of my post and kept getting interupted. My point is with oral admin of drugs, there is much interplay between tissue, blood, and drug and the rates and extent which molecules move back and forth, it is very difficult to make exact calculations such as the amount distributed into fatty tissue and how it exactly affects the effects of the drug. Even with the best data and calculations you still have issues.

If you choose the wrong model (one vs two compartment etc) you can over or underestimate some of the constants leading to incorrect things like cmax. You also absolutely need data from i.v. administration to properly do the kinetics of oral dosing which for some drugs is not available and thus the answers are best estimates. And last, even for things that seem obvious (such as the lipophilicity of diazepam leading to it greatly distributing into fatty tissue [large Vd in that compartment] which would increase its t1/2 (biological or terminal, I am using them the same), you do not always get this result from drugs you would expect it from such as cyclosporine. This is usually from variabilty in the patient but could be from other factors of the drug as well. So in a sentence, oral admin PK sucks . But let me answer a few of your questions as best as I can anyway.

You mentioned first order kinetics (I hope you studied it, I will be PMing you my quiz later). And someone mentioned that no drug explicity follows first order kinetics but generally is a mix of zero and first order. This is true, but in each model, the movement from one area to the next (be that simple elimination in one compartment IV model or abs, dist, elim in a multicompartment model) is thought to occur through first order kinetics. If you graph this on a simple concentration vs time graph you get a curve with a negative slope, zero order give straight line with negative slope. All this means that first order kinetics, the amount of drug changing depends on its concentration at that time and in zero order the amount changing is constant and not proportional to its concentration.

Regarding half lives. It is usually thought of the half life of a drug, like you would read in a drug package insert, is the time it takes to remove half the drug from the plasma through elimination and that still stands and is easiest to understand. But it is true that the time it takes for half to absorb or distribute are also called half lives (t1/2abs, t1/2dis). And just as with terminal half life, the equation is t1/2abs=0.693/ka, with ka being the absorption rate constant with units of 1/time. Generally ka>kd>>ke, so the t1/2 of absorption of clonazepam being 26 minutes is not too suprising.

I want to talk about distribution into adipose tissue and it acting as a resevoir but I have to start my work day. I will return.

 

[Kittycat5]

I should point out first order absorption kinetics gives you a Cp vs t graph with a positive slope.

 

[Kittycat5]

Ok Kdem, back to distribution. You asked if there is a shift from the central compartment to the peripheral ones on multiple dosing. With multiple dosing you will reach steady state after about 5 half lives assuming regular dosing intervals. If you were to stop administering the drug, I would say your statement is basically correct which I hope to explain even if we dont stop giving doses.

Each time you administer the drug, the same events happen, so in this respect, no there is not a shift. The drug absorbs, distributes, and eliminates exactly the same way. But we must consider where and how fast the drug distributes and how much, if any accumulates. Let me start off with the where first. As I have said , the physiochemical properties of the drug and the amount of blood perfusion are two of the most important factors influencing drug distribution. But the actual size (volume to be precise) of the organ whose tissue the drug is distributing also is quite important. Let's compare the adrenal glands with adipose tissue. The adrenal gland has a high rate and actual amount of blood flow but a tiny volume of just 0.02L (the perfusion rate is 100ml/min and blood flow amount 500ml/100ml tissue volume. Drugs rapidly distribute in and out of the adrenals and with such a tiny size, basically no drug would expect to accumulate within. Adipose tissue, on the other hand, has a huge volume of 10L. The rate of blood flow is actually higher than the adrenals (200ml/min) but the amount of blood volume per 100ml tissue volume is only 2ml/100ml. So what does this mean? Despite a higher actual rate of blood flow, the amount of actual blood reaching a unit volume of tissue (in our case 100ml tissue) is extremely low and only a small amount of drug is thus deposited in each small section. But the whole volume of adipose tissue is huge, so in total, a fair amount of drug is deposited in the fat with each round of circulation. This is a physiologic explanation for why lipohilic drugs like benzos slowly but extensively accumulate in the fat as opposed to the mathematical ones from PK modeling.

I want to talk about rate of distribution and accumulation but must sleep a bit. I will try to finish later.

 

[Kdem]

'You asked if there is a shift from the central compartment to the peripheral ones on multiple dosing. With multiple dosing you will reach steady state after about 5 half lives assuming regular dosing intervals. If you were to stop administering the drug, I would say your statement is basically correct which I hope to explain even if we dont stop giving doses.'

Actually, what I had in mind (I think!) is that when you start a drug, most of it will be in the central compartment. After multiple doses, there will be a shift to the periheral compartment.

Not to sidetrack the discussion, but I was under the impression that one of the organs diazepam accumulates in, is the adrenals. Just like the liver.

'This is a physiologic explanation for why lipohilic drugs like benzos slowly but extensively accumulate in the fat as opposed to the mathematical ones from PK modeling.'
They do ? According to sources, clonazepam accumulates to three times the daily dose when taken once daily. Given the half life (1-2 days), it doesn't look like it extensively accumulates in fat.

 

[Kittycat5]

Man, you are making me work. I am focusing on the PK models but in actuality a PK-PD model may be needed. While distribution kinetics are a pretty good way to show the discrepancy between half life and duration, it isnt the whole story. I am not as up to speed on PK-PD modeling, but basically it takes into consideration things like tolerance/hysterisis, receptor binding affinity, and down regulation of receptors along with the PK parameters to try and understand the variations among classes of drugs.

But clonazepam surely distributes rather extensively into the fat. Its Vd is around 3L/kg and anything over 1.2 shows, a drug isnt confined to the blood and distributed to tissue. And all benzos are lipophilic, so adipose tissue surely is a huge "sink" for all benzos. More later.

Edit. Not 1.2L/Kg but 0.7L/Kg. Above this, widely distributes, below confined to blood.

 

[PINKoPANaTHER]

I think at this point, the problem is not going to be solved by a further understanding of PD/PK of benzos. I would continue trial and error until you find something that works, because for me, tapering off of clonazepam was fairly straghtforward and was done successfully at a rapid rate. This is not to say your wrong about your assumptions, but that individual PK/PD can vary and even the most precise mathematical model cannot predict genetic variants in metabolism, distribution, and absorbance at this point in time.

I wish you luck regardless of how you proceed, because I understand the difficulty in coming off benzodiazipines

 

[Kittycat5]

I think at this point, the problem is not going to be solved by a further understanding of PD/PK of benzos. I would continue trial and error until you find something that works, because for me, tapering off of clonazepam was fairly straghtforward and was done successfully at a rapid rate. This is not to say your wrong about your assumptions, but that individual PK/PD can vary and even the most precise mathematical model cannot predict genetic variants in metabolism, distribution, and absorbance at this point in time.

I wish you luck regardless of how you proceed, because I understand the difficulty in coming off benzodiazipines

Very true. I think Kdem is interested in the science though but I may be wrong. Kdem, I feel I should apologize because I didnt really address your actual reason for making this thread. I would like to finish my thoughts but if you dont want to be bothered, I understand. The accumulation thing may touch on your question, though.

 

[Pharmokinetictal]

It's been a while since I took physical chem but I am currently a neuropsychopharmacologist. I got off 6mg clonazepam after 5yrs daily use and mixing with Xanax (I could take 120mg of Xanax at once and not notice it). It took 7 months but I did it with clonazepam. I'd failed before but only because of when I administered my doses. So at first I dose dumped in the morning because you have to remember that sleep disrupts the effective therapeutic half life of drugs because anaebolic metabolism helps redistribute the drug back into the blood.

I'm against Valium as a tapering agent because it IS 'dirty.' Diazepam alone does not have a particularly long half life. It's fast acting but is quickly oxidized and reduced to much less efficacious metabolites like oxazepam and nordiazepam and desmethyldiazepam. As a drug alone, diazepam is great...but it's lipophilicity makes it a terrible prodrug to metabolites that are even less effective and now exist mainly plasma protein and lipid bound at insignificant quantities.

Stick with clonazepam. Even lorazepam isn't worth trying.

However! There is a recognized beneficial practice many docs don't do but should. You seem very educated on BZDs so you may know this: the GABAa receptor is a pentameric construct. Drugs like alprazolam preferentially bind the alpha1 subunit and one other associated with hypnotic properties. Diazepam is a broad spectrum benzo in that it bind all alpha (1-5) subunits and therefore will induce a PKA/CREB-induced downregulation of all GABAARs. One practice is to frequently shift from one benzo to another--preferably two with different affinities for their respectively loving alpha subunits. That will prevent tolerance built, ironically during tapering.

So clonazepam to lorazepam to alprazolam (qid++), to clonazepam again. Docs don't like it cuz it looks weird to pharmacists but it is recognized in literature as effective for opioids and BZDs.

My method was to cut my dose by roughly 0.25mg/2 weeks and 0.5mg per month. So if I were at 2mg, I'd be using the 1mg tablets--maybe even the 0.5mg tabs. I would take 1mg in the morning, 0.5 at ~4pm, and 0.5mg at bedtime. The second week, I would do 0.5mg QID. Then I'd be ready for 1.25mg...'dump' 0.50mg in the morning, 0.50mg afternoon, 0.25mg bedtime first week. Then 0.5mg morning and 0.25mg at noon, afternoon, and bedtime and so forth.

Finally...look into etizolam. I don't know if docs can prescribe it but it can reverse tolerance, so says the literature! Good luck!

 

[Kdem]

Kittycat5,

I am very much interested. Not 'only' in the original question of the thread.

'But clonazepam surely distributes rather extensively into the fat. Its Vd is around 3L/kg and anything over 1.2 shows, a drug isnt confined to the blood and distributed to tissue. And all benzos are lipophilic, so adipose tissue surely is a huge "sink" for all benzos. More later.'
Are you sure ? It's a tricky question, since various sources say different things. Someone mentioned that clonazepam exists in two 'structures', that something like PKa/PH matters (I'm doing this by memory!). I think that the lipophilicity of clonazepam is medium to low. Of course, that's relative.
I did study the drug distribution at one time (post mortem human!), I think the concentrations were high in the CNS, bile, maybe a few other places. But fat, outside the CNS ? My guess would be, not that much. I'm too lazy to go looking for all that data, though.