Pharmacology - Active Metabolites of Benzodiazepines

[Laudaphun]

SWIM has been wondering about the active metabolites of benzos such as chlordiazepoxide(Librium) and diazepam(Valium). Both are listed as having active metabolites that have half lives much longer than the actual drugs themselves. I did a little looking and found that chlordiazepoxide is metabolized into desmethylchlordiazepoxide. Further reading showed that desmethylchlordiazepoxide also has an active metabolite which has a half life of 10-18 hours.

What SWIM wants to know is that basically if you take a librium, the chlordiazepoxide will have an effect and then the active metabolite is actually a series of at least 2 subsequent active metabolites? Take pill containing drug A which body breaks down into substance B, which happens to be active... body breaks down into substance C, which also happens to have an effect.. and so on until you add up half lives to get a 200 hour half life?

I guess SWIM is not really clear on what an active metabolite is... Would you define morphine as being an active metabolite of codeine?

[Ethyl]

Every substances will have to be dealt with...

If substance A breaks down to substance B and B to C and so on, everyone of them will have different half-lifes, so they leave the body in different times.
If they have long half-lifes like in the case of chlordiazepoxide(Librium) and diazepam(Valium), they the user/abuser will have accumulation of ALL of the substances.

If you ingest codeine, it will break down to other metabolites, one of them is morphine, that will need to be break down to other metabolites...
An active metabolite is just that.. a metabolite (break down product by our body) of a drug that has active effects.

Hope that clears you out.

[Micklemouse]

The stupendously long halflives of both the parent drug & it's active metabolites in the cases of chlordiazepoxide & diazepam are what makes them such usefull tools in alcohol & benzodiazepine withdrawal. Withdrawal symptoms could be seen as the brain going into shock due to a chemical it has grown accustomed to to the point of thinking it is necessary for functioning is suddenly no longer there. By switching from a short acting drug (e.g. alcohol or lorazepam) to a longer acting one the brain is fooled into thinking that the substance is still there, prevents over-excitation of previously inhibited neurons & has time to readjust while the withdrawal regime tapers down. It is also why people have less trouble coming off Fluoxetine (Prozac) than say Paroxetine (Seroxat. Paxil), Fluoxetine having a long halflife anyway, plus active metabolites.

[Laudaphun]

Here is a small list that SWIM has compiled so far... Active compounds, of a benzo, half-life, etc. Keep in mind, not all benzos are active themselves, but rather have active metabolites which are responsible for the action. And by (not active), I mean that the parent or prodrug itself is not active, but rather it is it's metabolites which are responsible for pharmacological action.

Diazepam
Active Metabolites: Nordiazepam, Oxazepam, Temazepam
Active Compounds in Blood: Diazepam (24 hours) Nordiazepam (60 hours) Oxazepam (8 hours) Temazepam (12 hours)

Chlordiazepoxide
Active Metabolites: Nordiazepam, desmethyl-chlordiazepoxide, demoxepam, oxazepam
Active Compounds in BLood: Chlordiazepoxide (10 hours), Nodiazepam (60 hours), desmethyl-chlordiazepoxide (?? hours), demoxepam (?? hours), oxazepam (8 hours)

Flurazepam (not active)
Active Metabolites: Desalkylflurazepam, hydroxyethylflurazepam
Active Compounds in Blood: Desalkylfurazepam (80 hours), hydroxyethylflurazepam (?? hours)

Halazepam
Active Metabolites: Nordiazepam
Active Compounds in Blood: Halazepam (14 hours) Nordiazepam (60 hours)

Prazepam (not active)
Active Metabolites: Nordiazepam
Active Compounds in Blood: Noridiazepam (60 hours)

Chlorazepate (not active)
Active Metabolites: Nordiazepam
Active Compounds in Blood: Nordiazepam (60 hours)

Lorazepam
Active Metabolites: NONE
Active Compounds in Blood: Lorazepam (15 hours)

Clonazepam
Active Metabolites: NONE
Active Compounds in Blood: Clonazepam (30 hours)

Quazepam
Active Metabolites: Desalkylflurazepam
Active Compounds in Blood: Quazepam (35 hours) Desalkylflurazepam (80 hours)

Estazolam (not active)
Active Metabolites: Hydroxyestazolam
Active Compounds in Blood: Hydroxyestrazolam (18 hours)

Midazolam
Active Metabolites: NONE
Active Compounds in Blood: Midazolam (2.5 hours)

Oxazepam
Active Metabolites: NONE
Active Compounds in Blood: Oxazepam (8 hours)

Temazepam
Active Metabolites: NONE
Active Componds in Blood: Temazepam (12 hours)

Triazolam
Active Metabolites: NONE
Active Compounds in BLood: Triazolam (2.5 hours)

Alprazolam
Active Metabolites: NONE
Active Compounds in Blood: Alprazolam (12 hours)

Nitrazepam
Active Metabolites: NONE
Active Compounds in Blood: Nitrazepam (16 hours?)

Nimtazepam
Active Metabolites:
Active Compounds in Blood:

Flunitrazepam
Active Metabolites:
Active Compounds in Blood:

Lormetazepam
Active Metabolites:
Active Compounds in Blood:

This is just a crude and quick list and will be a work in project... if SWIM doesn't forget about it.

Reputation Comments on this post:

Great post, i just realised it has no rep added, i refer it to sometimes.

[Politicalchalk]

Swim is curious...has read that oxazepam (for instance) is made in small amounts. Would this even small amount oxazepam (as a metaboite of diazepam, or anything else which has nordiazepam as a metabolite) be considered active, even if un-recognizable doses to the conciousness of the swimmer...many benzos seem to be breaking down into nordiazepam and/or oxazepam somewhere along the lines.

any thought?

Reputation Comments on this post:

10 points for making SWIM think! She is rather interested now.

[Laudaphun]

Yep, they are active to a certain degree. Even with small amounts, they no doubt work in conjunction to create the actual "Valium" effect. And it sticks in SWIM's head that she remembers reading that diazepam was excreted in small portions as temazepam. SWIM has a strong suspicion that being that at one of the metabolites is temazepam, and even though it would be in small amounts given the mg per mg difference in dosages, the fact that temazepam is an active metabolite lends it part of it's unique "flavor". You figure that diazepam itself is active, and then broken down into oxazepam, temazepm, and nordiazepam these would work in conjuction with one another to provide a unique effect. While SWIM typically would rather avoid drugs with many active metabolites, benzos are still particularly interesting for that reason. Diazepam seems to be something that people still hold in high regard. SWIM has a more comprehensive list around somewhere... just can't find it at the moment. But if I understand what SWIY is asking, you would be correct in that there are many many metabolites, some active, some not which some of the above listed benzos are broken down into, which would have an effect. SWIM is thinking that chlordiazepoxide actually has something like at least 3 significant active metabolites so I'm guessing diazepam has a few too... Will make additions to the diazepam and chlordiazepoxide entries.

As SWIM was trying to find the textbook, paper, or other reference material to find the more elaborate and detailed list of active metabolites she found a table that says temazepam has a very slow absorption into the stomach which SWIM immediately thought was false information, as temazepam has close to 100% bioavailability when taken orally and takes effect VERY rapidly. But SWIM also remembers that the actual peak <WILL INSERT LATER, NOT DIGGING THROUGH ALL THAT TEXT AGAIN ATM> is something like 2-3 hours. On top of that, the effects of the drug seem more pronounces than that of most benzos. Typically SWIM can feel acute effects from a benzo "the more pleasant" feelings such as alprazolam last maybe 20 minutes or so then fade, but temazepam seems to linger quite a while, and also seem to be fairly noticeable when they wear off as opposed to other benzos. SWIM began thinking and even if the drug is absorbed into the body very slowly, it's high bioavailability would make it sense of the potent and lingering effects noted. SWIM is thinking that the rapid onset is felt by a fairly small amount due to the high bioavailability of the drug which proceeds to slowly but steadily absorb, yielding a longer lasting "initial effect". Temazepam has always effected SWIM significantly different than other benzos in that the first short-lived wave of relaxation does not subside like that of other benzos such as alprazolam or lorazepam which seem to last (20 minutes maybe? then just therapeutic effects.) Perhaps this is typical of hypnotic benzos... SWIM doesn't know as temazepam is the only benzo she has experience with that would be considered a hypnotic. SWIM used to attain a good 6 hours of recreation from temazepam after which the effects wore off and it was time to redose. Temazepam in SWIM's experience has been the most habit-forming therefore she uses them more rarely now. Plus they skyrocket benzo tolerance very quickly for everything else. After being prescribed temazepam for 2 + years, SWIM has learned that they will catch up with you sooner or later, as opposed to alprazolam which SWIM has no problems with development of tolerance or cravings. That might seem odd to some, but this is just SWIM. SWIM can take the same dose of alprazolam everyday without feeling the need to increase dose, any loss of anxiolytic properties, or craving for a dose. I guess what SWIM is getting at is the fact that not just oxazepam is an active metabolite of diazepam, but temazepam is also. While SWIM doesn't have extensive experience with diazepam, she imagines that diazepam itself along with the active metabolites could make for a real nice benzo with unique effects. SWIM will have to investigate the proportions of which diazepam metabolizes into these and the timeframe at which oxazepam and temazepam would appear in appreciable quantities in the blood stream. Glad you pointed this out as it makes diazepam seem like it could posess a rather interesting pharmacology.

[Politicalchalk]

Yes, exactly! Sometimes I think faster than I type, and my sentences don't always make sense. But the synergy of various metabolites was quite indeed my reference.

[Solinari]

Does anyone know what active metabolites there are with nitrazepam?

[Politicalchalk]

Solinari -

Nitrazepam has no clinically active metabolites. The drug is excreted in human urine mainly as conjugated and non-conjugated aminonitrazepam and aceta-midonitrazepam. When given orally, 65 to 71% of the dose eventually appears in the urine and 14 to 20% in the feces. Only about 1% of the administered dose is excreted in the urine as unchanged nitrazepam. The major pathway involves hepatic nitroreduction.

Reputation Comments on this post:

	great stuff!
	the administration thanks you

[Solinari]

Thanks for finding that info out, i asked because some one always thought of diazepam like a combination of nitrazepam and temazepam, probably because of the metabolites of diazepam rather than anything else.

[Solinari]

I don't mean to bump old posts but the information in Laudaphun post is very useful and i have searched for it a few times to check it out. I couldn't find the same information in the other posts so maybe the info should be added to a sticky that's already present in some way.