![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 7 of 7. This is the beginning of the thread.
Posted by JaneB on October 7, 2003, at 11:37:24
How can it be that sleep meds in the same class can have such varied side effects? Prosom makes me sleep but then I cry at the drop of a hat next day. Same response to restoril, ativan, and I suspect Ambien (though I haven't tried it for a year.) What is so chemically different between the meds? Why is it that clonazepam is the only benzo that keeps me smooth but does not always help me sleep? Just thought of the answer to my own question. Probably because I take clonazepam on a continual basis--.50pm, .25 am. But it is losing its sleep inducing benefit. Should I increase it or supplement with something else?
Jane
Jane
Posted by linkadge on October 7, 2003, at 13:29:06
In reply to BIG differences between benzos?, posted by JaneB on October 7, 2003, at 11:37:24
Some of the benzo's affect other chemicals as well. I think Xanax, and Clonazepam has some effect on serotonin as well.
I know for many, Valium is a bit of a downer.
Linkadge
Posted by Shawn. T. on October 7, 2003, at 17:11:55
In reply to BIG differences between benzos?, posted by JaneB on October 7, 2003, at 11:37:24
Here's a detailed description of benzodiazepine pharmacology. I wish that there were a simpler way to explain it... the first paragraph isn't necessarily important, but some may find it interesting.
There are two different classes of benzodiazepine "receptors." One class is the peripheral benzodiazepine receptor that is found primarily on mitochondria in peripheral tissues; however, some are located in the brain. This receptor modulates the flow of cholesterol into mitochondria to allow steroid hormone synthesis to occur (see http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=109610 ). Diazepam (Valium) is known to act at these receptors; however, this activity probably does not elicit a very noticeable psychoactive effect.
The second class of benzodiazepine "receptor" is not really a receptor at all; it is a binding site on inhibitory GABA-A receptors. GABA-A receptors are pentameric proteins that consist of a number of different combinations of subunits. The actions of benzodiazepine drugs at GABA-A receptors are determined by the subunit compositions of these receptors. The drugs bind to a subunit cleft between the alpha and gamma subunits (see http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12171574&dopt=Abstract ). On the other hand, the agonist binding site for GABA lies between the alpha and beta subunits. The binding affinity and/or allosteric coupling of benzodiazepine drugs at GABA-A receptors is determined by specific amino acids in the alpha and gamma subunits (see http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12388542&dopt=Abstract ). The alpha subunit plays the largest role in determining the selectivity of benzodiazepines; alpha1, alpha2, alpha3, and alpha5 subunits determine whether or not a certain drug will bind with high affinity to a certain GABA-A receptor (see http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12871032&dopt=Abstract ). For example, zolpidem (Ambien) is selective for alpha1 subunit- containing receptors at therapeutic doses (see http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12680751&dopt=Abstract ). Researchers have found that alpha1 subunits are associated with the sedating effects of benzos; non-sedating benzos would therefore be expected to exhibit partial agonist activity (e.g. less than fully potent) or no activity at alpha1 subunit- containing GABA-A receptors.
Alpha2 and/or alpha3- containing receptors are likely to be associated with anxiety (see http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12871032&dopt=Abstract ). I don't know the exact selectivity profile of clonazepam; however, I believe that it is nonselective for the various alpha subunits. I suspect that it's not as potent as drugs like Ativan and Ambien at alpha1- containing receptors, but that's only speculation. What's likely happening in your case is a downregulation of alpha1 subunits; the long half-life of the drug combined with continual use has elicited a negative feedback response by neurons in your brain. Increasing the dosage may have an effect initially, but the loss of effect would likely occur again. Combining the clonazepam with an alpha1 selective sedative with a shorter half-life would probably be the better choice if your doctor/pharmacist finds the combination to be reasonable. You could also consider trying a supplement like valerian.
Shawn
Posted by Viridis on October 9, 2003, at 0:57:29
In reply to Re: BIG differences between benzos? » JaneB, posted by Shawn. T. on October 7, 2003, at 17:11:55
Hi Shawn,
I'm really impressed by your knowledge of benzodiazepine pharmacology, so maybe you'll have some insights into the following situation:
I've been taking 1 mg clonazepam (Klonopin)/day for about 2 1/2 years, and it continues to be effective for anxiety at the same dose. I also have alprazolam (Xanax) available for PRN use, and it worked very well for "breakthrough anxiety" for a long time. However, recently my tolerance to alprazolam seems to have increased dramatically, even though I only take it occasionally.
I asked my pdoc about this and he really couldn't explain it, except to say that he's seen this pattern before, and it seems to be specific to alprazolam. He didn't seem too worried, and just suggested that I take as much alprazolam as I need when I need it, as long as my frequency of use doesn't increase. He did add, though, that this is why he's especially cautious with alprazolam, whereas he has many patients who stay at the same dose of clonazepam for years.
He thinks that cross- tolerance to alprazolam from clonazepam seems unlikely, since the two are structurally quite different.
So, what's so difference between these two benzos, such that one can induce tolerance even with infrequent use, whereas the other just seems to plug away effectively for years at the same dose, used every day?
I realize that there probably isn't a simple answer, but any insights would be appreciated.
Posted by Shawn. T. on October 9, 2003, at 23:20:49
In reply to Re: BIG differences between benzos? » Shawn. T., posted by Viridis on October 9, 2003, at 0:57:29
Alprazolam is considered to be a nonselective benzodiazepine agonist (see http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12420154&dopt=Abstract ). I mentioned in the previous post that I believe that clonazepam is also nonselective. The binding affinities for these drugs at the various alpha subunits probably differ, but I don't have access to any data on the subject. My point is that cross tolerance probably does develop between the two drugs. In a mouse model of chronic benzodiazepine exposure, both drugs induced a similar pattern of tolerance (see http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1652596&dopt=Abstract ). In addition, evidence seems to suggest that alprazolam develops cross tolerance with other benzodiazepines in all but a few cases (see http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2889723&dopt=Abstract ).
I don't think that it's reasonable to judge the possibility of the development of cross tolerance between two drugs based upon the chemical structure of the drugs. On the other hand, I would expect benzodiazepines to differ in the levels of tolerance that they induce to various effects; this would depend on how they interact with the different GABA-A receptor subunits. Based on our current understanding of the pharmacology of alprazolam and clonazepam, I think that finding a pharmacological explanation for the phenomenon that you've experienced would be very difficult.
Shawn
Posted by Viridis on October 12, 2003, at 3:29:23
In reply to Re: BIG differences between benzos? » Viridis, posted by Shawn. T. on October 9, 2003, at 23:20:49
Hi Shawn,
Many thanks for the helpful info and links. I was skeptical, too, about the idea that structural differences would automatically invalidate the hypothesis of cross-tolerance between clonazepam and alprazolam. I'll relate this to my pdoc, who is very open-minded and doesn't mind being contradicted. He actually loves to learn about how these meds work, which is very refreshing.
So, my next question is: what do you know about Ativan (lorazepam)? I seem to need a fast-acting, short half-life benzo occasionally, and since I've apparently developed some tolerance to alprazolam (despite only sporadic use), might this be a valid substitute for alprazolam (e.g., is its subunit binding profile more selective)? I've never tried it, but am thinking of asking my pdoc for a trial prescription, perhaps to alternate with Xanax.
Any insights would be much appreciated.
Best,
Viridis
Posted by Shawn. T. on October 14, 2003, at 0:02:31
In reply to Re: BIG differences between benzos? » Shawn. T., posted by Viridis on October 12, 2003, at 3:29:23
I couldn't locate any research that involved identifying lorazepam's binding profile. One common problem with lorazepam is amnesia, but low doses should usually avoid this problem. You could also look into temazepam (Restoril); it has a somewhat shorter half-life than lorazepam. I don't know anything about its binding profile either. In general, it's safe to assume that most benzodiazepines (other than drugs like zolpidem) are nonselective for alpha subunits. However, do not assume that they're all equally effective at all subtypes of GABA-A receptors.
Shawn
This is the end of the thread.
Psycho-Babble Medication | Extras | FAQ
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.org
Script revised: February 4, 2008
URL: http://www.dr-bob.org/cgi-bin/pb/mget.pl
Copyright 2006-17 Robert Hsiung.
Owned and operated by Dr. Bob LLC and not the University of Chicago.