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
poster:Shawn. T.
thread:266360
URL: http://www.dr-bob.org/babble/20031004/msgs/266471.html