Benzodiazepine Pharmacology and Central Nervous System–Mediated Effects

"This review explains the mechanisms of action of BZDs, compares and contrasts popular BZDs on the market today, and describes specific BZD-mediated effects and side effects".

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3684331/

Much speculation as usual, they're still trying to figure it out. 

Background

Owing to the low therapeutic index of barbiturates, benzodiazepines (BZDs) became popular in this country and worldwide many decades ago for a wide range of conditions. Because of an increased understanding of pharmacology and physiology, the mechanisms of action of many BZDs are now largely understood, and BZDs of varying potency and duration of action have been developed and marketed. Although BZDs have many therapeutic roles and BZD-mediated effects are typically well tolerated in the general population, side effects and toxicity can result in morbidity and mortality for some patients. The elderly; certain subpopulations of patients with lung, liver, or kidney dysfunction; and patients on other classes of medication are especially prone to toxicity.

Methods

This review details the present knowledge about BZD mechanisms of action, drug profiles, clinical actions, and potential side effects. In addition, this review describes numerous types of BZD-mediated central nervous system effects.

Clonazepam behaves both as a GABA-A receptor agonist in a highly-potent, long-acting manner and also as a serotonin agonist.

Interesting that the phrase "Benzodiazepine Withdrawal Syndrome" is not used in the article, even though big pharma formally recognized its existence circa 2007.

NIMH is behind the curve on benzo science, and regulatory agencies are moving to the forefront, causing a decline in benzo prescriptions but also fear among physicians of prescribing benzos as would be appropriate in an Ashton-style tapered withdrawal.

Thanks for the share.

Really ?

'Because clonazepam displays low lipid solubility' I thought that all benzos were highly lipid soluble ?

'Clonazepam also has a relatively weaker binding affinity for GABA-A receptors than the other high-potency BZDs' BUT IT IS SO STRONG.

What the article made clear is that each of the benzos is different in makeup. And, of course, each individual is different in terms of how they metabolize different medications. The article also talked about accumulation, which obviously takes place when a longer-acting benzo is taking over a period of time.

Here are some key quotes for me:

Tolerance, dependence, and withdrawal are adverse effects associated with long-term use.

Drug interaction is another issue with BZDs. They are metabolized in the liver via the cytochrome p450 system and subsequently glucuronidated and renally excreted. Drugs that either attenuate (oral contraceptive pills, antifungals, and some antibiotics) or potentiate (carbamazepine, phenytoin, rifampin, St. John's wort) cytochrome p450 enzymes will either increase or decrease the elimination half-life of BZDs, respectively.

There are just so many factors involved in how individuals are affected by these medications.

Ugh, I hate that I sound like such a jaded skeptic, but it is what it is. 

What the article made clear to me is how little they know about anything.  It's all "present knowledge" in their own words.  I prefer the phrase "present theory", as it's liable to be amended if/when the latest and greatest new theory comes out.

Still, it's the most detailed article I've seen on attempts to explain the mechanisms of action.

Well I, for one, am very glad that I'm living now and not years ago, when even less was known about the mechanisms of these meds. I've looked up "benzodiazepine withdrawal" on PubMed and followed it back to the 1970s. While it's not possible to view many of those early abstracts anymore, the titles alone are enough to make one shudder. How about "withdrawal psychosis" or "neonatal withdrawal"? So, so sad.

These days, we all have internet access, and we can do tons of research, if we want. Anyone who was on these meds in the past was completely in the dark.

No kidding, Lap.  I shudder too.

I so wish we were able to access these archived articles, I'd love to read what was written back then.  Back before the days of Big Pharma influence.  I mean "withdrawal psychosis" seems to point to them acknowledging the physical dependence. 

Well, they clearly had some idea that it wasn't good to yank people off these medications in a quick manner. And they noticed that babies born to mothers taking these meds were in serious distress. But I doubt they had a handle on the mechanisms behind such things until later on.

I really do feel thankful that we can look these things up. The extent of our access to information on the internet is quite extraordinary. In the past few years, I've been able to go to a doctor with a scholarly article in hand and to ask critical questions of that person based on the content. I could never have done that before; I would have been completely uninformed -- and, perhaps, still on benzos.

Really ?

 

'Because clonazepam displays low lipid solubility' I thought that all benzos were highly lipid soluble ?

 

'Clonazepam also has a relatively weaker binding affinity for GABA-A receptors than the other high-potency BZDs' BUT IT IS SO STRONG.

it's also a GABA-b agonist which is unusual; it's sort of an odd duckling.