Barbiturates versus benzodiazepines?

[Veritatem]

So my research interest for this past month or so has been pretty much centered on CNS depressants. I have taken barbiturates, perhaps, twice in my life recreationally, anaesthesia and hospitalizations excepted. In both cases the substance was butalbital in doses less than 300 mg. Not sure if meprobamate is considered a true barbiturate or not, but I have quite a lot of experience with it through the use of carisoprodol. From my limited experience, barbs just "feel" dangerous, even in relatively moderate doses, not to mention that barbs have a terrible reputation for death even in mild overdose. Benzos, on the other hand, I have a lot of past experience with, and in much larger doses and varieties. They never felt as dangerous when benzos were the only drug taken; they just seemed to cause profound amnesia and various paradoxical reactions. I do know personally the pain and suffering (and possible lethality of benzo withdrawal; I can only imagine that barb withdrawal must be much more severe). If both barbs and benzos at their lowest common denominator produce their effects via GABA, what causes there to be such a major clinical difference in the safety of the medicines? Are benzos essentially "barb-lite" medicines or is the MOA totally different? Forgive me if these seem like a basic questions. I'm very interested in pharmacology, and have a basic understanding of a number of medicines but I'm not quite advanced enough yet to understand the finer details. Anyone have some experiences or knowledge that might help?

 

[sekio]

From the wiki page on barbiturate derivatives:

Barbiturates produce their pharmacological effects by increasing the duration of chloride ion channel opening at the GABAA receptor (pharmacodynamics: This increases the efficacy of GABA), whereas benzodiazepines increase the frequency of the chloride ion channel opening at the GABAA receptor (pharmacodynamics: This increases the potency of GABA). The direct gating or opening of the chloride ion channel is the reason for the increased toxicity of barbiturates compared to benzodiazepines in overdose

The simple answer is that although benzos and barbs both act at GABA_AR, they act at different sites on the receptor, thereby producing different but similar effects.

Barbiturates also have non-GABAergic activity at e.g. AMPA receptors and various ion channnels, especially in overdose, which contributes to the lethality. Benzodiazepines tend to be much more selective for the BZD site on GABA_A so produce much more "controlled" effects and are also safer in OD (higher TI).

 

[modocmodoc]

Barbiturates act like alcohols. Unlike benzodiazepines, which bind to a subunit on the GABAA site and increase the firing rate of the neuron, barbiturates are simple GABA agonists, so they, like ethanol exert the 'pressing the brake and the gas pedals' effect, as the brain attempts to counteract the agent by converting GABA to Glutamate. Removing the agonist (brake) leaves the car on full throttle (glutamate).

 

[Veritatem]

@sekio, thank you for that reference and the response. I should have looked that page over a little more throughly.

If I try to understand the basic concept (how I have to start or I'll never fully understand it) barbiturates, in addition to other effects, remove what I call the "self-limiting switch" on the sodium ion channel at GABA-A, Instead of closing at the right time, with barbs the channel is forced open. Benzodiazepines act on the BZD site more specifically, and their most basic function is not to force the channel open but to increase the frequency at which the channel opens normally, and increases the potency of the neurotransmitter released. Are there any errors in my understanding there?

Thanks for being so kind, by the way. Some places I have tried to get opinions or education on basics and I get a bunch of "UTFSE" or as one user on another forum said, "If you don't understand this, go back to high school chemistry", so I appreciate you taking the time to try and put it in terms I understand. I know a search engine provides virtually. unlimited raw data on most medicines, but hearing (or reading) an explanantion from an knowledgeable person helps me make sense of the data.

 

[Veritatem]

@modoc, thanks for the response. What role does the excess glutamate created by barbs play in this situation? I am somewhat familiar with physical addiction pathway and the role dopamine and glutamate play in that process, but I'm not very educated beyond that.

 

[modocmodoc]

Glutamate becomes toxic when it builds up (as in acute withdrawal/DT/seizure) - for instance, it is released in massive amounts if there is head trauma or a stroke or embolism. I'm not sure if its role is completely understood but the brain has a tendency to flood areas of itself with glutamate during life threatening events, probably to enhance short-term function at the expense of some neurons later on.

 

[modocmodoc]

Yes, you have it.

 

[AlphaMethylPhenyl]

thought it was that barbs become pom's at higher doses, and are pam's at lower doses.

 

[Limpet_Chicken]

Veritatem-GABAa isn't a sodium channel, the heteropentamer of subunits that form GABAa receptors is actually, a chloride ion channel.