Barbiturates explained and comparison to benzos

[swimming.since.99]

If you know anything about the mechanism of action of barbiturates and benzos, it's probably along the lines of: "They increase the length of time the Cl channel is open while benzos increase the frequency, and barbs are very easy to overdose on"

But there's more to it.

Benzos need your own GABA in order to work. Once GABA binds to the top of the beta sub-unit of the GABA-A receptor and opens the Cl channel, only then a benzo that is bound to the alpha sub-unit will work, by simply increasing the frequency GABA opens the channel.

Barbiturates DO NOT need your own GABA to work. If GABA binds to the top of the beta sub-unit of the GABA-A receptor, a barbiturate will increase the length of time the the Cl channel is open, HOWEVER, if GABA is not there, a barbiturate will both agonise the receptor instead of GABA and increase the length of the Cl channel opening. Barbiturates are both agonists and PAMs of GABA-A receptors. They also directly antagonise (block) AMPA and Kainate receptors, which is what makes them such effective CNS Depressants (and recreational depressants), but this is also what makes them so dangerous.

Such effective work at GABA receptors combined with antagonism at 2 of 3 of the most important excitatory receptors produces a dissociated and floaty feeling, as well carelessness, exceeding that of opiates. This also makes them effective for treating seizures, as Kainate receptors are well known to cause them. Long acting barbs like Phenobarbital will be great for anxiety relief, if not the danger that lies beneath the goodness of barbiturates. At a large enough dose (overdose obviously) effective work at GABA-A and blocking of excitatory receptors = death, although fast and painless.

It is impossible, in practice, to overdose on benzos. This is because they only work if GABA is present, and your brain controls the amount of GABA you have. Although benzos at insanely large doses do block Calcium channels, so at say 100,000mg Alprazolam (that's the LD50 of Alprazolam in rats) will cause immediate death, but that's 50,000 xanax bars which is impossible to consume. While 1000mg of Phenobarbital (only 10 tablets) will certainly kill you.

I hope this helped.

SWIM

 

[aced126]

Interesting, although why is respiratory depression and death a result of more cl- ions flowing through the channel?

 

[serotonin2A]

Interesting, although why is respiratory depression and death a result of more cl- ions flowing through the channel?

Because Cl ions hyperpolarize neurons, which eventually stops them from firing. It can be fatal if that happens to the neurons responsible for breathing and other vegetative functions.

 

[aced126]

Why does hyperpolarisation decrease firing rate?

 

[serotonin2A]

Why does hyperpolarisation decrease firing rate?

Because neurons fire when they are depolarized to ~-55 mV. If the membrane is hyperpolarized then a larger amount of membrane depolarization is required to reach -55 mV. So hyperpolarization makes it more difficult to stimulate neural firing.

 

[aced126]

I see, so the cl- ions flow out of the neuron then? Because there's a higher concentration of cl- in the neuron and a channel is now open?

 

[serotonin2A]

I see, so the cl- ions flow out of the neuron then? Because there's a higher concentration of cl- in the neuron and a channel is now open?

No, you have it backwards. Neurons normally contain a low concentration of chloride ions. The KCl transporter pumps chloride ions out of the cell, lowering the intracellular concentration of Cl-. The low chloride concentration helps to set the resting membrane potential at around -70 mV. Thus, when the GABA-A channel opens, there is chloride influx into the cell, hyperpolarizing the membrane.

 

[aced126]

No, you have it backwards. Neurons normally contain a low concentration of chloride ions. The KCl transporter pumps chloride ions out of the cell, lowering the intracellular concentration of Cl-. The low chloride concentration helps to set the resting membrane potential at around -70 mV. Thus, when the GABA-A channel opens, there is chloride influx into the cell, hyperpolarizing the membrane.

Surely chloride influx would mean a more negatively charged cell?

 

[serotonin2A]

Surely chloride influx would mean a more negatively charged cell?

It does make the inside of the cell more negatively charged, that is why it is said to be "hyperpolarized".

 

[aced126]

Is alcohol also an agonist and allosteric modulator at gaba a?

 

[serotonin2A]

Is alcohol also an agonist and allosteric modulator at gaba a?

It is a positive allosteric modulator.

 

[aced126]

Does it not agonise the beta sub unit like gaba does? If not, how come high doses of alcohol can kill similar to barbs but unlike benzos?

 

[endotropic]

Does it not agonise the beta sub unit like gaba does? If not, how come high doses of alcohol can kill similar to barbs but unlike benzos?

That's a great question. If I had to guess alcohol's high toxicity comes from interactions with multiple receptors, compared to the more selective benzos.

Also extreme doses of benzos can kill you, they just have a much wider window of safety compared to barbiturates.

 

[InterestingFACT]

Does it not agonise the beta sub unit like gaba does? If not, how come high doses of alcohol can kill similar to barbs but unlike benzos?

https://en.wikipedia.org/wiki/Theories_of_general_anaesthetic_action
Take a look at this. Solvents are... different. They at least probably don't really "fit" into the receptors they interact with. They're just solvents--they change the electrochemical environment of the brain, disrupt ion channels, etc.

EDIT:
https://en.wikipedia.org/wiki/Alcohol_intoxication#Mechanism
Also take a look at this.

 

[Flynnal]

Barbiturates can kill because they block 3 excitatory pathways:

1/ they block Kainate receptors
2/ they block AMPA receptors
3/ they block nACh receptors

They also greatly increase the efficiency of GABA as well as hijacking the GABA receptors by forcing the Cl- channels open. However, only at high doses do barbiturates actually hijack the GABA receptor itself.

But I'd say 1, 2 and 3 are why they are so deadly and why they kill so quickly.

 

[dez79]

And alcohol n benzos are easy enough to get a hold of but good ol barbs are lost in time inexcessable for all but the luckiest

 

[ungelesene_bettlek]

Interesting. I always thought that both Benzodiazepines and Barbiturates "only act as "positive allosteric moduators" for the GABA receptor, making it more sensible to GABA itself (the same is true for Methaqualone, Valeriana, Kava-Kava, Humulus Lupulus and dozend of other more or less efficient herbal sleep aids. Of course it is interesting that there are at least two different binding sites at the GABA receptor (besides the GABA binding sites themselves), one for Benzodiazipens and one for the Barbiturates (and also named accordingly). Contergan ("Thalidomid") seemed to work pretty similar to Barbiturates as sleeping aid, except for all the children born without arms and legs... The "Z-Drugs" (Zolpidem, Zopliclone and Zaleplon act on the Benzodiazepine receptor, which is kind of strange, since to me, they feel pretty much differen to Benzos (more like deliriants). AAh, and of course never forget Ethyl alcohol"

The only "true" GABA-Agonists I know of are GHB, Muscimol (of fly agaric fame) and its synthetic analogues Gaboxadol and Thiomuscimol. And Muscimol/fly agaric is a really different beasts to all the compounds mentioned above, although there are of course sleepy phases in a Amanita muscaria trip, which interchange with completele manic and psychedelic phases...

And what is still completely left out of the picture are narcotics like propofol and ether...

 

[endotropic]

The "Z-Drugs" (Zolpidem, Zopliclone and Zaleplon act on the Benzodiazepine receptor, which is kind of strange, since to me, they feel pretty much differen to Benzos (more like deliriants). AAh, and of course never forget Ethyl alcohol"

The GABA-A receptor has multiple different isoforms that produce distinct effects when activated. The "Z-drugs" only interact with the subtype responsible for amnesia/sedation, while the classical benzos are less selective in their interaction with different GABA-A isoforms.

 

[dez79]

I take care how much kava is drank it doesnt touch sides phenobarbitol