why plateau effect in Benzodiazepines?

[tarsuc]

Why not in Barbiturates?

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[glykon]

Why not in Barbiturates?

Because Benzos can't open the GABA channel by themselves, they need GABA to be present and there's only so much GABA in the CNS to depress it->plateau.
Barbiturates can open the GABA channel by themselves (even if GABA's not available anymore) so in high doses->coma->death.

 

[tarsuc]

thanks

 

[Phloston]

Km decreases with benzos.

Vmax increases with barbiturates.

So at a given , the reaction velocity that ordinarily equates to a plateau with benzos is still a positive-slope with barbiturates.

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And glykon is also right. I forget the name of the term for what he's describing, but I believe it's called direct gating. Barbiturates can do it but benzos can't.

 

[normtheniner]

We were told in pharm that barbs and alcohol both hold the GABA Cl- channel open.

Benzos binding to a specific receptor on the GABA Cl- channel increases the frequency of GABA binding.

So in short benzos have a ceiling because they're limited by the amount of GABA available in the cleft. Barbs and EtOH just hold the channel open longer and allow more Cl- to pass.

 

[Phloston]

We were told in pharm that barbs and alcohol both hold the GABA Cl- channel open.

Benzos binding to a specific receptor on the GABA Cl- channel increases the frequency of GABA binding.

So in short benzos have a ceiling because they're limited by the amount of GABA available in the cleft. Barbs and EtOH just hold the channel open longer and allow more Cl- to pass.

Is that true? Does EtOH increase Vmax like barbiturates? Or does it decrease Km like benzos?

 

[tarsuc]

er, phloston, but could you explain the vmax , km a bit more.

i understand the Vmax,Km concept

receptor is the GABAa receptor, but what is in this case when you talked about the substrate concentration?

 

[Phloston]

er, phloston, but could you explain the vmax , km a bit more.

i understand the Vmax,Km concept

receptor is the GABAa receptor, but what is in this case when you talked about the substrate concentration?

Vmax is the efficacy, or maximal extent to which a reaction can take place.

When Vmax is increased but Km is the same, the climber scales the mountain at the same speed but climbs higher.

Km is the , or substrate concentration, at 50% of Vmax. When Km decreases, you know the reaction is occurring more quickly (i.e. greater potency). When Km is decreased and Vmax is constant, the climber scales more quickly but doesn't climb to a greater height.

Benzos decrease Km, but don't change Vmax. This means the same reaction rate can occur at a lower concentration of substrate (i.e. GABA). But benzos don't change efficacy (i.e. they don't increase Vmax). Benzos increase frequency of Cl- channel opening.

Barbiturates increase Vmax but don't change Km. They don't change the frequency of Cl- channel opening. They instead increase the duration that the channel remains open.

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Just so you know, on my USMLE, they asked me the definition of Km. Very easy question, but quite a few people just don't take the time to look into it too heavily. It's just the at 50% Vmax.

 

[tarsuc]

SO do you mean to say that increased Vmax is analogous to duration of opening of Cl- channel, and decreased Km is analogous to increased frequency of Cl- channel opening?

 

[Phloston]

SO do you mean to say that increased Vmax is analogous to duration of opening of Cl- channel, and decreased Km is analogous to increased frequency of Cl- channel opening?

Yeah. If the channel is open for a longer period of time, a greater quantity of Cl- relative to what's ordinarily possible is able to influx, thereby increasing Vmax.

With increased frequency, there's still a cap to the amount of Cl- that influxes, so Vmax isn't changed, but the rate of influx per unit time is increased, so Km decreases.

 

[tarsuc]

Awesome explanation, thanks!!!!!

But isnt plateau phenomenon, the phenom by which the BZD even at max doses can never lead to coma, but plateaus off to medullary depression at the most; while barbs can progress from medullary depression to coma with no plateauing at max doses.

Are u talking about a platuea effect in the reaction velocity?

 

[image187]

Awesome explanation, thanks!!!!!

But isnt plateau phenomenon, the phenom by which the BZD even at max doses can never lead to coma, but plateaus off to medullary depression at the most; while barbs can progress from medullary depression to coma with no plateauing at max doses.

Are u talking about a platuea effect in the reaction velocity?

Ummm... benzodiazepines definitely can lead to coma and death in overdose, it's just a lot easier to accomplish with barbiturates.

 

[normtheniner]

Vmax is the efficacy, or maximal extent to which a reaction can take place.

When Vmax is increased but Km is the same, the climber scales the mountain at the same speed but climbs higher.

Km is the , or substrate concentration, at 50% of Vmax. When Km decreases, you know the reaction is occurring more quickly (i.e. greater potency). When Km is decreased and Vmax is constant, the climber scales more quickly but doesn't climb to a greater height.

Benzos decrease Km, but don't change Vmax. This means the same reaction rate can occur at a lower concentration of substrate (i.e. GABA). But benzos don't change efficacy (i.e. they don't increase Vmax). Benzos increase frequency of Cl- channel opening.

Barbiturates increase Vmax but don't change Km. They don't change the frequency of Cl- channel opening. They instead increase the duration that the channel remains open.

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Just so you know, on my USMLE, they asked me the definition of Km. Very easy question, but quite a few people just don't take the time to look into it too heavily. It's just the at 50% Vmax.

I'm just going by what my notes say. I haven't really put it all together yet as far as board prep. My notes say:

1. all of these drugs, or their active metabolites, bind to the benzodiazepine receptor on the GABA-chloride channel ionophore:
called the BZ1 receptor
a. also known as the GABAA receptor, which allows influx of chloride
b. effect is to make more GABA receptors available to GABA
c. enhanced inhibition through most of the CNS axis
d. because GABA is necessary for effect, there is a ceiling to the level of depression
produced by these drugs: little suicide risk unless mixed with other depressants


in another section it reads:

Some sedative-hypnotics exhibit increasing CNS depression without a ceiling--overdose can lead to asphyxiation due to respiratory failure. Ex.--ethyl alcohol and barbiturates.

And some have a ceiling to their depression of the CNS, may reach mild anesthetic levels, but rarely by themselves cause a lethal suppression of respiration. Ex.--diazepam, midazolam, zolpidem.