Benzodiazepines - Mode of Action?

[pema]

Benzodiazepines - Mode of Action?

Can anybody explain me how benzodiazepines really work? I looked for an explanation but there are some things I do not understand when this explanation is true. Maybe I have not enough medical knowledge. So I would be glad if someone could explain some things.

I read in the German wikipedia that benzodiazepines actually are no real GABA agonists but rather GABA synergists.
That's a little bit astonishing for me because there are so much different benzodiazepines that act so differently.
Translation from German wikipedia:

Benzodiazepines only act together with GABA and are not able to open the GABA-A-receptor alone. Strictly speaking they should be described as synergists and not as agonists.

Even high doses of benzodiazepines do not increase the maximum effect (that theoretically could be reached alone by GABA). They merely lower the GABA dosis that is needed for maximum effect. Pharmacologically spoken they lead to a horizontal displacement to the left of the dosis-effect-curve.

But why is it said that benzodiazepines lead to sleep but sleep shall not be really relaxing as normal sleep?
Shouldn't it lead to normal sleep if the effect is like described above?

Und why do different benzodiazepines have then such different effects? And I do not mean that some only act as muscle relaxant while others act as sedative or soporific.
I know people who takes benzodiazepins in order to get stoned. One of them told me that he don't like oxazepam to get stoned because being stoned on oxas should be not as good as being stoned on diazepam or flunitrazepam.

But there shouldn't be a difference if all benzos only would increase the effect of natural GABA. Shouldn't it then be only a difference in strength and duration? All that benzos do, is increasing naturally in the body produced effects. Right?

Shouldn't it be that benzodiazepines that are called muscle relaxants, become sedatives in higher dosage or soporifics in even higher dosage?
Is it that way?

There are benzos that are sold as "anxiolytic", "anticonvulsant", "muscle relaxant", "sedative" and "soporic". Is this only a matter of dosage? Could every benzodiazepine change the "effect class" (don't know the right English word) by different dosage?

 

[sekio]

There is actually more than one type of GABA-A receptor. The receptor itself is made up of 5 individual components and each of these components can be different. This basically means that some GABA-A subtypes will be responsible for sleep, some might be responsible for producing muscle relaxation, and another will be responsible for dampening memory.

Different benzodiazepines have different affinities for GABAA receptors made up of different collection of subunits, and this means that their pharmacological profile varies with subtype selectivity. For instance, benzodiazepine receptor ligands with high activity at the α1 and/or α5 tend to be more associated with sedation, ataxia and amnesia, whereas those with higher activity at GABAA receptors containing α2 and/or α3 subunits generally have greater anxiolytic activity.[10] Anticonvulsant effects can be produced by agonists acting at any of the GABAA subtypes, but current research in this area is focused mainly on producing α2-selective agonists as anticonvulsants which lack the side effects of older drugs such as sedation and amnesia.

Benzodiazepines are a fairly broad class of drugs- not all benzos bind to all the GABA-A receptors with equal affinity. Some prefer the "sedative" receptors and some rely more on muscle relaxant effects. Increasing the dose may allow the drug to activate the GABA-A receptors it has less affinity to but it won't always produce the same effect as a drug targeted specifically for the receptor. This explains why some benzos can be very powerful and some are useful only as mild relaxants.

Eventually you get to drugs like zopiclone/zolpidem that bind only to the sleep-inducing GABA-A receptor and very little else.

 

[Epsilon Alpha]

Benzo's bind to specific locations on GABA-A subunits, some of which are more sedative/hypnotic and others that are more anti-anxiety. When bound the make the GABA-A chloride ion channel open much more frequently, in a process known as positive allosteric modulation. The net result being more Cl- in the neuron, resulting in increased membrane polarization which reduces the neuron's likelihood of producing an action potential.

Benzo's absolutely rape sleep architecture btw, resulting in a very poor night's sleep... not to mention all the other horrific side effects they cause.

So tl;dr: depends on what GABA-A receptor subunit it has the higher affinity for.
Moving to Other Drugs as everything you've asked is on wikipedia