How would flumazenil interact with GABA antagonists?

[Crimpjiggler]

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I was horrified when I came across a thread about "floxing", its an adverse reaction caused by quinolone antibiotics which occurs in a small percentage of people that use them, it leaves them with peripheral neuropathy and other serious issues. From what I've gathered, it is caused by ciprofloxacin (or other quinolones) property as a potent GABA A receptor antagonist. I don't know why antagonism of these receptors kills/damages the neurons, maybe it binds irreversibly. Maybe its because the GABA activity can no longer balance out glutamate so glutamate neurotoxicity kills the neurons. I don't know but I'm thinking of a way to prevent this serious side effect from occuring. So an obvious way to mitigate this risk would be to co-administer a potent GABA agonist. They don't seem to be widely available, whereas there are hundreds of types of benzodiazepines in common use.

From what I know, benzos bind to the BZ site on the GABA_A receptor, this is an allosteric site and benzos act as positive allosteric modulators so what they do is alter the structure of the active site so that GABA can bind to it more effectively. Now the question I'm wondering is if benzos make the GABA_A active site more available for any GABA binding drug, or is it just GABA itself. Because if its the former, then I'd wonder if co-administering a benzo with cipro would actually increase the risk of an adverse reaction by making it easier for the cipro to bind to the GABA_A active site. Sorry, I know this is a really technical question and only people with in depth pharmacology knowledge can answer this, I figured a forum for doctors would be the best place to ask it, if you know of a better form I'd appreciate you pointing me in the direction.

Does anyone know of a study done on this? Any speculation is welcome so long as its based on solid science. Also I don't know a great deal about cipro or quinolones, so if anyone wants to share their knowledge on the pharmacology of them I'd appreciate it.

I find it strange that a molecule like this:

fits into the GABA active site so well. GABA is a tiny neurotransmitter, but the selective GABA_A agonists I know of look like this:

First GABA itself for comparison:

Muscimol (thats a naturally occuring alkaloid found in certain mushrooms):

Gabaxodol (thats a synthetic one, it was never approved as a drug for some reason which is a shame):

^^ Sorry I'm not a doctor, I'm a chemist, I like my chemical structures. Its kinda like porn for chemistry nerds.

So these selective GABA_A agonists aren't too different in structure to GABA itself. A safe experiment to learn more would be to see if benzos enhance the effects of gabaxodol of have no effect. If they have no effect, then it could mean that BZ binding shrinks the active site so that GABA gets bound more tightly. If thats the case, then all doctors should co-administer a benzo with quinolones because while floxing isn't that common, its very serious, it puts people out of commission for years. I'll never go near a quinolone for this reason. Unless its do or die, in that case I'll load myself up with picamilon (a GABA prodrug with better bioavailability) beforehand. I think an NMDA antagonist can't hurt either because glutamate excitotoxicity must play some role in floxing.

 

[zelman]

I don't think the mechanism of toxicity is known, and the incidence is so rare that a preventative treatment trial to figure it out is not feasible. Anyone else think otherwise?

 

[D1CE K]

I come onto SDN to do anything but talk about academics of no real value.


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[BidingMyTime]

Very interesting post & theory. As Zelman pointed out, the incidence is so rare (and pretty much every drug has the potential for very bad, but very rare adverse effects. I worked in a hospital once where we had a case of Steven-Johnson syndrome believed to have been caused by Tylenol--what are the chances, I had never heard of Tylenol being linked to Steven-Johnson's before that. I still don't worry about taking Tylenol.

We all take risks everyday, do you drive to work? Or anywhere? Undoubtedly, your risk of getting killed driving is greater than ever having "floxing" from quinolones.

The problem with trying to pre-treat for rare adverse effects, is that the drugs being used to pre-treat, also carry rare adverse effects, so nothing is gained. It is impossible to live life without risks, completely impossible. So the best course of action is to take reasonable precautions (wear seatbelts, only take medications when medically indicated, etc.) but after that, the rest is determine by God/Fate/HigherPower/Evolution/Whatever you choose to believe in.

 

[Wheresmyaricept]

You get a benzo, and you get a benzo, and you get a benzo! Everyone gets a benzo!!

Also, why is flumenazil in the topic name but never discussed?

But yeah, it's a really rare adverse effect. Quinolones are prescribed on a daily basis. Thousands of people take them every day. The incidence rate of what you're talking about is so small, it's not even worth wasting money on researching. Good intentioned, but who will it really help? Plus you're adding another pill people have to remember to take. Like it's hard enough to get people to finish their antibiotics, let alone take multiple drugs for X amount of days.