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Ca2+ / Na+ / k+ effects on Drugs

lemonman

Bluelighter
Joined
Sep 17, 2017
Messages
53
Hi
Take for example you take amphetamine. Could you please explain what Ca2+, Na+ and K+ do?.
Or you could take Ketamine which blocks NMDA. But there is Ca2+ , Na+ and k+ , so what does that do?. Is it good to have ca2+ or not if you want healthy effect from the drug.

Here are images explaining what I'm talking about, please see what is circled in red.
qhJy3C6.jpg




NAbkjSM.jpg



Thanks
 
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Ca2+ / Na+ / K+ are naturally present ions which are required for normal cellular signalling - cells will change their electrical potential by pumping cations in or out of themselves.

You don't need to take them as supplements, though, a healthy diet should contain all the sodium/potassium/calcium you need for healthy functioning.
 
Ca2+ / Na+ / K+ are naturally present ions which are required for normal cellular signalling - cells will change their electrical potential by pumping cations in or out of themselves.

You don't need to take them as supplements, though, a healthy diet should contain all the sodium/potassium/calcium you need for healthy functioning.
But if you took a drug that increased or decreased Ca2+/Na+/K+ what effect would it have on the brain in conjunction with the adderall? e.g: neurotoxicity. i need to understand that question as i must state if neurotoxicity or other different effects occur on an exam question, but a simple short' reply 'increased ca2+ increases neurotoxicity would do'.

Thank You.
 
But if you took a drug that increased or decreased Ca2+/Na+/K+

As far as I know, there aren't "drugs that increase Ca2+, etc. directly", the effect of greatly increased ion concentration isn't really relevant to in vivo effects due to feedback loops keeping ion concentration at "normal" levels (via ion transporters etc), though I'd imagine it would not be good in vitro.

You may want to read the Wiki article on neuronal depolarization for more info.
 
But if you took a drug that increased or decreased Ca2+/Na+/K+ what effect would it have on the brain in conjunction with the adderall? e.g: neurotoxicity. i need to understand that question as i must state if neurotoxicity or other different effects occur on an exam question, but a simple short' reply 'increased ca2+ increases neurotoxicity would do'.

Thank You.

IIRC, amphetamine increases intracellular calcium by releasing intracellular calcium stores, not increasing extracellular calcium uptake. Na+ and Ca2+ intake has no effect on amphetamine's pharmacodynamics, however, Mg2+ and especially Zn2+ do modulate amphetamine's effects in dopamine neurons. The effect by zinc on amphetamine's pharmacodynamics is not due to its role as an electrolyte; rather, it's due to its role as an allosteric modulator of the human dopamine transporter, which contains a high affinity zinc binding site.

The neurotoxicity of amphetamine is primarily mediated through marked elevations in brain temperature (i.e., one must take a dose high enough to induce hyperpyrexia in order for neurotoxicity to occur; hyperpyrexia is a medical emergency). High concentrations on synaptic dopamine contribute via oxidative stress from dopamine auto-oxidation (aka autoxidation) and increased ROS generation, but it is not the primary mechanism by which amphetamine induces neurotoxicity.

In contrast, methamphetamine has a multi-modal neurotoxic mechanism which arises through hyperpyrexia, dopamine autoxidation, sigma-1 receptor activation, the inhibition of EAAT2 (NB: EAAT2 is responsible for >90% of glutamate clearance in the brain) which leads to a marked elevation of synaptic glutamate, increased ROS+RNS generation, and possibly other mechanisms. In combination, these effects cause oxidative stress, promote excitotoxicity, trigger a neuroimmune response (i.e., microglial activation), and induce apoptotic signaling cascades in neurons.

FWIW, I wrote and cited both of the sections in the linked Wikipedia pages, so I know they're accurate.
 
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If your professor or course instructor says otherwise and claims that pharmacomodulation of Ca2+, Na+, and/or K+ does affect amphetamine- and/or methamphetamine-induced neurotoxicity in humans, please ask him/her for a reliable secondary medical source that supports this assertion and link it here.
 
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Thanks.

One final question,
What effect does Ca2+ , Na+ and K+ have on NMDA antagonists?
Say you take ketamine and then you take a drug that increases Ca2+ , Na+ and K+ , what mental effect would it have on ketamine ?
 
Thanks.

One final question,
What effect does Ca2+ , Na+ and K+ have on NMDA antagonists?
Say you take ketamine and then you take a drug that increases Ca2+ , Na+ and K+ , what mental effect would it have on ketamine ?

I can't really answer your entire question since my knowledge of ketamine and dissociative anesthetics in general is fairly limited in comparison to what I know about the pharmacodynamics of psychostimulants and monoaminergic drugs; however, simply due to the fact that ketamine is an NMDA receptor antagonist, concurrent administration with a neuronal CA2+ channel blocker (NB: there are at least 5 classes of calcium channels expressed in the brain, many Ca2+ channel blockers block just L-type Ca2+ channels) would synergistically reduce calcium influx in neurons. I'm not sure about the clinical significant of that drug interaction or the implications for neurotoxicity since there are a number of other Ca2+ uptake channel proteins expressed on neurons.

I don't think pharmacomodulation of Na+ uptake by common sodium channel blockers (i.e., drugs with a "-caine" suffix) would affect ketamine's pharmacodynamics, but again I don't know for sure. I have absolutely no idea about potassium.
 
About the NMDAr heavy metal binding site, what is its endogenous ligand, and physiological function?
 
The "heavy metal" site meaning Zn2+ site? I want to say that zinc is :)
 
The "heavy metal" site meaning Zn2+ site? I want to say that zinc is :)
The effect by zinc on amphetamine's pharmacodynamics is not due to its role as an electrolyte; rather, it's due to its role as an allosteric modulator of the human dopamine transporter, which contains a high affinity zinc binding site.
I didn't say this earlier, but I figure it's worth mentioning: similar to the NMDA receptor, the allosteric binding site for zinc on hDAT is an extracellular binding site.
 
Doesn't Pb also bind that Zn+ Binding site, and a few other of what we generally classify as heavy metals? pretty sure lead does the same.
 
About the NMDAr heavy metal binding site, what is its endogenous ligand, and physiological function?
As I understand it, both Mg and Zn impede the flow of ions through the channel, and the function of this seems to be that only when the post-synaptic cell is depolarized do the Mg/Zn blocks release, hence allowing ion flow.

What this physiologically means is that the post-synaptic cell must receive sufficient input (likely from different axons) in order to be depolarized, at which point ion flux can go on to activate processes like long term potentiation through the specific synapse at which there was NMDA receptor activation.

This serves as a bit of a "coincidence detector" in that different terminals/cells must have been releasing transmitters onto the post-synaptic cell at the same time in order to provoke sufficient depolarization -> dislodging of the Mg/Zn block, and may be a form of hebbian learning (neurons that fire together, wire together)


Edit: Sorry, didn’t see that being discussed was an apparently external Zn binding site on the NMDAr rather than Zn binding inside the channel pore
 
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Yes, I am under the impression, that there is a binding site for metals other than binding into the channel pore and being expelled during depolarization. An allosteric site, separate from the Mg binding site within the pore, like the polyamine regulatory site (which isn't meant to imply they fulfill the same function. Not sure what the purpose of the polyamine site is. Anybody care to give me a quick rundown of what it does? apparently huperzine A binds the polyamine allosteric site of NMDARs as an antagonist. Is this likely to reduce its efficacy as a nootropic via its anticholinesterase effects compared to selective anticholinesterases, or render huperzine-A of any use in tolerance regulation with say, opioids, amphetamines, etc?

'Co-incidence detector'? hah, thats the same term I use to describe my view of the NMDAr. Looks like our NMDA receptors are somehow firing in synchrony.
 
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