Mechanism of dead by nmda antagonists

[gleroy]

I heard some people actually died of the use of nmda-antagonists and I was curious what the mechanism behind this is.

I have found a study which tested how DXM affected breathing:

We investigated effects of dextromethophan (DXM), an NMDA receptor antagonist, on ventilation and metabolism in unanesthetized male and female weanling rats, and densities of neurons positive for the NR1 subunit in four medullary nuclei. Relative to saline, DXM treatment decreased oxygen consumption 12% in males and increased it 9% in females (interaction, P<0.05). DXM compared to saline decreased frequency of breathing significantly more in females than males when exposed to hypercapnia. During hypoxia, DXM relative to saline significantly decreased frequency and minute ventilation in males and increased these variables in females. NR1 positive neuron densities were significantly greater in females than males in the nucleus tractus solitarius (NTS), commissural nucleus of the NTS and hypoglossal nucleus due to higher counts. Few sex differences were noted in the dorsal vagal motor nucleus. Thus, in weanling rats NMDA receptor modulation of breathing is sex specific, as are the densities of NR1 positive neurons in medullary nuclei associated with control of breathing.

But DXM is a really dirty drug, so I think it is not a good case for other nmda-agonists. However an other one also points to this direction, this time for mk-801:

The aim of our study was to determine the role of excitatory amino acids in controlling cardiorespiratory activity. For this purpose we administered an antagonist of both N-methyl-D-aspartate (NMDA) and non-NMDA receptors (kynurenic acid), and an antagonist of the NMDA receptor complex (dizocilpine, more commonly known as MK-801) i.v. to chloralose-anesthetized cats while monitoring tracheal air flow, tidal volume, respiratory rate, inspiratory and expiratory durations, end tidal CO2, arterial blood pressure and heart rate. Administration of kynurenic acid in doses of 350 and 500 mg/kg produced respiratory depression as reflected by decreases in respiratory minute volume and increases in end tidal CO2. Inspiratory duration was increased with both doses and apnea (occurring during expiration) was observed with the high dose. Apnea was preceded by an apneustic pattern of breathing. Both doses resulted in an increase in blood pressure and, with the high dose, a later decrease in blood pressure was noted. Dizocilpine in doses ranging from 0.03 to 1 mg/kg produced dose-related decreases in respiratory minute volume, and increases in end tidal CO2. In addition, dizocilpine produced increases in inspiratory duration, an apneustic pattern of breathing and apnea (occurring during inspiration). Effects on blood pressure were similar to those observed with kynurenic acid. It is concluded that blockade of excitatory amino acid receptors results in pronounced effects on cardiorespiratory activity.

But that is in cats, not sure if that is applicable to humans. I couldn't find a lot of references, partly because these substances are actually researched in scenarios where people are hypoxic or have had a stroke. I also don't know how to interpret these articles, I have not studied pharmacology.

Another thing is that they can rise blood pressure, would they be able to cause a stroke then? But this is conflicting I found also studies, where there was a rise first in blood pressure and then it dropped again. So perhaps make your blood pressure so low the whole system collapses?


So my question is what is the mechanism of dead by an overdose of a nmda-antagonist? And also can they be lethal in normal dosages? (besides the dangerous behaviour they can induce)

 

[d1nach]

If you inject half a gram per kg of sodium or potassium chloride youll probably die. So i definitely dont think thats enough evidence. But one way my guess is i think like with salts they can mess with ion channels causing your heart to fail.

 

[gleroy]

That sounds reasonable. It should be pretty close then to a magnesium overdose then, right? But I guess the biggest risk is inapt behaviour..

 

[Pilll_head]

I work in the drug industry and I've seen tons of examples where a particular drug tested in rats (or other animals) didn't translate to humans. Also I don't think a 10% reduction in oxygen levels in blood would be enough to kill you. that's probably about like going from sea level to Denver. My guess is that the majority of overdoses are related to serotonin syndrome where the user was on an SSRI. Respiratory depression is usually what happens when you OD on opioids, so my guess is that DXM ODs would be a lot more common than they actually are if it acted as a respiratory depressant, considering the gigantic doses that robotrippers have reported taking (and lived to tell about it)

 

[gleroy]

Thanks! DXM is not a pure nmda-agonist and that can also mean to some other interaction could cause the breathing reduction. So DXM is not suitable to answer the question then.

BTW I am not trying to give nmda-agonists a bad name, I am just curious about why people do sometimes die from them, because I have (and are) experimented/experimenting with a couple myself. Personally I think they might be relative benign on the physical level, but I still would like to know. Not doing high dosages or something, but still. And there is little information available, for example on amphetamine and opiates there is a ton of information. Could you perhaps give some pointers where to look? And I also don't know how to interpret the information, for example I found the following piece in a MSDS of mk 801 (http://datasheets.scbt.com/sc-203137.pdf):

Large doses of calcium channel blocking agents may produce nausea, weakness, dizziness, drowsiness, confusion and slurred
speech. Marked and prolonged hypotension and bradycardia may result from second or third degree atrioventricular block, decreased cardiac output and junctional rhythms; death may ensue


It seems they are hinting that mk-801 might cause the same side-effects as a calcium blocker. But from what I read, is that there are many calcium channels. So I think that the above cannot be generalized to nmda-antagonists, right? Or do they mean that it is also a calcium blocker?

 

[gleroy]

I was reading about nmda-agonists and they are weaking the connection between two neurons, changing the weights. Disrupting long term potentiation. Could that be a reason they are anti-addictive? It would also explain the memory problems.. Does this mean that you don't remember an overdose on them? That could lead to dangerous usage, not remembering the negative effects and/or how much you took.