Based on the idea that esketamine's superior anaesthetic potential comes from a combination of activity on hyperpolarizable channels AND rapid NMDA antagonism and the fact that it's the other 2'-keto ACHAs (DCK / O-PCM, O-PCE) that are similarly immobilizing I would venture a guess that the 2'-keto lends them significant affinity / efficacy at these hyperpolarizable channels. Although if the onset must be rapid, that may also enable this synergistic anaesthetic / hypnotic effect. MXE appears to be least anaesthetic of these 4 I'd say.
I wouldn't say that this immobilization feels easy on the body, not at all - but that is subjectively and not about toxic effects: I'm just saying IMO it is not an easy body feeling. By comparison though: yes the polarity not only gives fast onset but also quicker excretion for drugs like K, MXE, O-PCE.. Upside is that it's not as long in the body doing things, downside is that it gets concentrated in your urine much more which can be harmful a la ketamine.
They can ruin your body in different ways, for drugs like ketamine it starts with affected bladder, gallbladder and eventually kidneys, liver... drugs like PCP require much lower doses but more acutely raise blood pressure for example. If you overdo it with drugs like that things like rhabdo can result... but at that point you should probably be more concerned with drug-induced psychotic episodes.
For K: first the major metabolic pathway demethylates the amine to yield norketamine, then the cyclohex ring is hydroxylated (I thought it was possible this happens twice to some extent but not sure), then this function is reduced iirc.
For PCP: the piperidine amine is reduced then all sorts of funky stuff happens to that pip ring - so very different metabolism.
An alkyl chain on the amine rather than a pip ring is sure to be metabolized as one of the first things, followed by preferred targets for CYP - you can predict what with smartCYP..