succinylcholine and AChE inhibitors

[WashMe]

On p 435 of FA it says that AChE inhibitors potentiate phase I of succinylcholine's action, but then AChE inhibitors are the antidote for phase II. I tried checking a few sources but I don't know what's going on here; I see that pseudocholinesterase metabolizes succinylcholine... not sure if that's part of the puzzle.

All I can figure is that perhaps acetylcholinesterase is able to metabolize succinylcholine (not sure if this happens), so giving an inhibitor allows for increased concentration of succinylcholine at the NMJ at the start of the block. Then, I figure that once the succinylcholine has worked for a while, if you give more inhibitor then the effect is to increase ACh levels and displace succinylcholine from receptors, ending the effect.

This sounds like a ridiculously *****ic explanation though.

Please help!

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[doctor internet]

I think First Aid is wrong on this.

You can only reverse non-depolarizing agents with AcHe inhibitors. The way that depolarizing agents like succinylcholine work is that they mimic acetylcholine at the synapse except are degraded by pseudocholinesterase instead of acetylcholineesterase, which takes much longer.

On the onset of taking succinylcholine, you receive an extreme increase in muscle activity due to the action of succinylcholine on the receptors. This is phase I or the depolarizing phase. Adding an AcHe inhibitor here would only serve to make the muscle activity even greater. Eventually, the receptors become desensitized and no longer respond to succinylcholine or acetylcholine. This is called Phase II and is really the onset of neuromuscular blockade. Adding an AcHe inhibitor at this phase would again do nothing because you would just be stimulating already desensitized receptors with no results.

In Lange Clinical Anesthesiology, it says this:

"Because depolarizing muscle relaxants are not metabolized by acetylcholinesterase, they diffuse away from the neuromuscular junction and are hydrolyzed in the plasma and liver by another enzyme, pseudocholinesterase (nonspecific cholinesterase, plasma cholinesterase, or butyrylcholinesterase). Fortunately, this is a fairly rapid process, because no specific agent to reverse a depolarizing blockade is available."

 

[Step1Hash]

I think First Aid is wrong on this.

You can only reverse non-depolarizing agents with AcHe inhibitors. The way that depolarizing agents like succinylcholine work is that they mimic acetylcholine at the synapse except are degraded by pseudocholinesterase instead of acetylcholineesterase, which takes much longer.

On the onset of taking succinylcholine, you receive an extreme increase in muscle activity due to the action of succinylcholine on the receptors. This is phase I or the depolarizing phase. Adding an AcHe inhibitor here would only serve to make the muscle activity even greater. Eventually, the receptors become desensitized and no longer respond to succinylcholine or acetylcholine. This is called Phase II and is really the onset of neuromuscular blockade. Adding an AcHe inhibitor at this phase would again do nothing because you would just be stimulating already desensitized receptors with no results.

In Lange Clinical Anesthesiology, it says this:

"Because depolarizing muscle relaxants are not metabolized by acetylcholinesterase, they diffuse away from the neuromuscular junction and are hydrolyzed in the plasma and liver by another enzyme, pseudocholinesterase (nonspecific cholinesterase, plasma cholinesterase, or butyrylcholinesterase). Fortunately, this is a fairly rapid process, because no specific agent to reverse a depolarizing blockade is available."

I agree with everything you said but I think the end of phase II is marked by the succinylcholine being degraded and leaving the receptors (and the nicotinic receptors return to resting state) thus allowing Ach to bind and that's why Neostigmine will help. This is how my professor explained it.

 

[Huzair]

On p 435 of FA it says that AChE inhibitors potentiate phase I of succinylcholine's action,

By saying 'potentiate' does it mean prolonging the phase I or speeding it up? Makes more sense if it speeds it up, as more ACh and SCh will lead to earlier desensitization.

 

[Aclamity]

I think First Aid is wrong on this.

You can only reverse non-depolarizing agents with AcHe inhibitors. The way that depolarizing agents like succinylcholine work is that they mimic acetylcholine at the synapse except are degraded by pseudocholinesterase instead of acetylcholineesterase, which takes much longer.

On the onset of taking succinylcholine, you receive an extreme increase in muscle activity due to the action of succinylcholine on the receptors. This is phase I or the depolarizing phase. Adding an AcHe inhibitor here would only serve to make the muscle activity even greater. Eventually, the receptors become desensitized and no longer respond to succinylcholine or acetylcholine. This is called Phase II and is really the onset of neuromuscular blockade. Adding an AcHe inhibitor at this phase would again do nothing because you would just be stimulating already desensitized receptors with no results.

In Lange Clinical Anesthesiology, it says this:

"Because depolarizing muscle relaxants are not metabolized by acetylcholinesterase, they diffuse away from the neuromuscular junction and are hydrolyzed in the plasma and liver by another enzyme, pseudocholinesterase (nonspecific cholinesterase, plasma cholinesterase, or butyrylcholinesterase). Fortunately, this is a fairly rapid process, because no specific agent to reverse a depolarizing blockade is available."

What you say makes sense, but when FA says that AChE inhibitors help in Phase II i just assumed they weren't talking about the portion of Phase II where the ACh receptors are completely desensitized (aka absolute refractory period), but rather the portion where they would just need a much larger stimulus (aka effective refractory period). In that case AChE inhibitors would help. Not sure about it tho

 

[Brotato]

FWIW here's what GT says:

Phase I Block (Depolarizing Phase): Succinylcholine binds the receptor →depolarizes the membrane; causes an initial discharge that produces fasciculations followed by a flaccid paralysis. Because succinylcholine is metabolized slowly, the membrane becomes unresponsive to further impulses.

Phase II Block (Desensitizing phase): Eventually, the membrane repolarizes, however remains unresponsive because it is desensitized. During later phase II, desensitizing agents are susceptible to reversal by ACh esterase inhibitors.

 

[Phloston]

My guess would be that, in phase-I, since succinylcholine and ACh are both reversible and competitive binders of the nicotinic receptor, if an ACh-inhibitor is given, although it will initially increase ACh binding, it will also increase the length of time that phase-I lasts because increased succinylcholine will remain unbound and waiting to bind. ACh dissociates very quickly (both absolutely and relative to succinylcholine), so even if giving an ACh-inhibitor increases ACh out-competition of succinylcholine momentarily, the succinylcholine that's already bound has depolarized the neurons, so not only will the ACh not have an effect, but it just increases the amount of succinylcholine that is on standby to bind.

In other words, if the neurons are depolarized beyond threshold, it's better to get all of the succinylcholine to bind at once than for it to linger around, because if this is the case, then the length of time of succinylcholine initial binding is greater with an ACh-inhibitor, phase-I is prolonged, and the block is potentiated for longer.

When FA says that the block is potentiated in phase-I, I don't think it means increased Vmax, with respect to the antagonism overall, as much as it means increased Km (which would yield a longer time that the patient is flaccid).

In phase-II, all of the succinylcholine is presumably mostly already bound and the neurons are desensitized. When succinylcholine unbinds and the neurons come out of the repolarization, any ACh available due to ACh-inhibitor-use will enable regain of function, so ACh-inhibitors don't potentiate a block here.

Yet again, I'm not an anesthesiologist, but those are just my thoughts on it.

 

[WashMe]

My guess would be that, in phase-I, since succinylcholine and ACh are both reversible and competitive binders of the nicotinic receptor, if an ACh-inhibitor is given, although it will initially increase ACh binding, it will also increase the length of time that phase-I lasts because increased succinylcholine will remain unbound and waiting to bind. ACh dissociates very quickly (both absolutely and relative to succinylcholine), so even if giving an ACh-inhibitor increases ACh out-competition of succinylcholine momentarily, the succinylcholine that's already bound has depolarized the neurons, so not only will the ACh not have an effect, but it just increases the amount of succinylcholine that is on standby to bind.

In other words, if the neurons are depolarized beyond threshold, it's better to get all of the succinylcholine to bind at once than for it to linger around, because if this is the case, then the length of time of succinylcholine initial binding is greater with an ACh-inhibitor, phase-I is prolonged, and the block is potentiated for longer.

When FA says that the block is potentiated in phase-I, I don't think it means increased Vmax, with respect to the antagonism overall, as much as it means increased Km (which would yield a longer time that the patient is flaccid).

In phase-II, all of the succinylcholine is presumably mostly already bound and the neurons are desensitized. When succinylcholine unbinds and the neurons come out of the repolarization, any ACh available due to ACh-inhibitor-use will enable regain of function, so ACh-inhibitors don't potentiate a block here.

Yet again, I'm not an anesthesiologist, but those are just my thoughts on it.

hmm... I like the sound of this

 

[richblood]

SUCCINYLCHOLINE ("Sux") = ACh agonist, but metabolized by Pseudocholinesterase in plasma (longer receptor binding duration than ACh).
Phase 1: Sux bind to ACh neuromuscular receptor, let the muscle membrane depolarize, and a transient muscle fasciculation occur. After that, while muscle membrane depolarization prolonged (as Sux still bind their receptors), inside the muscle cell, the sarcoplasmic reticulum take back their Calcium, and muscle relax (Flaccid Paralysis). AChEIs, which increase ACh concentration, is no use in this period, because ACh cannot do anything with already depolarized muscle membrane.
Phase 2: As time goes on, Sux diffuses and metabolized in plasma, allow the muscle to repolarize, and be ready for the next depolarization. However, after a long period of binding Sux, the ACh receptors have been desensitized, so that a greater concentration of ACh is required to activate them again. Then the antidote at this time, in phase 2, is AChEIs.
Cheers 🙂!

 

[brandonahead]

Here's a great video that explains all of this perfectly! From what I understand, phase 1 effect of succinylcholine is when succinylcholine originally binds to the nicotinic receptor and acts as a partial agonist that causes a strong constant depolarlizing effect due to not being able to be broken down that well because of low levels of pseudocholinesterase. Remember that acetylcholine is broken down by acetylcholinesterase, whereas succinylcholine is broken down by pseudocholinesterase. Because this is taking place in the synaptic cleft at the postsynaptic membrane, the levels of pseudocholinesterase is very low, compared to in the plasma everywhere else. Because of this, you get phase 1 causing tons of muscle twitching (fasciculations). The next phase is when the succinylcholine is unbound but because of such a powerful response to the depolarlization signals, you have receptor desensitization as a defense to this so now you end up with the originally wanted muscle paralysis.