Question about Succinylcholine

[Nikj]

I'm trying to learn the mechanisms behind the drug. I understand that SUX basically depolarizes the membrane, and if sufficient amounts are in the synapse that ACh cannot bind( because AChE cannot degrade SUX.) The result is basically a desensitized state.

Can anyone explain what is meant by this desensitized state? The way I conceptualize it, is that SUX basically causes an initial depolarization, but thereafter stays attached to the AChR, thus ACh cannot bind and initiate an action potential. Is this what is meant by desensitized?

Thanks, and apologies if this is the inappropriate forum for the question.


Nigel

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[dhb]

The way I conceptualize it, is that SUX basically causes an initial depolarization, but thereafter stays attached to the AChR, thus ACh cannot bind and initiate an action potential. Is this what is meant by desensitized?
Nigel

Yes

 

[Nikj]

Yes

Thank you!

 

[twoliter]

Thank you!

As a side note, you have 140 posts with 102 likes. That's a good ratio.

 

[anbuitachi]

I'm trying to learn the mechanisms behind the drug. I understand that SUX basically depolarizes the membrane, and if sufficient amounts are in the synapse that ACh cannot bind( because AChE cannot degrade SUX.) The result is basically a desensitized state.

Can anyone explain what is meant by this desensitized state? The way I conceptualize it, is that SUX basically causes an initial depolarization, but thereafter stays attached to the AChR, thus ACh cannot bind and initiate an action potential. Is this what is meant by desensitized?

Thanks, and apologies if this is the inappropriate forum for the question.


Nigel

I think you are focusing too much on Ach. Sux depolarizes and acts longer than Ach. The structure of Sux is just 2 Ach stuck together. It's a depolarizing block, not a competitive non depolarizing block.

 

[Nikj]

I think you are focusing too much on Ach. Sux depolarizes and acts longer than Ach. The structure of Sux is just 2 Ach stuck together. It's a depolarizing block, not a competitive non depolarizing block.

Is this because there is a relatively smaller amount of Pseudocholinesterase for degrading Sux compared to acetylcholinesterase for ACh?

 

[daneeka]

Even though sux acts on the ACh receptor, the real reason it works is the voltage-gated Na channel.

Sux binds to the AChR, which open and let cations in causing local endplate depolarisation. This sets off the voltage-gated Na channels, which open and cause widespread depolarisation. This cascades along the sarcolemma as more and more Na channels open.

The catch is: Na channels have 3 states - open, closed and refractory. On brief opening they quickly shut and become refractory; the only way they can be stimulated again is if the membrane potential hyperpolarises. This won't happen while the AChRs are left open.

So: sux sits around, not being broken down by AChE and keeping the channel open. This doesn't let the Na channels reset, and transmission is blocked = neuromuscular blockade.

If you leave sux around for even longer (high dose, repeat dose), the Na/K ATPase overcomes those open ACh channels leaking cations, and the membrane potential rises again even with all those refractory Na channels. Now, even if the sux goes away the membrane doesn't have a chance to hyperpolarise, and those Na channels stay stuck. This is thought to be the reason for phase II block.

 

[anbuitachi]

Is this because there is a relatively smaller amount of Pseudocholinesterase for degrading Sux compared to acetylcholinesterase for ACh?

What above poster said and, You need two Ach to bind to activate depolarization. Sux is 2 Ach so 1 sux binding = 2 ach binding so sux is better at activation. Also Ach is degraded by ache which is neuronal. Sux is broken by pseudocholinesterase which is mainly in the plasma, which is why you give a large dose of sux (b/c a lot of it will be broken before it gets to NMJ). Sux is mainly ended by redistribution from NMJ, not metabolism of the Sux itself

 

[Ronin786]

I'm trying to learn the mechanisms behind the drug. I understand that SUX basically depolarizes the membrane, and if sufficient amounts are in the synapse that ACh cannot bind( because AChE cannot degrade SUX.) The result is basically a desensitized state.

Can anyone explain what is meant by this desensitized state? The way I conceptualize it, is that SUX basically causes an initial depolarization, but thereafter stays attached to the AChR, thus ACh cannot bind and initiate an action potential. Is this what is meant by desensitized?

Thanks, and apologies if this is the inappropriate forum for the question.


Nigel

That is actually not correct.

Sux is a non-competitive inhibitor. The reason you can't initiate after the initial depolarization is because the receptor is in a refractory period. The sux molecule actually is metabolized incredibly rapidly by Pseudocholinesterase, hence its unique properties of onset and offset.