Pseudocholinesterase deficiency and Succinylcholine clearance/metabolism

[MTGas2B]

So, we had presumptive case of pseudocholinesterase deficiency (dibucaine inhibition test pending). Second time I've seen it, this time it wasn't my case. Anyway, the patient also has dialysis dependent chronic renal failure. It made me wonder, in a pseudocholinesterase deficient patient what is the primary route of elimination of succinylcholine. Is there enough function of the mutated pseduocholinesterase to metabolize the sux, or is renal and/or hepatic clearance the predominant route. The reason this came up was the question of should he be dialyzed to aid him in clearing the sux. He was dialyzed the day prior to surgery, and there would have been no other indication.

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[merlebo05]

Can someone explain this to me, I am confused. Acetylcholinesterase and plasma cholinesterase (pseudocholinseterase) are the same substance just in different locations. Acetylcholinesterase is at the NMJ which is responsible for the breakdown of Sux, whereas pseudocholinesterase is in the plasma. I know pseudocholinesterase def prolongs the effects of Sux: why is that when acetylcholinsterase is what breaks down Sux??? When you have a def in pseudocholinesterase do you also have a def in acetylcholinesterase?? Is that the answer to my confusion?? Its just the pseudocholinsesterase is what can actually be measured??

 

[Licoricestick]

Can someone explain this to me, I am confused. Acetylcholinesterase and plasma cholinesterase (pseudocholinseterase) are the same substance just in different locations.

Nope - AChE and pseudocholinesterase are similar, but different. Notably they have different substrate preferences. Pseudocholinesterase does not have a known endogenous function.

Acetylcholinesterase is at the NMJ which is responsible for the breakdown of Sux, whereas pseudocholinesterase is in the plasma.

Acetylcholinesterase breaks down acetylcholine. Psuedocholinesterase breaks down suxamethonium (and mivacurium). The vast bulk (90-95%) of sux is broken down in plasma by psuedocholinesterase (to succinylmonocholine and choline), thereby limiting the total amount that reaches the NMJ. Once at the NMJ, duration of action is determined by diffusion away from the binding site at the NMJ.

I know pseudocholinesterase def prolongs the effects of Sux: why is that when acetylcholinsterase is what breaks down Sux??? When you have a def in pseudocholinesterase do you also have a def in acetylcholinesterase?? Is that the answer to my confusion?? Its just the pseudocholinsesterase is what can actually be measured??

In a patient with pseudocholinesterase deficiency a much greater amount (exactly what proportion depends on how deficient they are) of sux reaches the NMJ. Higher concentration at NMJ means it takes longer to diffuse away therefore you have a prolonged duration of action. As the two enzymes are different (and therefore encoded by different genes) a mutation in pseudocholinesterase does not cause any problems with acetylcholinesterase, thereby leaving NMJ function normal in the absence of pharmacological intervention.

And of course a patient with pseudocholinesterase deficiency will also have a prolonged block with mivacurium.

 

[merlebo02]

"Acetylcholinesterase breaks down acetylcholine. Psuedocholinesterase breaks down suxamethonium (and mivacurium). The vast bulk (90-95%) of sux is broken down in plasma by psuedocholinesterase (to succinylmonocholine and choline), thereby limiting the total amount that reaches the NMJ. Once at the NMJ, duration of action is determined by diffusion away from the binding site at the NMJ."


OK, that makes since. Thanks so much!!!

 

[InductionAgent]

And of course a patient with pseudocholinesterase deficiency will also have a prolonged block with mivacurium.

This of course is purely academic in the US, since mivacurium is no longer on the market here.

 

[Licoricestick]

This of course is purely academic in the US, since mivacurium is no longer on the market here.

I don't even know if it is available here to be honest. But I am expected to know about it. Heck, I'm expected to have quite a thorough understanding of halothane and you can't get that in Australia anymore. Hard to get a good understanding when you can't play with the toys.


As for the OPs question.... we don't seem to be getting very far!
Any of the more experienced people floating around know the answer? Have any idea?

Best I've got is wikipedia (sadly) which says 10% of sux is renally excreted, but there is no reference for it. None of my books comment on clearance outside of metabolism.

 

[MTGas2B]

Best I've got is wikipedia (sadly) which says 10% of sux is renally excreted, but there is no reference for it. None of my books comment on clearance outside of metabolism.

I saw the same number quoted, not from wikipedia, but in Micromedex and it referenced the drug packaging. I wondered how significant it was in pseudocholinesterase deficiency. I could find anything in my lit search, and all of my attendings I've asked are stumped. My guess is its not significant.

 

[InductionAgent]

Epocrates states that 10% of succinylcholine is eliminated unchanged in the urine.

The 2001 edition of the American Hospital Formulary Service (AHFS) Drug Information states "up to 10% of a dose of succinylcholine is excreted unchanged in the urine."

If there were a serious defect in pseudocholinesterase, I feel confident in stating that renal elimination would become an important factor.