Esterases

[Prof Kam lecture, 2006; Examiner report 2000 March Q14; WG21:p101; SH4:p218; CEACCP 2004 Vol 4(1) "Pharmacology of neuromuscular blocking drugs"; CEACCP 2004 Vol 4(5) "Anticholinesterase and anticholinergic drugs"]

• 4 types of cholinesterases

At neuromuscular junction

Acetylcholinesterase

Also see [Anticholinesterase]

• aka true cholinesterase, or specific cholinesterase
• Found in NMJ
• Highest affinity for acetylcholine, but also hydrolyse other choline esters

From [CEACCP 2004 Vol 4(5) "Anticholinesterase and anticholinergic drugs"]

• Two forms of acetylcholinesterase
  * Soluble and insoluble
• Soluble forms are found in CSF and chlinergic nerve terminals
• Insoluble forms are found in NMJs
  * Also found in RBC --> Function unknown

In plasma

Plasma esterase

Also see [Depolarising NMBDs]

• aka butyrylcholinesterase, pseudocholinesterase, non-specific cholinesterase [???], serum cholinesterase, plasma cholinesterase
  * Called butyrylcholinesterase because it hydrolyses butyrylcholine more quickly
• Found in liver, skin, GIT smooth muscles, kidney, and brain, as well as plasma
  * [CEACCP 2004 Vol 4(5)]
• Responsible for the metabolism of
  * Suxamethonium
  * Mivacurium
  * Ester local anaesthetics
  * Diamorphine [CEACCP 2004 Vol 4(5)]
  * Aspirin [CEACCP 2004 Vol 4(5)]
• Actual physiological function is unknown
  * [CEACCP 2004 Vol 4(5)]
• Potential problem with congenital and acquired dysfunction
  --> Pseudocholinesterase variants common and may have clinical implications
  * Acquired dysfunction include physiological, pathological, and drug interactions
• Physiological role unknown
• Large capacity to metabolise suxamethonium
  --> Only a small fraction reaches the NMJ
• When plasma esterase level is <75% of normal
  --> Start to see prolongation of suxamethonium effect
• Synthesized in the liver
• Elimination half-time of plasma cholinesterase = 8-16 hours
• A tetrameric glycoprotein
  * 4 identical subunits, each with one active catalytic site

Changes in plasma cholinesterase activity

• Decrease in plasma cholinesterase activity could be due to
  * Decreased hepatic production
  * Drug-induced decrease (due to inhibition, or competition)
  * Genetic (atypical plasma cholinesterase)
  * Pregnancy
  * Burns [SH4:p244]
• Increase in plasma cholinesterase activity
  * Obesity
  * Genetic (inherited as a C5 isoenzyme variant)

NB:

• Resistance to suxamethonium could be due to
  * Increase in plasma cholinesterase activity
  * Pharmacodynamic changes (e.g. myasthenia gravis)

 

Hepatic production

Liver disease must be severe before decreased production of plasma cholinesterase is sufficient to prolong the action of suxamethonium

Drug-induced (inhibitors)

• Neostigmine (but not edrophonium)
  --> Profound decrease in plasma cholinesterase activity
  * Even after 30min, activity level is only about 50% of control
• Other anticholinesterase in insecticides, and in treatment of glaucoma, myasthenia gravis
  * e.g. organophoshate, physostigmine
• Chemotherapeutic drugs (nitrogen mustard, cyclophosphamide, azathioprine)
• Metoclopramide
• High oestrogen level (e.g. in term pregnancy)
  --> 40% [SH4:p218] decrease in plasma cholinesterase activity or 25% [PI]
  * But overall duration of action of suxamethonium is about the same due to increased Vd
• Fluoride is a potent inhibitor of plasma cholinesterase [SH4:p243]
  * But clinical significance in vivo is uncertain
• Pancuronium [SH4:p243]
  --> Inhibitor of plasma cholinesterease
  --> Prolongs duration of mivacurium by slowly hydrolysis
• Trimetaphan [PHW2:p267]
  * A competitive antagonists at all nicotinic ganglionic receptors (including adrenal cortex)
  * Does NOT act on nAChRs at NMJs

Drug-induced (competitors for the enzyme)

• Etomidate
• Ester local anaesthetics
• Methotrexate
• Esmolol [CEACCP]

Atypical plasma cholinesterase

See [Atypical plasma cholinesterase]

Red cell esterase

• Found in cytosol of RBC
• Metabolism of esmolol and possibly remifentanil
• Not reduced in pt with pseudocholinesterase deficiency

Non-specific plasma esterase

• aka tissue esterase
• NOT pseudocholinesterase
• Metabolism of remifentanil and atracurium
• High capacity system
  * Not affected by hepatic metabolism
• Level reduced in aged patients