3. Old stuff
          3.1. Old pharm stuff (pre 2009)
              3.1.4. Physiology
 3.1.4.6. Esterases 

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