Pharm-00A14: Discuss the roles of the plasma esterases on drugs used in anaesthesia 67%

“Esterases”
- Heterogenous group of enzymes that metabolise drugs containing an ester bond (COO-)
→ hydrolyse ester bond to form an alcohol and an alkanoic acid
- They are produced in the liver, red cells and tissues → found in plasma (non-specific
plasma esterase and pseudocholinesterase), NMJ (true cholinesterase or AChE), and RBC
(red cell esterase)
- Metabolism is organ-independent and high capacity (Ie. high clearance) → produces
metabolites that are generally inactive

Types of “plasma esterases”:

(1) Pseudocholinesterase (or plasma cholinesterase; PC)

- Tetrameric glycoprotein enzyme (4x identical subunits, each with an active catalytic site)
that is synthesised in the liver and found in plasma
- It metabolises:
o (i) Suxamethonium (SCh) → depolarising NMBD
 SCh is hydrolysed into succinylmonocholine (weak metabolite with 1/20th
activity), which is then hydrolysed to succinic acid + choline
 Hydrolysis is so rapid and efficient → only 10-20% SCh reaches NMJ →
brief paralysis (3-5 mins)
o (ii) Mivacurium
 Most is hydrolysed by PC (90%) → trans-trans and cis-trans isomers
hydrolysed (at 88% rate that of SCh) into inactive metabolites
(monoesters and quaternary amino alcohols)
 Rapid hydrolysis → short duration of paralysis (12-30 mins)
o (iii) Ester LAs
 Rapidly hydrolysed by PC into inactive water-soluble metabolites excreted
in urine → results in short duration of LA action, which is a/w ↓ risk of
LA accumulation and systemic toxicity

↓ PC activity leads to ↓ metabolism of SCh and mivacurium (causing prolonged paralysis)

and ester LAs (causing LA accumulation and risk of systemic toxicity) → this occurs
with:
- (1) Quantitative deficiency in PC
o ↓ hepatic synthesis of PC due to severe liver disease or malnutrition
- (2) Qualitative deficiency in PC (Ie. normal quantities but reduced PC activity)
o (a) Drug-induced – All AChEi (EXCEPT edrophonium), Chemotherapy
agents (esp cyclophosphamide), Metoclopramide, Ester LA, OCP,
Ketamine, Lithium, Pancuronium, Esmolol
o (b) Disease states – Renal failure (esp on dialysis), cardiac failure, TTX,
cancer states, burns
o (c) Hypothermia
o (d) Pregnancy
o (e) Genetically-aberrant atypical PC – Homozygous atypical, silent or
fluoride-resistant alleles cause significantly ↓ PC activity (cf. homozygous
usual alleles); heterozygous alleles caused partly ↓ PC activity

(2) Non-specific plasma esterase (NSPE):

- Aka. “tissue esterases” → synthesised in various tissues and found in plasma
- It metabolises:
o (i) Remifentanil
  Rapid hydrolysis into an inactive carboxylic acid metabolite (1/4600th as
potent), which is excreted in urine
 Independent and short CSHT (3 mins) with a fixed elimination t ½ of 3-
10 mins → permits easy titration with rapid onset/offset
o (ii) Atracurium
 Hydrolyses 60% of atracurium into an inactive quaternary alcohol and
acid → but also forms a CNS toxic metabolite (laudanosine), which can
stimulate epileptic activity at high levels
o (iii) Etomidate
- NSPE activity is NOT affected by hepatic dysfunction, but its levels are ↓ with aging

(3) Red cell esterase (RCE):

- Enzyme produced and found in RBC
- It metabolises:
o (i) Esmolol → β1-selective competitive antagonist
 Rapid hydrolysis into inactive acid metabolite and methanol
 Brief elimination t ½ (9 mins) and short CSHT → permits easy titration
with rapid onset/offset
o (ii) Remifentanil (partly)
- RCE activity is NOT affected by hepatic dysfunction or deficiencies in PC activity