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

67%

Background
Plasma esterases are enzymes that hydrolyse ester bonds to form alcohol and carboxylic acid
- found in plasma, NMJ, RBC, hepatic sinusoids
- high capacity ! high clearance
- mostly synthesised by liver ! ↓[esterase] in severe hepatic disease
- cholinesterases at NMJ inactivate acetylcholine ! terminate EPP
- important in inactivation of drugs containing ester linkage

Types
Non-specific plasma esterases
- metabolise remifentanil ! ultrashort acting opioid, half time is context insensitive
- metabolise atracurium ! non-depolarising aminosteroid NMB, 2/3 ester hydrolysis +
1/3 Hoffman elimination (N.B. cisatracurium undergoes minimal ester hydrolysis)
- relatively little variability in plasma esterase activity amongst individuals

Plasma cholinesterase
- metabolise choline esters
- metabolise suxamethonium ! depolarising NMB, rapid hydrolysis in ECF (does not
metabolise at NMJ)
- metabolise mivacurium ! short-acting non-depolarising NMB, rapid hydrolysis
- metabolise ester local anaesthetics ! rapid hydrolysis; ↑toxicity if deficient
A number of factors can alter plasma cholinesterase activity
Activity measured by dibucaine number ! lower number = lower activity

(1) Inherited deficiency

Autosomal recessive pattern
1:3000 homozygote (DN 20)
1:500 heterozygote (DN 40~60)

(2) Acquired deficiency

Liver disease ! ↓production! ↓activity
Pregnancy

(3) Drug interaction

Anticholinesterase (e.g. neostigmine)
LAs (e.g. dibucaine)
Metoclopramide
Cyclophosphamide

NMJ acetylcholinesterase
- Specifically metabolises acetylcholine at NMJ
- Minimal effects on commonly used drugs

Red cell esterases

- Metabolises esmolol – short acting β-blocker (t1/2β = 9 min)
- Metabolises remifentanil
Examiner’s comments

67% of candidates passed this question. Good answers included an overview of the unique
properties of the esterases and their pharmacological implications followed by a discussion of
pseudocholinesterase (butyrylcholinesterase) and non-specific plasma and red cell esterases.
ie.

Overview; Hydrolysis of ester bonds with drug inactivation by esterases

High capacity/clearance enzymes produced in liver and red cells

Non organ dependent drug metabolism with generally inactive metabolites

Exceptions including laudanosine and salicylic acid

Pseudocholinesterase;

Metabolism of succinylcholine, mivacurium, and ester local anaesthetics

Potential problems with congenital and acquired dysfunction

Common congenital pseudocholinesterase variants and clinical implications

Acquired dysfunction including physiological, pathological and drug interactions

Non specific plasma esterases;

Metabolism of remifentanil, atracurium

High capacity systems little effected by hepatic metabolism

High clearance of remifentanil with infusion and independent short context sensitive t1/2

Atracurium and laudanosine

Red Cell esterases;

Metabolism of esmolol and possibly remifentanil

High clearance of esmolol with short duration, titratable

Some problems with answers included; extensive discussion of acetylcholinesterase and

detailed discussion of pseudocholinesterase with none of plasma and red cell esterases.