Enzymology of cholinesterase and its relevance to peri-operative medicine
Choline is an important nutrient and the main source of which includes diary products such as eggs, meat and milk. Humans can also produce endogenous choline within the liver. (Corbin & Zeisel 2012). Choline has a role in many physiological processes including both lipid transport, cell signalling and neurotransmission (Leermakers et al., 2015). There is increasing evidence linking choline deficiency with disease pathology such as non-alcoholic fatty liver disease (Fischer et al., 2007), growth retardation (Semba et al., 2016), and pathophysiology of neural tube defects (Shaw et al., 2004).
Choline combines with acetic acid to form acetylcholine, a pivotal neurotransmitter within the parasympathetic nervous systemcholine and esters combine to form cholinesters, which have widespread biological activity
Cholinesterases are the enzymes which metabolise cholinesters .They differ in substrate, and distribution throughout tissues. Acetylcholinesterase break down acetycholine (Korabecny & Soukup 2021), important in neurotransmission. pseudocholinesterase (also known as butyrylcholinesterase) (Korabecny & Soukup 2021).
can be distinguished chemically from acetylcholinesterase by its ability to metabolise the synthestic compound butyrylcholine (Silver 1974). Within the human body, both acetycholinesterases and pseudocholinesterase are largely found within the nervous system (Benner et al., 2021). Acetylcholineterase is also found in excitable tissues such as muscles and most RBCs and placenta.
Profile of pseudocholinesterase enzyme
Pseudocholinesterase is responsible for the breakdown succinylcholine into choline and succinic acid (Whittaker & Wijesundera 1951). pseudocholinesterase is synthesised within the liver, and has been proposed as a marker of liver function and may be an independent prognostic marker in pancreatic cancer patients (Klocker et al., 2020). Any condition which affects liver function, such as pregnancy, may reduce pseudocholinesterase levels.mez-Cantarino et al., 2020) Maiorana & Roach 2003).
Pseudocholinesterase deficiency and its relevance to anaesthesia
Pseudocholinesterase deficiency can be either congenital or acquired. and results in the affected person may be unable to break down succinylcholine, mivacurium and other ester-linked muscle relaxants (Robles et al., 2018), with important implications for anaesthetic and its practise leading to a potential prolonged neuromuscular blockade. It is also important to recognise other conditions or drugs which could affect enzyme activity.
Genetics of PChE deficiency
Congenital pseudocholinesetrase deficiency is an austomal recessive trait. The most common genetic variant of the pseudocholinesterase gene or butyrylcholinesterase gene K variant (p.A539T) (Jasiecki et al., 2019), however there are . numerous variants . The most clinically relevant include dibucaine-resistant or atypical, fluoride-resistant, silent variant and the K-variant (Rico-Mora et al., 2018).
The local anaesthetic dibucaine acts as an inhibitor (Lehmann & Liddell 1969). In pharmacology the dibucaine number is often referred to as the percentage inhibition of pseudocholinesterase enzyme. Commonly, a normal dibucaine number within normal individuals is 80% or above. While, heterozygotes have 40%-60% and less than 20% for homozygotes.
Disease conditions and drugs which affect plasma cholinesterase
Before considering the use of anaesthetic agents such as mivacurium, suxamethonium and ester-linked local anaesthetics a detailed anaesethetic history must be taken which should include a family historyThere are certain conditions which can cause raised plasma cholinesterase, includingobesity, fatty liver disease and thyrotoxicosis. A comprehensive list of both physiological and pathological conditions which increase plasma cholinesterase can be recalled by using the acronym CHOLINESTERASE (table 1).
List-1 Physiological and pathological conditions which increase plasma “CHOLINESTERASE”
C Chorea and Concusion
H Hypertension and Hyperlipidaemia
L Liver e.g. fatty liver
I Intestinal e.g. exudative enteropathy
N Nephrotic syndrome
E Endocrine e.g. thyrotoxicosis
S Sex e.g. male
E Endocrine e.g. diabetes
S Schizophrenia and anxiety
List-2 Physiological and pathological conditions which decrease plasma “CHOLINESTERASE”
Conditions which can decrease plama cholinesterase levels are detailed in table 2, also remember them by using the acronym CHOLINESTERASE .
C CCF and CPB
H HELLP syndrome
O Organophosphorous poisoning
L Liver e.g. carcinoma, cirrhosis, abscess, end-stage liver failure
I Inherited e.g. atypical PChE
N Neoplasm(heptic), Nutritional(anorexia)
E Endocrine e.g. myxedma
S Sex e.g. female,particularly when pregnant
E Endotoxic shock
S Sepsis,Severe burns
Alternative muscle relaxants should be considered in these patients. Rrocuronium is an option as it can be rapidly reversed by sugammedex
Pharmacological agents/medicine which affect plasma cholinesterase
There are many drugs which affect cholinesterase enzyme inhibition, such as rivstagimine and galantamine in the treatment of myasthenia gravis and Alzheimer’s dementia respectively. Other drugs such as methylprednisolone can result in longer than normal paralysis in anaesthesia. While many medications have been found to result in longer than normal paralysis in anaesthesia, List 3 mentions medications which can result in suxamethonium paralysis or ”SCOLINE-APNOEA”.
List 3: Drugs which potentiate suxamethonium or mivacurium leading to ”SCOLINE-APNOEA”:
S Steroids e.g Methylprednisolone acetate
C Cyclophosphamide, Chlorambucil
O Opiate e.g. diamorphine*
L Local anaethetics such as cocaine
I Intoxication with organophorous compounds
N Neostigmine, pyridostigmine, physotigmine
E Ecothiophate eye drops
A Aspirin **
N Nausea/Vomiting treated with metoclopramide
O Oral Contraceptive Pills
E Esmolol and Etomidate
A Asthma medications suchas the long-acting β2 agonist Bambuterol
*Diamorphine is rapidly hydrolysed to 6-acetylmorphine by pseudocholinesterase hence more slowly to morphine by the liver.
**aspirin is metabolised by pseudocholinesterase enzume, deficiency will prolong the effect of aspirin
Pre-clinical history of suxamethonium and Introduction into clinical anaesthesia
Suxamethonium was initially discovered in 1906 by Hunt and Taveau when it was used in already curarised animals to study effects on the cardiuovascular system.However it was not until 1949 that Bovet discovered suxamethonium had a role in neuromuscular blockade (Durant & Katz 1982)(Lee C 2009). It was then introduced within clinical anaesthesia in Europe and the USA in 1951 (Durant & Katz 1982).
Suxamethonium is the only commercially available depolarising muscle relaxant. Pharmacologically, Suxamethonium (also known as ‘succinyl choline’ and ‘scoline’) is an esterificationof two acetylcholine molecules and is broken down by pseudocholinesterase to succinic acid and choline.
Suxamethonium acts as a muscle relaxant by causing rapid onset neuromuscular block by combining with nicotinic acetylcholine receptors on the neuromuscular junction(Fawcett 2019). It has a prolonged action compared to acety;choline as it is not metabolised by acetylcholinesterase. It has to unbind from the receptor and be metabolised by pseudocholinesterase.
Suxamethonium is used in situations where rapid or short term muscle relaxation is required. such as facilitating a rapid sequence induction (RSI) of anaesthesia, or attenuating muscle convulsions during electrocovulsive therapy (ECT)(Zolezzi 2016). The use of suxamethoinium for RSI is reducing following the introduction of rocuronium
The pharmacology of suxamethonium can often be remembered using the acronym SUXAMETHONIUM, see below:
S Suxamethonium is a depolarising neuromuscular blocking agent
U Ubiquitously used during paid sequencing induction
X X-linked Duschenne dystrophy*
A Aqueous solution with pH 4
M Methylparaben is a preservative
T The T1/2 is less than 60 seconds (Donati 2003)
H Hypersensitivity (Type-1 anaphylaxis)
O Obesity, in obesity an increase in dose is required
N NH4 (bisquarternary compound)
I Incompatible with alkaline solution e.g. thiopentone PH 10.6
U Uterine,vascular and GI smooth muscles not relaxed
M Metabolised by plasma cholinesterase(succinylmonocholine has 1/10th potency)
* suxamethonium administration results in rhabdomyolysis and hyperkalaemia (Gurnaney et al., 2009)
Side effects of suxamethonium
Like all neuromuscular blocking agents, suxamethonium also has numerous side effects
A list of side effects of SUXAMETHONIUM has been described below.
S Scoline apnoea
U Unpredictable phase 2 block
X X-linked Duchenne Muscular Dystrophy: Rhabdomyolysis and hyperkalaemia
A Anaphylactic reaction
E Eyes, increase in intraocular pressure (Pal et al., 2011)
H Hyperkalaemia (Hovgaard HL, Juhl-Olsen 2021)
O Oropharyngeal secretions increased
I Increase intracranial pressure
U UMN injury induced hyperkalaemia (Gronert et al., 1975)
M Malignant Hyperthermia
*will increase neuromuscular blockade as neostigmine prevents the breakdown of plasma cholinesterase
Situations in which the use of SUXAMETHONIUM may be avoided or contraindicated
S Scoline apnoea risk
U Uraemia (due to renal failure increasing levels of potassium)
X X-linked Duschenne dystrophy
M Malignant Hyperthermia
E Exotoxinaemia e.g tetanus, botulinum
H Heart (Brugada syndrome)
O Ocular trauma (penetrating)
N Non-anaesthetised/awake patient
I Infection/abdominal sepsis
U UMN injury
M Multiple sclerosis, and Guillaine Barre syndrome and Huntington chorea
Where we should carefully consider the use of suxamethonium
Pseudocholinesterase deficiency will prolong the duration of action of suxamethonium. It may be congenital (genetic), inherited in various forms as an autosomal recessive trait, or acquired (due to the action of drugs or disease). The action of other muscle relaxants such as Mivacurium may also be affected
The following recommendations are made regarding the use of suxamethonium.
- During rapid sequence induction, if suxamethonium is used then a nerve stimulator should be used to identify recovery from succinyl induced paralysis before non-depolarising muscle elaxant being given.
- Cocaine is used in some ENT procedures and if that is followed by either suxamethonium or mivacurium, the chances of scoline apnoea increase.
- Psychiatric patients who take phenelzine and suxamethonium being given during ECT could result in longer paralysis.
- Alzeheimer patients taking tacrine carry the risk of scoline apnoea.
Is this the time to say goodbye to Suxamethonium?
Anaesthesia has evolved as a specialty, but may be unique in that fewer anaesthetic drugs are commonly used in practise now than were decades ago. Drugs whose use has been abandoned includecyclopropane, etomidate, propanidid, enflurane, alcuronium, and omnapom. Other drugs may be abandoned due to side effects on the environment (such as nitrous oxide and desflurane) (Yasny & White 2012).
The use of suxamethopnium has changed with time and at one point it was so popular in Europe and US that its sale was in hundreds of kilograms (1980s). whilst it remains a unique and important drug, which has taught us much about the anatomy, physiology and pharmacology of the neuromuscular junction (NMJ) , it does have very many serious potential side effects and the advent of rocuronium (which can have a very rapid onset compared to other non depolarising agents) and sugadammex (which can rapidly reverse it) may have the effect of making suxamethonium redundant, which can rapidly reverse rocuronium.
- Dr Sher Mohammad, Consultant Anaesthetist, Sheffield Teaching Hospitals, NHS Foundation Trust
- Dr Danish Siddiqui, Consultant Anaesthetist,University Hospital of North Midlands
- Dr Mohammad Ghazan Bashir, Trainee (MO) anaesthetics, Khyber Teaching Hospital, Peshawer KPK
- Dr Asif Zia, Trainee(MO) North West General Hospital, Peshawer KPK
- Dr Zain Ahmed Shah, Foundation Year 1 trainee, Frimley Health, NHS Foundation Trust
- Dr Nishant Kalra, Clinical Fellow Speciality Registrar, Sheffield Teaching Hospitals, NHS FT
- Dr Rajeev Singh, Clinical Fellow Speciality Registrar, Sheffield Teaching Hospitals, NHS FT
- Dr Gul Hasan Khan, ACCS trainee, Sheffield Teaching Hospitals, NHS Foundation Trust
- Dr Ahmed Gharib, Clinical Fellow, Anaesthetics, Sheffield Teaching Hospitals, NHS Foundation Trust
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