4. Anticholinesterases

Question 1

Intro

Answer 1

inhibit the breakdown of acetylcholine is not confined to
anaesthesia, and these agents find medical indications in conditions as diverse as
dementia and myasthenia gravi

Question 2

Cholinesterase enzymes

Answer 2

There are two forms: acetylcholinesterase and butyrylcholinesterase
(plasma cholinesterase). These enzymes were characterized as ‘true’ and
‘pseudo’ cholinesterase, but this terminology is no longer used.

The physiological function of plasma cholinesterase is not fully elaborated, but its anaesthetic relevance lies in its metabolism of esters such
as suxamethonium, mivacurium, diamorphine and aspirin.

Question 3

Plasma cholinesterases and Anticholinesterase

Answer 3

The actions of plasma cholinesterase are antagonized by anticholinesterases,
and so the administration of neostigmine, for example, to a patient who is
paralysed with suxamethonium would extend the duration of the block.

The main
relevance of anticholinesterases (sometimes referred to as choline esterase inhibitors)
lies in their antagonism of acetyl cholinesterase.

Question 4

Acetylcholine metabolism:

Answer 4

The breakdown and recycling of acetylcholine in the cholinergic junction is a highly dynamic process, with many thousands of molecules being hydrolyzed by acetylcholinesterase each second.

Anticholinesterases prolong the survival of acetylcholine in the cleft of muscarinic and nicotinic junctions with effects that are predictable from the functions mediated by those receptors.

The most extreme manifestations of acetylcholine excess are seen in cases of organophosphate poisoning.

Question 5

Muscarinic effects:

Answer 5

These include bradycardia, bronchoconstriction and bronchorrhoea
as well as increased gastrointestinal secretions and motility.

Question 6

Nicotinic effects:

Answer 6

Nicotinic effects: These are evident more in overdose or organophosphate poisoning
than after administration of conventional doses. They include muscle fasciculations,
weakness and cramping

Question 7

CNS effects:

Answer 7

CNS effects: These are also mainly apparent in overdose or poisoning. Features may
include agitation, confusions, tremors, ataxia and, in extreme cases, convulsions and
loss of consciousness

Question 8

Clinical Uses of Anticholinesterases

Answer 8

Reversal of neuromuscular blockade:

Competitive inhibition of the post-junctional receptor
in the neuromuscular cleft by muscle relaxants is reversed by anticholinesterases
which restore the levels of available acetylcholine.

Neostigmine is the main agent that is used for this purpose.

Question 9

Treatment of myasthenia gravis

Answer 9

: Myasthenia gravis is an autoimmune condition characterized by the formation of antibodies against post-synaptic acetylcholine receptors at the neuromuscular junction.

As the number of effective receptors decrease there is a progressive reduction in muscle strength,

particularly involving the bulbar muscles.

Its estimated prevalence is 1 in 5,000 of the population, and it is
twice as common in women than men.

Edrophonium is used for diagnosis, while
pyridostigmine is the primary cholinesterase inhibitor used for treatment

Question 10

Treatment of the central anticholinergic syndrome

Answer 10

Treatment of the central anticholinergic syndrome:

A relative or absolute reduction of cholinergic transmission
in the central nervous system defines the central
anticholinergic syndrome, which can occur following treatment or overdose with
primary anticholinergic drugs such as atropine or hyoscine,

or with drugs that have a secondary anticholinergic action such as the phenothiazines.

Its clinical features are relatively non-specific and include agitation and disorientation with more predictable manifestations such as flushing, pyrexia, dry skin, mydriasis and sinus tachycardia.

Physostigmine is given as first-line management

Question 11

Treatment of dementia:

Answer 11

Alzheimer’s disease is characterized, amongst other things,
by central depletion of acetylcholine in the cerebral cortex and the hippocampus.

Anticholinesterases such as donezepil increase the concentration of acetylcholine and
appear to slow the rate of deterioration.

They do not cure or reverse the process of neurodegeneration.

Question 12

Summary of Drugs in Clinical Use

Answer 12

Neostigmine

Pyridostigmine

Physostigmine

Question 13

Neostigmine

Answer 13

: This is the anticholinesterase with which anaesthetists are most
familiar via its routine use for reversal of neuromuscular blockade. As a quaternary
ammonium compound it does not cross the blood–brain barrier. After binding to the
anionic site of acetylcholinesterase and then to an esteratic subsite, the drug is
hydrolyzed, but in a process that takes some minutes, hence its sustained effect.

Onset and time to peak effect are rapid (1 and 10 minutes, respectively), but the
duration is relatively short-lived at around 20–30 minutes. It is usually given
intravenously (the quoted dose is 50–70 micrograms kg–1, but administration is
better titrated to the degree of residual neuromuscular block)

Question 14

Pyridostigmine

Answer 14

This is a neostigmine analogue which has 25% of its potency but
which has a longer duration of action (4–6 hours).

Its onset time is prolonged at up to 15 minutes,
and so it is not a suitable agent for the reversal of neuromuscular
block.

It is, however, the preferred agent for the treatment of myasthenia gravis

Question 15

Physostigmine

Answer 15

Physostigmine:

Unlike neostigmine and pyridostigmine,

physostigmine lacks a quaternary ammonium group and so crosses the blood–brain barrier.

It can therefore be used to treat the central anticholinergic syndrome (0.5–2.0 mg intravenously).

It is a natural alkaloid metabolized by non-specific plasma esterases.

Question 16

Edrophonium

Answer 16

: This is another quaternary ammonium compound, but one which
has a very short duration of action of around 10 minutes. The effectiveness of reversal of neuromuscular blockade is less predictable than with neostigmine,
although in equipotent doses its muscarinic effects are less pronounced. Its predominant
use is in the diagnosis of myasthenia gravis and as a means of predicting the
patient’s response to the longer-acting anticholinesterases.

Question 17

Donepezil, rivastigmine and galantamine

Answer 17

Donepezil, rivastigmine and galantamine.

These three acetylcholinesterase inhibitors
are approved by NICE for the treatment of mild and moderate dementia.

Donepezil is a selective inhibitor of acetylcholinesterase and has no effect on plasma
cholinesterase.

It has a long half-life and can be given daily.

Rivastigmine inhibits both forms of cholinesterase and with a shorter half-life is given twice daily.

Galantamine is both a cholinesterase inhibitor and a presynaptic nicotinic modulator.
Any clinical significance of this second action is unclear

Question 18

Organophosphate Poisoning

Answer 18

Organophosphates are used particularly widely in agricultural settings where they are
found in pesticides, insecticides and herbicides.

They inactivate acetylcholinesterase by phosphorylation of the serine hydroxyl moiety that is located on each of the six active sites of the enzyme.

The resultant accumulation of acetylcholine is accompanied
by excessive cholinergic, nicotinic and central nervous system effects which, in
cases of accidental poisoning, are frequently fatal

Question 19

Management

Answer 19

: In addition to supportive management,

the treatment of organophosphate poisoning includes the use of anticholinergic drugs such as atropine or glycopyrronium, together with reactivation of the enzyme by pralidoxime.

This binds directly to the organophosphate molecule and effectively reactivates the enzyme.

It is ineffective once the organophosphate has bound irreversibly to acetylcholinesterase
and so must be given at the latest within 48 hours of poisoning.