20. Cholinesterase Inhibitors (Anticholinesterases) and Reversal Agents

Question 1

How do anticholinesterases exert their effects?

Answer 1

> They inhibit the action of
acetylcholinesterase by occupying
its active site,

which prevents it from breaking 
down acetylcholine (ACh).

> These agents are used to
reverse the effects of non-depolarising
neuromuscular blocking drugs,

as they increase the amount of ACh
available to compete with the
muscle relaxant at neuromuscular junction.

> They are also used in the 
diagnosis and treatment of 
myasthenia gravis
and form an active ingredient 
in pesticides and nerve gases.

Question 2

How are these drugs classified? Anticholinesterases are classified according to their duration of action:
Short acting:

Answer 2

Short acting:

> Edrophonium
(trade name Tensilon)

• Duration: 10–20 minutes.

• Mode of action:
Competitive antagonist of ACh
at the active site of acetylcholinesterase.

• Uses: In the diagnosis of myasthenia gravis
(Tensilon test) –
following administration,
muscle power improves.

Question 3

Medium acting:

Answer 3

Medium acting:

> Neostigmine

• Duration: 1–2 hours.
• Mode of action:

Carbamlyates the active site
of the enzyme.

Once bonded,
it is hydrolysed like ACh,
but the process takes much longer.

It also inhibits the action of
plasma pseudocholinesterase

and
so will prolong the effects of
suxamethonium and mivacurium.

• Uses:

Reversal of competitive neuromuscular
blocking drugs and treatment of
constipation on the ICU.

> Pyridostigmine

• Duration: 2–3 hours.
• Mode of action: As for neostigmine.
• Uses: Orally, in the treatment of myasthenia gravis.

Physostigmine

• Duration: 0.5–5 hours.
• Mode of action: As for neostigmine.
• Uses: Topical eye drops in the treatment of glaucoma.

Question 4

Long acting:

Answer 4

Long acting:

> Echothiophate

• Duration: Weeks.

• Mode of action:
Phosphorylation of the
active site of the enzyme.

The bond is covalent and the
enzyme takes weeks
to hydrolyse the drug.

• Uses: Treatment of glaucoma.

This class also includes:

> Sarin, VX –
nerve gases used in chemical warfare.

> Tetraethyl pyrophosphate (TEPP) –
an insecticide.

In toxic doses
(e.g. organophosphorus poisoning),
anticholinesterases can
cause

SLUDGE syndrome (
salivation, 
lacrimation, 
urination, 
defecation,
gastrointestinal upset, 
emesis) 

and

cause death by paralysis of the
respiratory muscles.

Treatment is with antimuscarinic agents, 
such as
atropine 
and 
pralidoxime.

Question 5

What are the side effects of a conventional dose of neostigmine?

Answer 5

Cardiovascular:

> Bradycardia

> Hypotension

Respiratory:

> Bronchoconstriction

> Increased secretions

Neurological:

> Miosis and blurred vision

> Low dose: muscle contraction

> High dose:
large amounts of ACh at NMJ may render neuromuscular
transmission obsolete.

Gastrointestinal:

> Increased secretions

> Peristalsis

> Nausea and vomiting

Other:
> Sweating

To offset these unpleasant effects,
neostigmine is usually given with an
antimuscarinic agent such as glycopyrrolate.

Question 6

Neostigmine

Type
Dosage
Preparation

MOA

Answer 6

NEOSTIGMINE

Anticholinesterase quaternary amine

• Tablets: 15 mg
• Solution: 2.5 mg/mL
• Mixed with glycopyrrolate:

2.5 mg neostigmine + 0.5 mg glycopyrrolate/mL

DOSE
• 0.05 mg/kg IV

MOA
• Binds to esteratic site of acetylcholinesterase (AChE),

the enzyme which breaks down acetylcholine (ACh)

• Neostigmine is hydrolysed by AChE,
but much more slowly than ACh would be

• As enzymes’ active sites are occupied by neostigmine, more ACh is available at the
neuromuscular junction (NMJ)

• Increased quantity of ACh at NMJ allows more efficient competition with non-depolarising muscle
relaxants

CHEMICAL PROPERTIES
• Nil

Question 7

Neostigmine

Absorption

Distribution

Metabolism

Excretion

Answer 7

METABOLISM AND EXCRETION

• Metabolised by plasma esterases

• Small amount of hepatic metabolism,
these products excreted in bile

• Remainder excreted in urine

ABSORPTION/
DISTRIBUTION

• Poorly absorbed orally
• Oral bioavailability 1−2%
• Protein binding 10%
• VD 0.4–1 L/kg

• Max effect in 7–11 min,
lasts 4 hours

• t½ 15–80 min

USES
• Reversal of neuromuscular blockade caused by
non-depolarising muscle relaxants

• Myasthenia gravis
• Paralytic ileus

Question 8

Neostigmie

side fx

Answer 8

EFFECTS
CVS
• Bradycardia
• Hypotension
RS
• Bronchoconstriction
• Increased secretions
CNS
• Miosis and blurred vision
• Low dose: muscle
contraction
• High dose: large
amounts of ACh at NMJ
may block
neuromuscular
transmission as
receptors ooded
GI
• Increased secretions
• Peristalsis
• Nausea and vomiting
OTHER
• Sweating

Question 9

Edrophonium

EDROPHONIUM

Answer 9

Edrophonium

Anticholinesterase-quaternary amine

• Solution: 10 mg/mL

DOSE

• Tensilon test =
2 mg followed by 8 mg if no improvement in strength

MOA

• Binds reversibly to esteratic site of acetylcholinesterase, (AChE),
the enzyme which breaks down acetylcholine
(ACh)

• Competes with ACh for this binding site hence reducing rate of breakdown of ACh

• So, more ACh available to activate nACh receptor and
cause muscle contraction

CHEMICAL PROPERTIES
• Nil

EFFECTS
Mainly result from  activation
of muscarinic receptors by ACh
CVS
• Bradycardia
• Hypotension
• Cardiac arrest reported
RS
• Bronchoconstriction
• Increased secretions
CNS
• Miosis and blurred vision
• Low dose: muscle
contraction
• High dose: large amounts
of ACh at NMJ may render
neuromuscular transmission
obsolete
GI
• Increased secretions
• Peristalsis
• Nausea and vomiting
OTHER
• Sweating

Question 10

Edrophonium

Metabolism
Excretion

absoprtion
distribution

Answer 10

METABOLISM AND EXCRETION

• No information

ABSORPTION/ DISTRIBUTION

• VD 0.9−1.3 L/kg
• Max effect in 2 min, lasts 10 min
• t½ 110 min

USES
• Reversal of neuromuscular blockade caused by
non-depolarising muscle relaxants

• Diagnosis of myasthenia gravis (‘Tensilon test’ – following drug administration, muscle strength
improves. Tested by EMG)

• Differentiating between myasthenic crises (where
strength improves) and cholinergic crisis in patients
with myasthenia gravis (where it worsens)

Question 11

Sugammadex

prep

Doses

MOA

Answer 11

Sugammadex

SUGAMMADEX
Modified y-cyclodextrin
Trade name: Bridion

• Approved for use in Europe in July 2008

• Clear colourless solution: 100 mg/mL in 2 mL or
5 mL vials

DOSE
• Moderate block: 2 twitches, 2 mg/kg

• Deep block: 1–2 post-tetanic count, 4 mg/kg
• Immediate reversal from RSI, 16 mg/kg

• At these doses recurrence of blockade is not a
clinical problem

MOA
• Its ring-like structure enables drug to
encapsulate rocuronium and vecuronium in its
lipophilic core

• The active site of the muscle relaxant is bound
to carboxyl groups in the cyclodextrin so it cannot
interact with the acetylcholine receptors at
the neuromuscular junction (NMJ)

• Causes reversal of neuromuscular blockade

Question 12

USES
Sugammadex

Effects

Answer 12

• Reversal of neuromuscular blockade
caused by rocuronium and vecuronium

• Can be used confidently to reverse effects, even
following an intubating dose of rocuronium

EFFECTS

CVS

• Cardiovascularly stable

• Avoids need to give anticholinesterase and
antimuscarinic to reverse neuromuscular blockade,
with their attendant side-effects

OTHER
• Also has affnity for pancuronium, though not licensed for its reversal

• Affnity:
rocuronium>vecuronium >pancuronium
• Produces rapid reversal because encapsulating the
muscle relaxant in the plasma creates a
concentration gradient between plasma and NMJ,
which causes rocuronium/ vecuronium to diffuse
away from NMJ into plasma

Question 13

Sugammadex

METABOLISM
AND EXCRETION

Answer 13

METABOLISM
AND EXCRETION
• Both cyclodextrin and cyclodextrin-aminosteroid
complex excreted in urine

ABSORPTION/
DISTRIBUTION

• Biologically inactive
• No protein binding
• t½ 1.8 hours