8.7 Anticholinesterases

Question 1

How do anticholinesterases exert their effects?

Answer 1

They inhibit the action of acetylcholinesterase (AChE)

by occupying its active site,

thus preventing it from breaking down acetylcholine (ACh).

However, the actions of anticholinesterases
are not specific to the neuromuscular junction
(NMJ); therefore,

autonomic cholinergic effects are also seen
(bradycardia, salivation).

Thus, anticholinesterases are often given with an anticholinergic
(e.g. glycopyrrolate).

Question 2

What are the indications for anticholinesterases?

Answer 2

• Reverse effects of non-depolarising neuromuscular blocking drugs
  by increasing the amount of ACh available to compete with the
  neuromuscular blocking drugs at the neuromuscular junction
• Diagnosis of myasthenia gravis (Tensilon test)
• Treatment of myasthenia gravis
• Active ingredient in pesticides and nerve gases
• Treatment for urinary retention
• Treatment for paralytic ileus
• Treatment for glaucoma

Question 3

How do you classify anticholinesterases?

Answer 3

There are three groups of anticholinesterases based on their mechanisms of
action:

1. Easily reversible inhibition
2. Formation of a carbamylated enzyme complex
3. Irreversible inactivation by organophosphorus compounds

Question 4

Easily reversible inhibition

Answer 4

• Only example is edrophonium.
• Phenolic quaternary amine.
• Used to distinguish between a myasthenic crisis
  (muscle power improved) and
  cholinergic crisis (clinical symptoms worsened).
• The amine group is attracted to the anionic site of AChE,
  whilst its hydroxyl group forms a hydrogen bond
  at the esteratic site, stabilising the complex.
• ACh is therefore unable to reach the active site of AChE.
• This complex is easily reversible; therefore,
  ACh can compete with edrophonium for AChE.

Question 5

Formation of a carbamylated enzyme complex

Answer 5

• e.g. neostigmine, pyridostigmine, physostigmine
• Carbamate esters
• Produce a carbamylated enzyme when reacting with AChE
• This complex has a slower rate of hydrolysis than ACh and AChE
  complex; therefore, it stops AChE hydrolysing Ach

Question 6

Irreversible inactivation by organophosphorus compounds

Answer 6

• Organophosphate compounds are highly toxic.
• They are the main ingredients in insecticides (e.g.
  tetraethyl pyrophosphate [ TEPP]) or nerve gases (e.g. Sarin).
• Esteratic site of AChE is phosphorylated by organophosphorus
  compounds, resulting in enzyme inhibition.
• The complex formed is very stable and is resistant to hydrolysis or
  reactivation.
• Plasma cholinesterases are also inhibited.

Question 7

How does organophosphate poisoning present?

Answer 7

Organophosphates are highly lipid soluble
and therefore rapidly absorbed across the skin.

Toxic manifestations include nicotinic and
muscarinic effects,
autonomic instability,
CNS effects.

Mild
* Miosis, blurred vision
* Excess salivation
* Headache
* Nausea
* Mild muscle weakness and muscle twitching
* Mild agitation

Moderate
* Pinpoint pupils, conjunctival injection
* Disorientation
* Coughing, wheezing, sneezing, drooling
* Bronchospasm and difficulty in breathing

severe
* Confusion and agitation
* Convulsions
* Cardiac arrhythmias
* Respiratory depression and arrest
* Coma and death

Question 8

How do you treat organophosphate poisoning?

Answer 8

General
* Ensure person protective equipment is worn
and that patient has been decontaminated.

• Remove patient’s clothing if not already done
  and place in double bag,
  seal, and store securely.
• Shower, wash down, or rinse with liquid soap and water.
• Irrigate eyes with lukewarm water/normal saline solution.
• If ingestion of organophosphates within previous 2 hours, activated
  charcoal may be used.

specific
* Airway: Intubate and ventilate if required,
use suction on secretions.

Avoid suxamethonium.

• Breathing: 100% oxygen.
• Circulation: Large bore access, ABG, U&E, glucose, monitor ECG, and
  treat arrhythmias.
• Alert local health protection team and seek expert advice (e.g. Toxbase).

Question 9

Drugs

Answer 9

Drugs
* Atropine:
For moderate and severe symptoms, give atropine 0.6–4 mg IV
(child 20 mcg/kg IV), every 10–20 minutes until secretions dry up.

• Pralidoxime:
  2 g or 30 mg/kg IV for adult over 4 minutes. Continue every
  4–6 hours or commence infusion. May be continued for 7 days until
  atropine is not required.
• Diazepam: 5–10 mg iv adult, 1–5 mg iv child.