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Cholinesterase Inhibitors: Including Insecticides and Chemical Warfare Nerve Agents
Part 2: What are cholinesterase inhibitors?

Course: WB 1098
CE Original Date: October 16, 2007
CE Renewal Date: October 16, 2010
CE Expiration Date: October 16, 2012
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Learning Objectives

Upon completion of this portion of the case study, you should be able to:

  • Identify the chemical responsible for the acute pathology in cholinesterase inhibitor poisoning.
  • Describe how cholinesterase inhibitors, including organophosphorus compounds (e.g., pesticides, nerve agents) and carbamates block the ability of acetylcholinesterase to break down acetylcholine.

The Primary Toxic Effect of Cholinesterase Inhibitors

Acetylcholinesterase inhibitors (which, for brevity, we will refer to as cholinesterase inhibitors) are chemicals whose primary toxic effect is to block the normal breakdown of the neurotransmitter, acetylcholine. This normal breakdown is shown in Figure 1 below.

Breakdown of Acetylcholine by Cholinesterase (Optional Reading)

Figure 1. Breakdown of acetylcholine.

Breakdown of Acetylcholine (Optional Reading)

They do this by occupying and blocking the site where the neurotransmitter, acetylcholine, attaches to the enzyme, acetylcholinesterase. If you are interested in the details at the chemical level, see the Optional Reading below.

How Acetylcholine is Blocked (Optional Reading)

Figure 2 below shows how a cholinesterase inhibitor (in this case, a nerve agent) attaches to the serine hydroxyl group on acetylcholinesterase. This prevents acetylcholine from interacting with the cholinesterase enzyme and being broken down.

δ + Indicates that phosphorus is partially electropositive.

δ – Indicates that oxygen is partially electronegative.

Diagrams modified from Wiener, S. W., and R. S. Hoffman. "Nerve Agents: A Comprehensive Review." Journal of Intensive Care Medicine 19, no. 1 (2004): 22-37.

Attraction of Cholinesterase Inhibitor to Acetylcholinesterase (Optional Reading)

Figure 2. Partially electropositive phosphorus is attracted to partially electronegative serine.

Molecular Bond Changes (Optional Reading)

Figure 3. Transition state showing which bonds break and which ones form.

Cholinesterase Inhibitor Attached to Cholinesterase (Optional Reading)

Figure 4. Cholinesterase inhibitor attached to acetylcholinesterase preventing the attachment of acetylcholine.

Effects of Blocked Acetylcholine Breakdown

This leads to the build up of excessive levels of the neurotransmitter, acetylcholine, at the skeletal neuromuscular junction and those synapses where acetylcholine receptors are located

Thus, the primary manifestations of acute cholinesterase inhibitor toxicity are those of cholinergic (neurotransmitter) hyperactivity. (Carlton, Simpson et al. 1998)

Other Effects of Cholinesterase Inhibitors (Optional Reading)

There are also other delayed and chronic pathological effects of inhibitors of the cholinesterase enzyme which are less well understood.

Cholinesterase inhibitors can have effects on a variety of non-cholinesterase enzymes and neurotransmitters, as well. (Somani and Husain 2001) However, the significance of these effects is not well understood.

Review of Definitions

Acetylcholine: a chemical neurotransmitter found widely in the body. It triggers the stimulation of post-synaptic nerves, muscles, and exocrine glands.

Acetylcholinesterase (generally referred to as cholinesterase): an enzyme that rapidly breaks down the neurotransmitter, acetylcholine, so that it does not over-stimulate post-synaptic nerves, muscles, and exocrine glands.

Acetylcholinesterase inhibitor (generally referred to as cholinesterase inhibitor): a chemical that binds to the enzyme, cholinesterase, and prevents it from breaking down the neurotransmitter, acetylcholine. With toxic doses, the result is that excessive levels of the acetylcholine build up in the synapses and neuromuscular junctions and glands.

Two Classes of Cholinesterase Inhibitors

Two classes of cholinesterase inhibitors are organophosphorus compounds and carbamates. The key differences are listed in the table below. (Erdman 2004)

 
Organophosphorus Compounds
Carbamates

Molecular structure (Ecobichon 1996)

Notes:

“R” denotes a variety of groups that attach to the basic structure.

“P=S” of organophosphorus compounds can be substituted for “P=O.”

“RL” of organophosphates may attach via an “O” to “P.”

Toxicity (Marrs and Dewhurst 2000)

Higher

Lower

Duration of action (Tareg, B et al. 2001)

Longer

Shorter

CNS toxicity (Tareg, B et al. 2001)

More common

Less common

Key Points

  • Cholinesterase inhibitor toxicity is due to a decrease in the ability of cholinesterase to breakdown acetylcholine which results in excessively high acetylcholine levels.
  • Cholinesterase inhibitors fall into two classes, organophosphorus compounds, and carbamates. The former are generally have higher toxicity, longer duration of action and more commonly cause CNS toxicity.

   

Progress Check

3. Cholinesterase inhibitor toxicity is due to (Choose ALL correct answers)

A. Excessive levels of the enzyme acetylcholinesterase.
B. Depressed activity of the enzyme acetylcholinesterase.
C. Excessive levels of the neurotransmitter acetylcholine.
D. Depressed levels of the neurotransmitter acetylcholine.
E. None of the above.

Answer:

To review relevant content, see Primary Toxic Effect of Cholinesterase Inhibitors in this section.

4. Which of the following are true about organophosphates? (Choose ALL correct answers)

A. They include pesticides.
B. They include nerve agents.
C. They are less toxic than carbamates.
D. They have a longer duration of action than carbamates.
E. None of the above.

Answer:

To review relevant content, see Two Classes of Cholinesterase Inhibitors in this section.

5. Cholinesterase inhibitors block the ability of acetylcholinesterase to break down acetylcholine by? (choose the ONE best answer)

A. Occupying the binding site on cholinesterase to which the acetylcholine would attach.
B. Preventing the release of acetylcholine from its attachment on cholinesterase.
C. Attaching to acetylcholine which prevents its attachment to cholinesterase.
D. None of the above.

Answer:

To review relevant content, see Cholinesterase Inhibitors Block the Normal Breakdown of Acetylcholine in this section.

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