Chemical Weapons III. How Nerve agents work

Crossposted at Politicook.net

I had a change of plans.  It is easy to understand that materials like chlorine or phosgene, or even mustard agents work because they chemically attack cells, either destroying proteins and lipids, of by corrupting DNA.

Nerve agents work very differently, so this aside may shed some light on how these horrible materials work.  First, some basic physiology.  There are numerous chemical messengers in the body and brain, including dopamine (why people get addicted, but that is another post), norepinephrine, GABA, serotonin, and many others.  This has to with one called acetylcholine.

Here is a structural diagram of acetylcholine.

This neurotransmitter is involved, amongst other things, with voluntary and involuntary muscle movement.  It also has to do with such actions as breathing, secretion of fluids, and eye pupil size.  It is an excititory neurotransmitter, meaning that its presence causes nerves to fire, in contrast to an inhibitory neurotransmitter, where its presence prevents nerves to fire.  This is an extremely important distinction, so please keep it in mind.

Because acetylcholine is an excititory neurotransmitter, it has to be stopped when its job is done.  Animals have an enzyme that does just this, by the tongue twisting name of "acetylcholinesterase".  This is a large protein, and its sole job is to decompose acetylcholine once it has jumped from one synapse to the other.  This enzyme is present in all of us, and is essential for survival.

Acetylcholinesterase inactivates residual acetylcholine.  Unlike many neurotransmitters, acetylcholine activates nerve transmissions by a brief connection with the receptor on the opposite side of the synapse, then is cast away.  It does bond, but only transiently, before being offcast.  Then the receptor regains its original quaternary structure, and ready to play again.  It is up to acetylcholinesterase to destroy the excess acetylcholine to prevent it from making those nerves fire over and over.

Here is a graphic of synaptic communication.  This one is general:

This does not show acetylcholinesterase.  Acetylcholine is not normally reabsorbed, so the diagram is not completely accurate, but it was the best one that I could find.  Instead of a reuptake pump as in this diagram, acetylcholinesterase degrades acetylcholine into choline and acetate, which are recycled later.

The important part of the diagram is to see that a neurotransmitter has to be expelled from one side of the synapse, and then activate a receptor on the other side.  Most of the time, and in keeping with this diagram, the neurotransmitter is ejected after the receptor is activated, and reabsorbed.  In the case of acetylcholine, it is ejected and destroyed by acetylcholineserase.

Once acetylcholine triggers the receptor, the target organs are activated.  Skeletal muscle contracts, and cardiac muscle relaxes.

The muscle contractions also affect the diaphragm, causing it to seize in a contracted manner.  But our friend acetylcholineserase comes to the rescue by destroying the acetylcholine, preventing it from reactivating the pathway.  Thus our bowels and bladders relax, our muscles relax, and our diaphragm relaxes and allows us to breathe in a big draught of air.

This occurs constantly in the body, regulated by other enzymes and feedback control mechanisms.  This is important, because if your muscles did not not tighten and relax constantly, they would become weak.  If your eyes did not constantly react to light, you would become blind.  If your diaphragm did not contract and relax, you would suffocate.

The nerve agents act by binding to acetylcholinesterase, making it so that it can not do its job.  Acetylcholine accumulates and thus makes the nerves keep on firing, rather than firing once and stopping.  The result is the the skeletal muscles contract and become rigid, while heart action is decreased.  Without immediate medical intervention, death results from a combination of stoppage of breathing due to the diaphragm going into a contracted permanent state and the heart action decreasing and finally stopping.

Large doses of atropine reverse the symptoms, but do not reverse the damage to acetylcholinesterase.  Here is a structural diagram of atropine:

Atropine binds to the acetylcholine receptor without triggering it.  Thus, atropine poisoning results in skeletal muscle relaxation, heart rate increase, and widely dilated pupils.  Many people have been the the eye doctor and had their pupils dilated for an examination.  Thus, the competition between atropine and acetylcholine reverses the symptoms of nerve agent poisoning, but does not cure it.  Over time, the atropine is destroyed by the body and symptoms often reappear, especially after high doses of nerve agents.

The body replenishes its supply of acetylcholinesterase, assuming that one lives, but only very slowly.  Repeated, subclinical doses of nerve agents can reduce levels to the point that another subclinical dose can cause full poisoning symptoms.  People who work around these materials are required to get a baseline acetylcholinesterase measurement, and periodic checks to try to prevent this from happening.

One might guess that a solution would be to regenerate the damaged acetylcholinesterase, and one would have guessed correctly.  That actually cures the condition, rather than just reversing the symptoms.  The drug developed for that is pralidoxime.  Here is the structural formula:

This material is generally used as the chloride (called 2-PAM chloride).  Pralidoxime strips the phosphate from the nerve agent from acetylcholinesterase, reactivating the enzyme and being converted, along with the phosphate fragment of the nerve agent, into relatively inert materials.  The problem is that it works more slowly than atropine, so atropine is essential to preserve life while the pralidoxime takes effect.

Soldiers who are serving is suspected chemical threat areas are issued protective clothing, of which there are several levels depending on the threat assessment.  A respirator is the minimum level of protection, with specially treated HEPA filters and activated carbon.  In military lingo they are called protective masks, since the cover the entire face.  Nerve agents can get into the system from the eyes, and other agents irritate the eyes anyway.  In each mask carrier is what is called a "Mark V" kit, which contains two sets of autoinjectors (think of a adrenaline pen used by people with serious allergies to insect stings.  You just put in on a large muscle, usually your thigh, and it injects a measured dose for you), one set with atropine and the other with pralidoxime.  That way a soldier can medicate himself, since the probability of a medical person reaching her or him before death is very low.  Part of the doctrine is to bend the needle from each injector and hang the injector on the pants leg so when medical help does arrive it is fast to see how much medication has been self administered.

Do not be deceived:  these treatments are far from 100% effective.  Depending on the dose, there may not be enough medication in a Mark V kit to save one, and any delay in administration reduces the chance of recovery.  Part of the reason is that the nerve agent binds with acetylcholinesterase rather weakly at first, but as time passes, stronger bonds develop.  This is called "aging" of the complex, and one it has aged, pralidoxime can not undo the binding.  Agent GD (see previous diary) seems to be the worst for that, meaning that its complexes with acetylcholenesterase ages faster than those of other nerve agents.

In closing, almost everyone here has sprayed insects and seen the convulsions as the muscles contract, and how fast death comes.  The Nazis did some truly horrific experiments way back when by injecting G agents IV into concentration camp inmates.  I have seen films (if anything, the Nazis were hell bent on documentation) where Jewish and Romani (Gypsy) people were given IV doses, and in some cases the muscle contractions were so fast and so powerful the spontaneous compound fractures would occur because the bones could not take the strain caused.  Nice folks, those Nazis.  I do not have a link to those films, and probably would not post it if I did.  There are some pretty gruesome animal study films at the end of the Wikipedia entry for Nerve Agents, but I do not think that I will link those, either.

I will hang around for a while for questions, comments, etc. as is my practice.  I do not diary and leave except under extraordinary circumstances.  Warmest regards, Doc.