Chemical weapons keep making headlines these days, be it the use of sarin in Syria or Novichok in the UK. An interesting fact hardly ever covered by the media is that the chemical structure of these compounds is relatively simple. An average, modern pharmaceutical drug tends to be much more complex and difficult to make. This is not particularly surprising, as most research into these agents was done 50 or more years ago, when the art of organic synthesis was not as advance as it is now. Nonetheless, these compounds (and nerve agents in particular) are extremely efficient. It is quite interesting to analyze, from a neuroscience perspective, what exactly these compounds are doing to our body to cause such a devastating effect.

Nerve agents are most commonly deployed in chemical warfare. However, they are more common than most of us understand. Compounds with similar structures are sometimes found in insecticides used in agriculture.

How nerve agents work?

All nerve agents work in a similar fashion, though they vary significantly in chemical structure. Due to this variance in chemical composition, they differ in toxicity and other properties. Nerve agents primarily belong to a group called the anticholinesterase inhibitors, and they act by causing paralysis or dysfunctioning of the nervous system.

To better understand the functioning of these agents, let’s look at the underlying physiology of the nervous system. All functions of our body are controlled by nerve cells. This includes the movement of muscles and the work of internal organs and cardio-respiratory apparatus. Our brain sends regular electrical signals to vital organs to keep them regulated. Once these signals reach the target organ, they release chemicals called neurotransmitters. When the brain sends messages to regulate the heart and respiration, nerve endings release a neurotransmitter called acetylcholine that mediates the communication between the neural system and organs and muscles.

Although there are many neurotransmitters helping to regulate the functioning of smooth and skeletal muscles and internal organs, acetylcholine is the most important of them all. Once released by neurons, acetylcholine forces the muscles to contract. Acetylcholine molecules get destroyed in milliseconds by a specific enzyme called acetylcholinesterase to ensure that muscles can relax back again. This contraction and relaxation of muscles ensures the smooth functioning of skeletal muscles, body movements, respiration, heartbeat, and much more.

Thus, for proper functioning and contraction of any muscles in the body, the firing of acetylcholine (in synaptic space) and its quick destruction by acetylcholinesterase is essential.

Now imagine a situation when acetylcholine fired from nerve endings is not destroyed due to a lack of acetylcholinesterase. Now the muscles contract but they cannot relax back. This would result in paralysis. Muscles cannot remain contracted forever and they would be damaged. It is how all nerve agents work: they inhibit acetylcholinesterase, making it non-functional and thus causing muscular paralysis.

Types of nerve agents

Nerve agents were primarily developed either for military purposes or to be used as insecticides. For these very different needs, nerve agents should be either volatile and non-persistent, or non-volatile and highly persistent.

G-series nerve agents were developed by Germans before the second World War. Sarin, tabun, soman, and cyclosarin are some of the representatives of this class of agent. These compounds are non-persistent, which means that they are less stable, cannot remain in the environment for long, and have a shorter washout period from the human body.

The V-series of nerve agents is another significant class of these compounds. They are highly persistent and have an oil like consistency. It means that they can remain stable in the environment for long time and have exceptionally long washout periods. VE, VG, VX, VR, and VM are some of the representatives of this class.

The Novichok series of agents were created by the Soviet Union between the 1960s and 1990s. They were designed to ensure that they remain undetectable by adversaries.

Although these three classes are well known, it is evident that there are many more classes perhaps unknown to the general public due to the secrecy surrounding this technology. Importantly, all of these compounds have a similar mode of action, even though they differ in physical properties and toxicity.

Exposure consequences and antidotes

Once a person is exposed to a nerve agent, the chemical effectively paralyzes various muscles of his/her body, including respiratory and cardiac muscles. Thus, in the end, the person dies due to respiratory and cardiac failure. After initial exposure, many of the agents cause immediate irritation of mucous membranes resulting in a runny nose and burning sensation, followed by the blurring of vision, tightness in chest, urination, defecation, stomach aches, vomiting, epileptic seizures, and finally death due to cardio-respiratory failure.

Acetylcholine is also a vital neurotransmitter for communication between brain cells. This means that nerve agents cause neural damage that is, in many cases, irreversible. Even if a person is revived after exposure, neural damage or psychiatric changes may continue to persist for years. Surviving victims of nerve agent poisoning continue to suffer from fatigue, cognitive deficits, and many other neural symptoms.

The anticholinergic drug atropine remains the first line of help in most cases. This is a widely available drug and may help to counteract many nerve agent effects, especially those related to respiration, heart, and skeletal muscles. Atropine is a part of many emergency kits.

Biperiden is another drug used to treat nerve agent exposure. It is slow to act, but it can cross the blood-brain barrier, and thus helps to counter the central nervous toxicity of these agents.

Pralidoxime chloride is an activator of anticholinesterase and may also help to counter the toxic effect of nerve agents.

Apart from the above-mentioned three drugs, there is an array of supportive drugs and treatments that may help to counteract the effects of nerve agents, help to maintain the functioning of critical organs, and also play a role in faster washout of some of these agents from the body.

References

Newmark, J. (2009). CHAPTER 56 – Nerve Agents. In M. R. Dobbs (Ed.), Clinical Neurotoxicology (pp. 646–659). Philadelphia: W.B. Saunders. doi:10.1016/B978-032305260-3.50062-9

Organisation for the Prohibition of Chemical Weapons. (n.d.). Nerve Agents. Retrieved March 21, 2018, from here

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