Cholinesterase Inhibitor Poisoning - Etiology, Clinical Manifestations, Evaluation, and Management

Introduction:

Acetylcholine is a neurotransmitter that plays a role in many biological processes, including the nervous system. Cholinesterases are enzymes that break down acetylcholine. Among the most lethal and practical chemical warfare agents are nerve agents. It is wise to have some familiarity with nerve agents, given the widespread threat of terrorism. The more well-known nerve agents include Sarin (also called GB), Soman (sometimes called GD), and VX. Though they were never utilized in battle, World War II saw the best use of these volatile insecticides, which were first created in the early to mid-1900s from chemically related pesticides. The 1995 Sarin gas attack on the Tokyo subway and the 2017 binary VX assassination of Kim Jong-Nam are two more recent instances of the usage of nerve agents. In more recent times, attempts to kill Sergei Skripal and Alexei Navalny have used "Novichok," or newer poisons, which are more powerful than VX. Acetylcholinesterase is inhibited by all G agents, V agents, and Novichok agents.

What Is the Etiology of Cholinesterase Inhibitor Poisoning?

The principal substances employed as nerve agents are:

• Sarin (RS)-propane-2-yl methylphosphonofluoridate, also known as GB.

• Tabun ethyl dimethyl amido cyano phosphate, commonly known as GA.

• Soman (O-pinacolyl methylphosphonofluoridate), commonly known as GD.

• VX (ethyl (2-[bis (propan-2 yl) amino] ethyl sulfanyl) (methyl) phosphinate).
• VE-O-ethyl-S-(2-(diethylamino) ethyl) methylphosphonothioate.

• VG - phosphorothioate, O, O-diethyl-S-[2-(diethylamino) ethyl].

• VM-O-ethyl-S-(2-(diethylamino) ethyl) methylphosphonothioate.

The G group chemicals, which resemble organophosphate insecticides structurally, were first created in Germany in the 1930s for use as chemical weapons. Following World War II, the United States and England created the V group. All of these substances produce the same signs and symptoms as organophosphate intoxication, but they are stronger, more persistent, and, in the case of Soman, occasionally irreversible. They are, therefore, potentially more dangerous.

What Is the Pathophysiology of Cholinesterase Inhibitor Poisoning?

Acetylcholinesterase inhibition at the nerve junction is the primary mechanism used by all nerve agents to cause their effects. The chemical forms a covalent bond with the cholinesterase active site, blocking the enzyme's ability to hydrolyze acetylcholine at the nerve junction. As a result, acetylcholine builds up, and the muscarinic (membrane protein) and nicotinic (channel protein) acetylcholine receptors in the central and peripheral nervous systems are overstimulated. If the symptoms are not addressed right away, the major process of acetylcholine breakdown is hindered, which prolongs the consequences. Muscle paralysis, respiratory failure, increased respiratory secretions, convulsions, coma, and death are some of the clinical outcomes.

What Happens in Cholinesterase Inhibitor Poisoning?

As they are often generated in liquid form, the agent can be dispersed in large quantities through aerosolization. Although inhalation has the most rapid and significant effects, the chemicals can also enter the body through ocular (eye), cutaneous (skin), or stomach absorption. Once ingested, these substances become essentially active and continue to have an impact on the body until they spontaneously reverse themselves through hydrolysis (Sarin and Soman) or oxidation (VX).

Following their breakdown, these substances are normally eliminated by the kidneys and expelled in the urine. Oximes can also counteract these medications for a short while. The time frame varies depending on the agent but can be anywhere between seconds and hours. The agents go through a chemical change at the end of this period of time known as "aging," which permanently bonds them to the acetylcholinesterase enzyme.

What Are the Clinical Manifestations of Cholinesterase Inhibitor Poisoning?

Organophosphate nerve agents will cause a cholinergic crisis (over-stimulation of the neuromuscular junction) in patients who are exposed. Both the dose and the exposure method have an impact on the speed at which symptoms appear and how severe they are. A thorough history encompassing possible exposures over the past 24 to 48 hours is crucial due to the dose-dependent nature of the effects and the varied speeds of onset from the various absorption pathways. These substances are absorbed by a variety of routes, and the muscarinic and nicotinic structures nearby will be the target of their immediate actions. Local reactions like muscle twitching and perspiration (sweating) may happen when these substances come into touch with the skin and start to absorb. Miosis (pupillary constriction), a symptom of ciliary muscle (eye muscle) failure, and lacrimation are ocular (eye) symptoms.

How Is Cholinesterase Inhibitor Poisoning Evaluated?

The environment in which patients were exposed to nerve agents should be taken into consideration when evaluating them. In order to avoid future exposure to the victim and medical professionals, it is essential to decontaminate right away with frequent showers and the removal of all clothing. Identifying the precise nerve agent should not put off treating symptoms in people who have experienced a known or highly probable terrorist attack.

All organophosphate compounds receive the same general therapy, and being aware of the symptoms of a cholinergic crisis can guide both diagnosis and treatment. After taking the necessary steps to protect oneself and the rest of the team from secondary exposure, evaluation and treatment should follow the standard airway, breathing, and circulation priority. The respiratory system needs special attention because failure there will almost certainly result in the patient's death.

There is no real-time laboratory test available to identify these compounds. In order to identify exposure to nerve agents, many tests are employed. The military and related institutions use M8 or M9 paper for quick non-specific detection in the field. However, GC-MS or Ion spectrum mobility is employed to specifically identify the nerve agents. Both of these approaches, however, are ineffective for figuring out how much of an agent someone was exposed to. The most popular technique for achieving this goal is to utilize colorimetric tests to assess the degree of acetylcholinesterase inhibition in red blood cells (RBC). The limitations of assessing RBC acetylcholinesterase inhibition's specificity have led to the development of more sensitive, non-invasive monitoring techniques, like carbon nanotube-based sensors.

How Is Cholinesterase Inhibitor Poisoning Managed?

• The first line of defense against nerve agent exposure is the protection of the caregiver and patient decontamination.

• Wear personal protective equipment (PPE) in accordance with regional institutional regulations; rubber suits and respirators with charcoal filters will offer general protection. It is also required to thoroughly irrigate the patient to eliminate any remaining fluid.

• By encouraging hydrolysis and oxidation, further treatment of contaminated environmental surfaces with hot water and basic solutions (pH more than eight) will aid in the destruction of the nerve agents.

• The goal of treatment for exposure to organophosphorus nerve agents is to keep the respiratory system healthy.

• Bronchoconstriction, higher secretions, and decreased respiratory drive are all symptoms of acetylcholinesterase inhibition, which has a noticeable impact on the respiratory system. In order to open the airway and control secretions, additional oxygen must be given, and early intubation should be taken into account.

• Atropine, oxime-derivatives (Pralidoxime and Obidoxime), and possibly Diazepam are the pillars of medical treatment. In order to reduce the negative consequences of too much acetylcholine at the receptor site, Atropine works by competitively blocking the acetylcholine receptor, mostly at the muscarinic sites. The nerve agents are removed from the acetylcholinesterase enzyme by oxime derivatives such as Pralidoxime, allowing it to start hydrolyzing acetylcholine once more.

• Acetylcholine excess can have significant CNS consequences that can lead to seizures that need to be treated with intravenous (IV) Benzodiazepines.

• Atropine and Pralidoxime autoinjectors are available and are carried by organizations with a high exposure risk, such as the military. If an autoinjector is not accessible, both drugs can be administered intravenously or intramuscularly (IM), but they should be administered simultaneously or shortly after one another.

• Atropine should be taken twice a day at a dose of 2 mg until the symptoms of cholinergic muscarinic excess start to fade.

• The goal of Atropine therapy is specifically titrating to pulmonary secretions-related death. Pralidoxime can be injected slowly into the vein at doses of 15 to 25 mg/kg.

• The usual dosage for Diazepam for treating seizures is 5 to 10 mg orally.

• Additionally, preventative medications like Pyridostigmine can be utilized with agents like Soman, where aging happens almost instantly. These substances prevent the nerve agent from attaching to acetylcholinesterase by competing with it.

Conclusion:

Cholinesterase inhibitors are intended to be deadly. Death will follow if these chemical attacks are not swiftly identified and countered. How effectively and rapidly the recognized harmful effects are handled greatly affects the prognosis. Supporting respiratory function is essential for positive long-term results, especially in the absence of instantly accessible antidotes, as respiratory failure is the cause of the majority of deaths after exposure to organophosphate nerve agents.