Hello everyone and welcome to this week's blog post. This week's article is the second in a two-part series on poisons. If you haven't read last weeks article, you can read it here. In this week's article, I will first explore two of the most deadly natural poisons - tetrodotoxin and batrachotoxin. I will then examine some of the mechanisms behind how antidotes work.
Tetrodotoxin
Tetrodotoxin is a very powerful neurotoxin that affects nerves, preventing them from functioning correctly. It is commonly found in many different species including octopuses, cuttlefish, ribbon warms, newts and pufferfish. Interestingly, this toxin is not produced by the animal itself, but by bacteria that form part of the organism's microbiome.
This toxin can then enter the body after contact with these foods - either through touch or by ingestion. Most famously, tetrodotoxin poisoning occurs when people eat pufferfish which has not been prepared correctly.
Pufferfish, or fugu, are considered a delicacy in Japan and other parts of Asia. Since the fish contains tetrodotoxin, it needs to be prepared very carefully to remove traces of this toxin. In particular, the ovaries and liver of the fish need to be removed, as they contain high concentrations of this toxin. For that reason, the preparation and sale of pufferfish are tightly regulated - chefs who use the fish must get licenses from the government and store any offcuts in a locked container to prevent them contaminating the waste supply.
There have been cases in the past where the pufferfish was not caused correctly, causing people to die from fugu poisoning. Indeed, in 2018, there was a scare in Gamagori, Japan when five packets of poisonous fish were sold in the supermarket. This fish was poisonous as the liver had not been fully removed. Once this poisonous fish was detected, it was immediately recalled and loudspeakers in the city warned people of the danger.
Tetrodotoxin is incredibly lethal - it has an LD50 of around 5-8 micrograms per kilogram. As I mentioned in last week's article, LD50 is one of the most commonly used figures when comparing the toxicity of different substances. This figure gives the amount of substance required to kill 50% of the animals tested on.
Tetrodotoxin is able to cause harm to humans as it competes with sodium ions - it blocks sodium ion channels in nerves. This prevents sodium ions from moving across the membrane, thus disrupting depolarisation and preventing action potentials spreading across the nerves. Consequently, tetrodotoxin prevents nerves from functioning correctly.
Symptoms of tetrodotoxin poisoning can have a rapid onset (within minutes) or delayed onset (within a few hours). Initial symptoms include numbness and tingling of the lips, dizziness, vomiting, speech difficulties and difficulties in moving. Paralysis and muscle weakness then quickly spread across the body, as the motor neurons stop functioning. If left untreated, the toxin can cause respiratory muscles to stop working, causing shortness of breath and respiratory arrest. In addition, it can also affect the heart, causing abnormal heart rhythms and abnormally low blood pressure. Exposure to this toxin usually results in death within the first 4 to 8 hours, though death can occur as early as 20 minutes afterwards.
Despite its toxicity, tetrodotoxin is being researched for medical uses. Specifically, according to a paper published in 2017, this toxin could be used for treating cancer-related pain.
Unfortunately, there is no current antidote for tetrodotoxin poisoning. Instead, treatment involves reducing the amount of poison absorbed by the person. This can be done by getting them to eat charcoal or by inducing vomiting. In addition, if the person goes into respiratory arrest, then they can be ventilated to help the body recover.
Batrachotoxin
Batrachotoxin is also a very powerful neurotoxin. It has an LD50 of 2 micrograms per kilogram, making it an incredibly lethal substance. It is commonly found on a variety of poison arrow dart frogs in tropical reasons.
After entering the body, batrachotoxin causes damage to nerves and muscles. This is because it stops sodium ion channels in the cell membrane of these cells from closing. This increases the permeability of the membrane to sodium ions, causing mass sodium ion movement into the cell. Ammonium, potassium and caesium ions also flow into the neurone. These ions cause an irreversible depolarisation in the cell, preventing it from conducting any more signals. Consequently, the muscle remains contracted.
As a result, symptoms of batrachotoxin poisoning include irreversible muscle paralysis, as well as salivation, numbness and tingling of the affected area. In addition, since the heart muscle cells are particularly susceptible to the poison, arrhythmias, fibrillation and cardiac failure are all common symptoms of infection.
Currently, there is no known antidote for batrachotoxin poisoning. According to chemeurope.com, the mechanism behind how batrachotoxin affects the body is similar to the toxin digitalis, it is hoped that some treatments that work for digitalis may work for batrachotoxin. Currently, treatment involves reducing the amount of poison absorbed by the person. This can be done by getting them to eat charcoal or by inducing vomiting. In addition, if the person goes into respiratory arrest, then they can be ventilated to help the body recover.
Antidotes
Antidotes can be defined as chemical substances than negate the effect of a poison or a toxin. Antidotes have a number of beneficial effects. For instance, they can reduce the harmful effect the poison has on the body by decreasing the dose of toxin the body absorbs and reduce the length of time the body is exposed to the toxin. Thus, they can greatly increase the chance of survival after exposure to a toxin.
There are several ways in which antidotes can work. For example, antidotes can work by directly binding to the toxin. This reduces the amount of 'free' toxin in the body, thus reducing its harmful effects on the body. There are two different ways in which toxins can bind to chemical agents.
The first is specific binding, where the antidote is specific to the toxin. For example, the antidotes for heavy metal poisoning are chelating agents. These agents can react with metal ions to form a stable, water-soluble substance, thus neutralising the effects of the toxin.
In addition, nonspecific binding can also occur. This is where the antidote is not specific to the toxin, but rather has properties that allow it to bind to many different poisons. For example, activated charcoal is often used as an antidote as it has a high adsorption capacity, so can bind to a large number of toxins, thus preventing them from being absorbed by the body.
Furthermore, antidotes can also work by acting on the toxin-binding site. According to a paper published in 2019, antidotes can affect the enzyme pathways. For instance, methanol poisoning is treated by a competitive inhibitor of alcohol dehydrogenase, thus reducing the concentration of toxic metabolites that are formed. Additionally, antidotes can also inhibit receptors, preventing the toxin from binding and affecting the body.
Antidotes can also help reduce the number of toxic metabolites in the bloodstream or help convert the metabolites into a less toxic form. For example, one of the antidotes for paracetamol poisoning restores glutathione stores in the liver, which helps the toxic metabolites of paracetamol get removed. Furthermore, antidotes can also counteract the harmful effects of the toxin in other ways.
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Sources:
Hagen, N. A., Cantin, L., Constant, J., Haller, T., Blaise, G., Ong-Lam, M., du Souich, P., Korz, W., & Lapointe, B. (2017). Tetrodotoxin for Moderate to Severe Cancer-Related Pain: A Multicentre, Randomized, Double-Blind, Placebo-Controlled, Parallel-Design Trial. Pain research & management, 2017, 7212713. https://doi.org/10.1155/2017/7212713
Chacko, B., & Peter, J. V. (2019). Antidotes in Poisoning. Indian journal of critical care medicine : peer-reviewed, official publication of Indian Society of Critical Care Medicine, 23(Suppl 4), S241–S249. https://doi.org/10.5005/jp-journals-10071-23310