Tox and Hound – Oh, the Nerve!

by Dan Rusyniak

OK, I am going to dive into this whole Russia controversy. Now before you go getting all political on me, I am not talking about the Muller probe. I am talking about the recent suspected poisoning of a former Russian Spy in England. While Russia has been the prime culprit of several other poisonings on British Soil (e.g., Ricin¹, Polonium², Gelsemium BuzzFeed) the recent attack was brazen (I just like saying that word) and dangerous not just for the intended victim but also for the public. It is also harder for Russia to deny it.

So, what happened?

On March 4th, a former Russian spy named Sergei Skripal and his daughter, Yulia, left their house in Salisbury, England (home of Joseph Fiennes) to go into town. I imagine Sergei was excited to see his daughter; she had arrived the previous day from Russia. She was one of Sergei’s few surviving family members. His wife had died six years early from cancer. His son died a year early from mysterious causes. His mother was dying in Russia and his brother had died two years before. I would imagine with all these family members dying, Sergei was a little paranoid. As it turns out, he had a right to be. So, when he left that afternoon for a lovely day with his daughter he no doubt would have made sure to lock his doors.

Why was Sergei right to be paranoid? Because he had betrayed Russia. This is a crime that Putin views as unforgivable. Sergei Skripal was a Russian Military officer who in the mid-1990’s started handing over secrets to the British government. Through this relationship, he outed over three hundred Russian spies throughout Europe. He was eventually caught, and in 2004 was thrown in a Russian prison. However, as part of a spy swap, he was released to England in 2010. No doubt that since that time, he has had a target on his back. It was his hands, however, he needed to be most careful of. That is because Russia would use a diabolical plot to try and kill a traitor – smearing an organophosphate gel on his doorknob (iNews). (Now, where have I heard of a political leader using an organophosphate to kill someone in broad daylight before? (USA Today).)

So, what is this Novichok agent that was used to try and kill Skripal? It is an organophosphate pesticide. The same type of compound farmers might spray on fruit trees or cotton to kill insects. It is also the same type of compound commonly called a nerve agent. It is similar to VX, Soman, and Sarin (to name a few). All of these compounds, whether dropped in bombs or sprayed on trees, work through a similar mechanism – they inhibit the enzyme acetylcholinesterase. And as it turns out you need this enzyme, because, left unchecked, acetylcholine causes big problems. As healthcare providers, we kind of know this already. Anyone who has ever experienced or seen a “vagal” episode got a whiff of the effects of excess acetylcholine. We call these vagal episodes because the vagus nerve releases acetylcholine. And, if overstimulated it causes dramatic lowering of the heart rate and blood pressure (also makes you sweat, causes tunnel vision or miosis, and creates the need to move your bowels). And keep in mind vagal episodes only last minutes. Imagine the chaos that ensues when acetylcholine is left unchecked for a long time.³

Clinical toxicity from organophosphates results from the overstimulation of two different acetylcholine receptors. The first is the muscarinic receptor. This causes the most recognizable features of organophosphorus poisoning. That is because all the juice makers in your body (e.g., sweat glands, salivary glands, GI glands, tear glands, etc.) make juice when muscarinic receptors are stimulated. This is the classic SLUDGE mnemonic or as Howard likes to say it is like squeezing out SpongeBob. And while nobody is going to salivate to death, it is hard to ignore a patient who is oozing from every orifice. The muscarinic effects that kill people are cardiopulmonary and neurologic. The cardiac effects are related to the vagal innervation of the heart. As I described above, this causes bradycardia and hypotension. The pulmonary symptoms are much worse. That is because not only do your lungs have glands that make fluid and mucous, but the bronchioles and the pulmonary vessels are innervated by muscarinic receptors.⁴ Overstimulated, you get increased pulmonary secretions, increased bronchospasm, and decreased blood flow – Yikes. Nothing like a toxin that makes you wheeze and drown. We kind of know this already though. You probably remember that one of the tests used to make the diagnosis of asthma is a methacholine challenge. What is methacholine but an acetylcholine-like molecule that stimulates muscarinic receptors? You also know the opposite of this in ipratropium bromide. Or what is better known as the other half of the duo neb (the Garfunkel to albuterol’s Simon – you’re humming Bridge over Troubled Water in your head now aren’t you?) What is ipratropium (Atrovent)? It is a muscarinic receptor blocker (antagonist). I bet you clever nerds already noticed that the word ipratropium looks like atropine. That is because atropine is also a muscarinic antagonist; that is why you give it to bradycardic patients.

The last muscarinic effect I will mention, although there are others, is neurologic. Along with all the muscarinic receptors in your body, you got lots in your brain. When you overstimulate these, you get altered mental status, coma, and seizures.⁵ Because most of the agents we are discussing are lipid soluble, seizures may be more prominent with the organophosphate weapons of war. That is because fat-soluble drugs penetrate the brain better, which is where seizures occur. Additionally, increased lipid solubility allows the nerve agents to be absorbed through the skin (more on that later). Wait, I forgot one more muscarinic effect: pupils. When stimulated, the muscarinic receptors in the eye cause miosis. That’s why ophthalmologists use pilocarpine (a muscarinic agonist) to treat glaucoma (big pupils raise the ocular pressure in glaucoma). And while having small pupils will not kill you (unless you are driving at night) it is an important physical exam sign. Very few things cause really small pupils. When you see a patient with small pupils remember COPS (Clonidine, Opioids/Organophosphates, Pilocarpine, Sedatives). The last clinical effects to talk about are mediated by the nicotinic receptors (as if the muscarinic effects aren’t bad enough). These receptors, like the muscarinic, are stimulated by acetylcholine. Where this causes problems is the autonomic ganglia and skeletal muscle. I won’t mention much about the ganglia as that would take way too long and, believe, me no one wants me to go into the whole autonomic ganglia (pre, post, parasympathetic, sympathetic, adrenal) story. Suffice it to stay that you get an increased release of adrenaline (epinephrine) when you stimulate autonomic ganglia. That’s not such a bad thing in organophosphate poisoning. It is also why people like nicotine (at small doses). The other effect of stimulating nicotinic receptors is not helpful – skeletal muscle paralysis. This is because acetylcholine to binds to nicotinic receptors at the neuromuscular junction causing muscle contraction. But wait. I thought you said you get paralysis? If acetylcholine stimulates muscle contraction, shouldn’t an organophosphate give me Hulk-like-strength? Nope, sorry. That’s because neuromuscular nicotinic receptors are weird. If you block them (like cisatracurium does) you get paralysis. But, if you overstimulate them (like succinylcholine does) you also get paralysis; this is why succinylcholine causes muscle contractions followed by paralysis (Hulk SMa…).

So, let me summarize: an organophosphorus nerve agent will cause you to drown, wheeze, and seize. It also makes you weak (paralyzed) and slow (bradycardic).

What agent did the Russians use? The reports are they used an organophosphate in a class called Novichok.^6,7 The Novichok agents were synthesized by Russia in the 1970s. They had two evil advantages. One is they were incredibly toxic – they are 10 times more toxic than Sarin and 5-8 times more toxic than VX. The other is that they are binary agents. What that means is Novichok consists of two chemicals that are not toxic but when mixed together they create a potent organophosphorus compound. This has two benefits (again if you are evil). One is it means you can make the separate agents and not violate international treaties on making chemical weapons. The other is that it makes it safer to transport to, say, another country to kill someone.^8,9 But once formed, these organophosphorus agents are really toxic. That means when your victim comes into contact with the Novichok agent they are also going to get sick fast. So, if you say put the agent on the doorknob of the person you want to kill, you may not have time to get to the airport and get out of town, to say Russia, before the cops are onto you. This is where again the Russians were clever. They created a weaker and slower absorbed gel form of the Novichok. So that when touched, it would take time before the victim got sick. This would give those who committed the crime time to escape. That’s why Skripal had been out for several hours before he and his daughter got sick; it was about 3-4 hours after they left their home before being found unconscious on a park bench. Enough time, as it would turn out, for the perpetrators (a bad doctor and a colonel) to escape (The Sun).

One other possible advantage of the Novichok agents is that only Russia has them. Therefore, no one could detect it. This is where the Russians went wrong. Because if James Bond movies have taught me anything, it is that the Brits are good at gadgets and detection. This is why, once it was known that the agent was a Novichok, the British were able to boldly exclaim that either the Russians were behind the attack, or someone had gotten into Russia’s stockpile of nerve agents. The other big problem is that other people, besides the intended target, were exposed. This included a detective who got sick after responding to the scene where Sergei and his daughter were found. It includes the shopkeepers and others who interacted with Sergei and Yulia while they were absorbing the poison. It is thought that up to 130 people were exposed (The Guardian). And more recently two unwitting pedestrians. Four months after the original attack, a couple out on a walk found a discarded perfume bottle. Being a gentleman, the boyfriend gave it to his girlfriend who put it on and four hours later both were unconscious. She would later go on to die.

So, let’s just process this whole event. A Russian military officer becomes a spy. He gets caught and is sent to Britain as part of a prisoner swap. Years later Putin’s government sends two men on a plane with the ingredients for one of the deadliest nerve agents known to man. They assemble them in a modified perfume bottle and spray it on the doorknob of the former Russian spy causing a series of events that results in multiple people ending up in the ICU and killing one person who was not even the target.

Wow, they have some nerve!

Doorknob by Clem Onojeghuo