VX nerve agent,  which has been in the news lately with the killing of Kim Jong-nam, is another example of an organophosphate anticholinesterase.

The newspapers and other media have recently reported that it was the VX nerve agent that was used to kill Kim Jong-nam, the half-brother of North Korea’s leader, in Malaysia. VX nerve agent is an example of an organophosphate anticholinesterase. Other examples of organophosphate anticholinesterases include the chemical weapon sarin and the organophosphate insecticides such as a malathion.

VX (S-2 Diisoprophylaminoethyl methylphosphonothiolate) is one of the most toxic nerve agent known. It is especially insidious as it is a highly viscous, tasteless and odourless liquid that can easily be transferred via clothing to be absorbed into the body by inhalation, ingestion, skin contact, or eye contact.

Although more potent and fast-acting, the effects of VX poisoning would be the same as for any organophosphate anticholinesterase. Inhibition of acetylcholinesterase will result in increased levels of acetylcholine at all cholinergic synapses in the body.

In the parasympathetic nervous system, there will be a potent parasympathomimetic effect resulting in bradycardia (M2 receptors), bronchoconstriction and increased secretions in airways (M3 receptors), salivation (M3 receptors), lacrimation (M3 receptors), miosis, blurred vision (especially far vision), diarrhoea, abdominal cramps, nausea and urinary incontinence.

In the sympathetic nervous system, there will be increased acetylcholine at the cholinergic innervation of the eccrine sweat glands resulting in sweating (M3 receptors).

In the central nervous system, there will be increased cholinergic activation of both muscarinic and nicotinic receptors resulting in nausea and vomiting (M1 receptors), confusion, ataxia, slurred speech, generalised convulsions and coma.

At the neuromuscular junctions (NMJs), increased availability of acetylcholine would initially result in skeletal muscle twitching and fasciculations due to activation of nicotinic receptors. However, this would very soon be replaced by depolarising block and subsequently block due to desensitisation of the nicotinic receptors resulting in weakness and flaccid paralysis.

As VX is an organophosphate anticholinesterase, could Kim Jong-nam have been saved by administration of atropine and pralidoxime?

If the medical team attending had known that it was organophosphate anticholinesterase poisoning then, possibly, yes.

Atropine is a muscarinic receptor antagonist. It can block the parasympathomimetic (e.g. bradycardia, bronchoconstriction, salivation etc.) and CNS musarinic receptor-mediated effects (e.g. nausea and vomiting) of anticholinesterase poisoning.

Pralidoxime is an acetylcholinesterase regenerator. Organophosphates are suicide inhibitors of the acetylcholinesterase. The organophosphate molecule binds to the acetylcholinesterase and is destroyed leaving a phosphate group bound to the enzyme blocking its activity. Pralidoxime binds to the acetylcholinesterase reversible and has higher affinity for the phosphate group than the enzyme and so pulls the phosphate group off the enzyme, reactivating the enzyme. This process can work only if its organophosphate poisoning and only if pralidoxime is given before “ageing” of the organophosphate inhibited enzyme.

But the atropine is itself a poison and pralidoxime is itself a weak anticholinesterase.  These drugs would themselves have caused more harm than good if it was not anticholinesterase poisoning in the case of administration of atropine or specifically organophosphate anticholinesterase poisoning in the case of administration of pralidoxime. It would have been difficult for the medical team attending on the spot to have known at the time that it was a case of organophosphate poisoning.  Moreover, the onset of the actions of agent VX is extremely rapid. If treatment was to have been administered, it would have had to be administered very quickly.

 

Update 4 October 2017:

Recent news reports on the trial of Siti Aisyah and  Đoàn Thị Hương charged with the murder of Kim Jong-nam have revealed more details of the medical presentation and treatment.  It is reported that Kim Jong-nam was treated at the airport clinic where he presented sweating profusely, with bloodshot eyes, clutching his head and apparently in pain. His face was red and he had miosis (constricted pinpoint pupils).   He had a mixture of saliva, blood and vomit in his mouth. He had very low blood pressure, heart rate and oxygen levels. As discussed above, the sweating, miosis, salivation, vomiting, bradycardia and low oxygen levels are consistent with organophosphate poisoning. The attending medical team astutely administered atropine and also adrenaline to combat his low blood pressure, heart rate and oxygen levels.