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Sarin - A Whiff of Death

In the wee hours of 4th April, 2017, 83 innocent people died during an air strike in the war torn nation of Syria. The civil war is by far the deadliest conflict of this century. Thousands have died and millions have been displaced from their homes. And though there is no definitive scale to measure the pain and suffering, the attack on 4th April was reported to be the most inhumane of them all. Post mortem examination found traces of Sarin – a colourless, odourless gas as the cause of death. Civilians who inhaled this poisonous gas suffered an almost instant, painless, suffocating death, without any external marks of violence, making it the perfect crime.

So what makes Sarin one of the most toxic chemical weapons?

It is easier to understand the toxicity of this compound if we know the normal physiological mechanisms of neuromuscular transmission.

All skeletal muscle fibers are innervated by myelinated nerves. The nerve endings contain acetylcholine – the major neurotransmitter which enables muscle contraction. The process of skeletal muscle contraction is a result of meticulously orchestrated events occurring at the neuromuscular junction (NMJ).

The nerve ending has numerous voltage gated Calcium channels. When an electrical impulse from the spinal cord reaches the nerve endings, a change in the voltage opens the calcium channels. Calcium ions from the junction enter the nerve endings and aid the release of acetylcholine from the nerve terminal into the NMJ.

The muscle fibers have acetylcholine gated ion channels. Acetylcholine binds to it’s receptors and opens up these channels. At the resting state, the muscle fibers have a net negative resting membrane potential of -80 to -90 millivolts. Hence when the ion channels open, the postitively charged Na+ ions present in the NMJ move into the muscle fibre, depolarises it and produce a positive potential known as the End plate potential. If the strength of the end plate potential is more than the threshold, an action potential is generated and the muscle contracts.

 
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Hypothetically, if electrical impulses in the nerve reach the NMJ one after the other in rapid succession, a state of fatigue is reached when all the acetylcholine in the nerve ending is depleted and no more is available to contract the muscle. In reality such a state of muscle exhaustion rarely occurs voluntarily. However the same principle is exploited by a group of pharmacological agents, without which the field of general surgery is practically unimaginable. They are the skeletal muscle relaxants.

Succinylcholine is a depolarising muscle relaxant. Having a similar structure, it mimics the action of acetylcholine when injected intravenously. It depolarises the muscle in rapid succession to such an extent that the muscle cannot contract anymore creating a state of muscle relaxation. On the other hand, curare group of drugs such as d-tubocurare and atracurium block the acetylcholine receptors and prevent acetylcholine from binding to the receptors. This kind of muscle relaxation is known as non depolarising muscle relaxation.

Like every other drug or chemical mediator in the body, acetylcholine is also degraded and rendered inactive. Once acetylcholine is released into the NMJ, its action lasts only for a few milliseconds as it is rapidly metabolised by the enzyme acetylcholinesterase. Inhibitors of this enzyme increase the cumulative concentration of acetylcholine in the NMJ with every electrical impulse. The excess acetylcholine stimulates the muscle fibers repetitively and leads to muscle spasm.

This is the mechanism of toxicity of Sarin – an organophosphorous compound (OPC). OPC is a major constituent of pesticides and chemical weapons. Once inhaled, the excess acetylcholine causes spasm of laryngeal muscles leading to suffocation and death.

And that's how a small whiff can prove to be so deadly!

Author: Soundarya V (Facebook)

Sources and citations

Katzung, Bertram G, et al. Chapter - 27: Skeletal Muscle Relaxants. Basic and Clinical Pharmacology, 12th ed., McGraw Hill - Lange, pp. 467-471.

Guyton, Arthur C. Chapter - 7 : Excitation of Skeletal Muscle: Neuromuscular Transmission and Excitation - Contraction Coupling. Guyton and Hall Textbook of Medical Physiology, edited by John E. Hall, 12th ed., Elsevier, pp. 83-86.