NMJ – PharmaNUS

Category: NMJ

Ganglionic blockers versus depolarising NMBAs

May 5, 2021 / phcdgs / 0 Comments

High-dose nicotine induces depolarising blockade and subsequent secondary non-depolarising blockade at autonomic ganglia. Meanwhile, depolarising NMBAs induce depolarising block consisting of Phase I and Phase II. Is it the same thing?

Yes, they are essentially the same mechanisms as far as the nicotinic receptors go. It is primarily a difference in terminology. Although secondary non-depolarising block is a more scientifically descriptive term than Phase II, the depolarising NMBAs are already called “depolarising” to contrast with the non-depolarising NMBAs (direct nicotinic receptor antagonists). It would therefore be confusing to say that depolarising NMBAs have a secondary non-depolarising block. Hence, the common usage of the Phase I and Phase II terminology.

Depolarising versus non-depolarising NMBAs

May 5, 2021 / phcdgs / 0 Comments

What is the difference between a depolarising and a non-depolarising NMBA? Do both result in flaccid paralysis?

Depolarising neuromuscular blocking agents (NMBAs) are potent agonists at nicotinic receptors that cause depolarising block (and necessarily also the secondary desensitising/non-depolarising block). In contrast, non-depolarising NMBAs are direct competitive nicotinic receptor antagonists.

An important difference is that non-depolarising NMBAs can be reversed by increasing acetylcholine (ACh) levels by using an acetylcholinesterase inhibitor such as neostigmine. Depolarising NMBAs cannot be reversed in the same way since increasing ACh availability just causes more depolarizing block (and inevitably secondary desensitising/non-depolarising block).

As depolarising NMBAs initially cause activation, they will cause twitching/fasciculation followed by rigid paralysis on onset (although this phase is over quickly) before switching to flaccid paralysis. In contrast, non-depolarising NMBAs will go straight to progressive flaccid paralysis.

How long is the window before ageing of acetylcholinesterase after organophosphate poisoning?

Organophosphates essentially irreversibly inhibit acetylcholinesterase by leaving a phosphate group bound to the enzyme. Oximes, such as pralidoxime, reversibly bind to acetylcholinesterase and have high affinity for binding to phosphate groups. They can, therefore, bind to acetylcholinesterase, pick up the phosphate group inhibiting the acetylcholinesterase, and take the phosphate group with them when they leave the acetylcholinesterase. Thus pralidoxime can be used to regenerate acetylcholinesterase after organophosphate poisoning.

A limitation of pralidoxime is that it is only effective in a limited time window before ageing of the organophosphate inhibition of acetylcholinesterase occurs. Pralidoxime itself binds to and competitively inhibits acetylcholinesterase. Therefore, if pralidoxime is administered after all the organophosphate-inhibited acetylcholinesterase has already aged, pralidoxime will just make the anticholinesterase poisoning worse. It is therefore important to administer pralidoxime in the appropriate time window.

Why does it matter that neostigmine is resistant to hydration or hydrolysis?

March 2, 2017 / phcdgs / 0 Comments

Why do we say that neostigmine inhibition of acetylcholinesterase is resistant to hydration or hydrolysis? Why do some textbooks say resistant to hydration, while others say resistant to hydrolysis? Are hydration and hydrolysis the same thing?

Neostigmine is an example of a carbamate anticholinesterase. It inhibits the breakdown of acetylcholine by acetylcholinesterase and so increases the availability of synaptic acetylcholine wherever it is release. Clinically it is used to reverse non-depolarizing neuromuscular blockade (e.g. coming out of surgical anaesthesia) and in the treatment of myasthenia gravis. It is also sometimes used to increase gastrointestinal motility on postoperative or neurogenic ileus and in the treatment of urinary retention secondary to bladder atony.

Acetylcholinesterase works by rapidly hydrolyzing acetylcholine (which is an ester of acetic acid and choline) to acetic acid and choline. Carbamate esters competitively inhibit acetylcholinesterase by occupying the active site on the enzyme and taking much longer to be hydrolyzed. They work by forming a carbamoylated acetylcholinesterase-drug complex that is resistant to hydration and hence is resistant to hydrolysis.

Hydration and hydrolysis are not the same thing. Hydration is the addition of water (H₂O) whereas hydrolysis is the breaking of a bond by reaction with water. However, in the case of the carbamoyl group attached to acetylcholinesterase the hydrolysis is a two-step process: first requiring hydration (addition of the water) before hydrolysis (breaking of the bond between the carbamoyl group and the acetylcholinesterase). Hence, for the carbamate anticholinesterase inhibition of acetylcholinesterase, the resistance to hydrolysis is a consequence of resistance to hydration.

Why is succinylcholine considered an “indirect” anticholinergic?

February 25, 2017 / phcdgs / 0 Comments

Succinylcholine is a direct nicotinic receptor agonist but is used clinically as an indirect anticholinergic.

Succinylcholine (suxamethonium) is a highly potent agonist at the neuromuscular junction (NMJ) nicotinic acetylcholine receptors. It is a direct cholinergic agonist in that it binds to the same binding site as the endogenous transmitter acetylcholine and activates the receptor in the same manner as acetylcholine. In contrast, non-depolarising neuromuscular blocking agents (NMBAs), such as pancuronium, are direct antagonists at NMJ nicotinic acetylcholine receptors. NMBAs are direct anticholinergics and can be used to produce paralysis when required under surgical anaesthesia.

In the context of autonomic pharmacology, indirect agonist effects are any effects mimicking the effect of the endogenous transmitter and other direct agonists not caused by direct agonism at the receptor. Conversely, indirect antagonist effects are any effects mimicking the effect of direct antagonists not caused by direct antagonism at the receptor.

Although it is a direct agonist of nicotinic acetylcholine receptors, clinically succinylcholine is used as an indirect anticholinergic to block the action of nicotinic acetylcholine receptors at the NMJ causing paralysis when required under surgical anaesthesia. The paralysis is caused because succinylcholine activates the nicotinic acetylcholine receptors so intensely that depolarising block occurs (Phase I) followed by desensitising block (Phase II). The clinically desired paralysis mimics the direct anticholinergic effect of the NMBAs but is produced indirectly via the depolarising block and desensitising block secondary to direct agonism at the receptor. Therefore, succinylcholine is an indirect anticholinergic.

VX Nerve Agent

February 24, 2017 / phcdgs / 0 Comments

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.