The drug that works
by never letting go.

• Structure: two acetylcholine molecules joined through their acetyl groups. It is an agonist, not an antagonist.
• Dose: 1 mg/kg for tracheal intubation in adults, roughly three times its ED95 of 0.3 mg/kg. Complete suppression in about 60 seconds.
• Offset: hydrolysis by plasma cholinesterase — which is not present at the junction. Recovery is by diffusion away from the junction down a reversed gradient.
• Phase I block is the normal depolarising block. Phase II develops with repeated or large doses and looks non-depolarising on a monitor.
• Prolonged block follows reduced enzyme activity, genetic or acquired. The dibucaine number reports genotype, not enzyme quantity.
• Adverse effects divide into those from depolarisation (hyperkalaemia, arrhythmias) and those from fasciculation (myalgia, raised intraocular, intracranial and intragastric pressure).

Suxamethonium binds the nicotinic acetylcholine receptor and opens the channel exactly as acetylcholine does. Sodium enters, the end-plate depolarises, and if enough receptors are activated together a muscle action potential propagates — which is the fasciculation seen clinically. So far this is transmission, not block.

The difference is what happens next, and it is the whole drug. Acetylcholine is hydrolysed within milliseconds by acetylcholinesterase sitting in the junctional cleft. Suxamethonium is not: its hydrolysing enzyme, plasma cholinesterase, is in plasma and liver, and none is present at the junction. The drug therefore remains bound and the end-plate stays depolarised. Persistent depolarisation drives the voltage-gated sodium channels in the perijunctional membrane into inactivation, and a zone of electrical inexcitability a millimetre or two wide surrounds the end-plate. No further action potential can cross it, and the muscle relaxes.

A phase I block is the block produced by a single ordinary dose. Its signature on a nerve stimulator is the opposite of a non-depolarising block on almost every count, and each difference traces back to the same fact: an agonist is occupying the receptor, not competing for it.

Two of those rows carry reasoning worth setting out properly.

Why there is no fade

Fade is a presynaptic phenomenon. Sustained high-frequency stimulation depends on a positive-feedback loop: acetylcholine acts on presynaptic nicotinic receptors to mobilise more transmitter from the reserve pool. A non-depolariser blocks those presynaptic receptors as well as the postjunctional ones, the loop fails, release cannot keep pace, and successive responses decline. Suxamethonium does not block them, so a phase I block reduces every twitch equally and fades none of them.

Why an anticholinesterase makes a phase I block worse

This is the one that reads backwards, because the same drug that reverses a non-depolarising block deepens a depolarising one. The resolution is to ask what acetylcholine is doing in each case.

In a non-depolarising block the problem is competition: an antagonist is occupying sites acetylcholine needs. Inhibiting acetylcholinesterase raises junctional acetylcholine, which shifts that competition back in acetylcholine’s favour and displaces the antagonist. The block lifts.

In a phase I block the problem is the opposite: an agonist is already there, holding the end-plate depolarised and the perijunctional sodium channels inactivated. Adding more agonist to a junction whose difficulty is too much agonist action does not relieve anything — it sustains the depolarisation and deepens the block.

A second, entirely separate mechanism compounds it. Neostigmine inhibits plasma cholinesterase as well as acetylcholinesterase — and plasma cholinesterase is the enzyme that clears suxamethonium. So the suxamethonium itself is metabolised more slowly and stays longer. One effect is pharmacodynamic, at the receptor; the other is pharmacokinetic, in the plasma. They point the same way.

The practical consequence: an anticholinesterase is not a way out of a suxamethonium block. If a block is prolonged, the management is to sedate and ventilate until it resolves — which is the same answer arrived at in section 06 from the other direction.

With repeated doses, an infusion, or a large single dose, the character of the block changes. Fade appears on the train-of-four, tetanic stimulation fades, post-tetanic facilitation appears, and an anticholinesterase now antagonises rather than augments. That is a phase II block: a depolarising drug producing the monitored picture of a non-depolarising one.

The obvious question is how an agonist comes to produce fade, when fade is the signature of competitive antagonism. The answer is that a phase II block is not one mechanism but several running together, and no single one of them accounts for the whole picture.

Why a second dose produces fade

1 · Presynaptic receptor block. This is the main contributor. The nerve terminal carries its own prejunctional nicotinic receptors, and they are the ones responsible for mobilising transmitter from the reserve pool during repetitive demand — the positive-feedback loop that makes a sustained train possible. At ordinary concentrations suxamethonium does not interfere with them. At the higher-than-usual concentrations produced by a second dose or an infusion it blocks them, the feedback loop fails, release cannot keep pace with the stimulus, and successive responses decline. That is fade, arrived at from the presynaptic side rather than by competition at the postjunctional receptor.

2 · Desensitisation of postjunctional receptors. A receptor can bind an agonist with great avidity and yet not open its channel; in that state it is desensitised. Receptors shift between resting and desensitised states continuously, with or without a drug present, but an agonist promotes the shift and — because it binds desensitised receptors tightly — can trap them there. A desensitised receptor is a channel removed from the pool available to carry end-plate current, so as their number grows, transmission weakens.

3 · Channel block. Suxamethonium is a slender molecule, and having opened a channel it can also enter and plug it. This is covered in the next subsection, because it behaves quite unlike competition at the binding site.

4 · Ionic disturbance at the junction. Channels that keep reopening allow a continuous efflux of potassium and influx of sodium, and the resulting electrolyte imbalance distorts the function of the junctional membrane itself. Calcium entering through those open channels can disrupt the receptors and the sub-end-plate structures. The sodium–potassium ATPase works harder as intracellular sodium rises, pushing the membrane potential back toward normal — but as long as the drug is present the channels keep opening and the flux continues.

What determines whether a phase II block develops is correspondingly untidy: the duration of exposure, the drug and its concentration, the type of muscle being measured — fast-twitch and slow-twitch behave differently — and interactions with the anaesthetic agents running alongside it. No single threshold dose is stated in the sources used for this lesson, and none is given here.

Channel block, and why it matters for reversal

A drug can obstruct the ion channel itself rather than compete for the acetylcholine recognition site, and there are two ways to do it. In a closed-channel block the molecule sits in the mouth of the channel and prevents ions passing — which it can do whether or not the channel is open. In an open-channel block the molecule enters a channel that acetylcholine has already opened and lodges part-way through. The second is use-dependent: a molecule can only enter while the channel is open, so the more the channel is used, the more block accumulates.

The consequence is the one that matters clinically. Because the action is not at the acetylcholine recognition site, channel block is not competitive antagonism and is not relieved by raising acetylcholine. Worse than merely useless, raising acetylcholine makes channels open more often and therefore moresusceptible to a use-dependent blocker — and there is evidence that neostigmine itself can act as a channel-blocking drug.

So the management of a prolonged block, whatever its phase, is the same: sedate and ventilate, monitor recovery objectively, and let it resolve.

Plasma cholinesterase — also called butyrylcholinesterase or pseudocholinesterase — is synthesised in the liver and circulates in plasma. It hydrolyses suxamethonium to succinylmonocholine, which is weakly active, and then more slowly to succinic acid and choline. Under 10% of a dose is excreted unchanged in urine. The elimination half-life of the parent drug is about 47 seconds.

Because hydrolysis happens in plasma and not at the junction, only a fraction of an injected dose ever arrives. The sources differ on the fraction — Peck gives 20%, Stoelting 10% — and the number is not the point. The point is the consequence: the rate of plasma hydrolysis, rather than anything happening at the junction, sets the duration of block, and anything that lowers enzyme activity lengthens it.

Three esterases, and which drug belongs to which

“Esterase” covers three distinct enzymes in anaesthetic practice, and attributing a drug to the wrong one leads directly to the wrong prediction about which patients it behaves oddly in.

Two consequences are worth drawing out. A patient with an atypical plasma cholinesterase variant has a prolonged block with both suxamethonium and mivacurium, because both depend on the same enzyme — but behaves entirely normally with atracurium, remifentanil and amide local anaesthetics, which do not. And plasma cholinesterase hydrolyses ester local anaesthetics only; the amides are cleared hepatically, which is why the two classes behave differently in liver disease.

Four alleles at a single locus on chromosome 3 produce the ten recognised genotypes: usual, atypical (dibucaine-resistant), silent (no enzyme activity) and fluoride-resistant. The great majority of people are homozygous for the usual gene and metabolise suxamethonium normally.

Dibucaine is an amide local anaesthetic that inhibits normal plasma cholinesterase far more effectively than it inhibits the variant enzymes. The percentage of enzyme it inhibits under standard conditions is the dibucaine number.

Fluoride-resistant variants exist alongside the dibucaine-resistant ones and are tested the same way, with a different inhibitor: the fluoride number is about 60 in the usual genotype and about 36 in the homozygous fluoride-resistant one.

Rarer still are variants associated with increased enzyme activity, in which resistance to suxamethonium and mivacurium has been described — the same axis, running the other way.

The list is long, but it is not arbitrary. Every effect below follows either from the sustained depolarisation itself or from the fasciculation that precedes it, so splitting it by mechanism turns a list to be memorised into two short chains to be reasoned through.

Malignant hyperthermia is a rare inherited disorder of skeletal muscle, autosomal dominant, with a reported incidence in the region of 1 in 50,000 to 70,000 anaesthetics. The abnormality is in the ryanodine receptor — specifically the RYR1 isoform of skeletal muscle, encoded on chromosome 19 — which functions as the calcium release channel of the sarcoplasmic reticulum. An abnormal receptor allows uncontrolled calcium release into the cytoplasm, producing sustained muscle rigidity and a very high rate of ATP consumption, with the heat, carbon dioxide and lactate that follow. Cell breakdown gives myoglobinaemia and hyperkalaemia.

Suxamethonium is a trigger, along with the volatile anaesthetic agents. Masseter spasm after suxamethonium may be the first sign.

Suxamethonium is unusual in that almost everything about it can be derived from a single sentence: it is an agonist whose clearing enzyme is not at the junction. Work outwards from that and the rest assembles itself.

1. It binds and opens the channel, so the muscle fires before it relaxes — hence fasciculation, and hence myalgia, raised intraocular pressure and raised intragastric pressure, which are all mechanical consequences of muscles contracting out of step.
2. The depolarisation is sustained, because plasma cholinesterase is nowhere near the cleft. Sodium channels around the end-plate inactivate, and the block follows.
3. Sustained depolarisation moves potassium out of cells — a small rise normally, a dangerous one wherever extrajunctional receptors have proliferated: burns, denervation, prolonged immobility, progressive muscle disease.
4. It is structurally two acetylcholines, so it stimulates muscarinic receptors too — bradycardia and junctional rhythms, worse on a second dose.
5. Duration is set by plasma hydrolysis, not by anything at the junction.So anything that lowers enzyme activity, genetic or acquired, lengthens the block — and nothing about the junction itself is abnormal in those patients.

Two results run against the intuition the chain sets up, and both are worth holding separately: aspiration risk is not increased, because barrier pressure is preserved; and the intubating dose is not reduced in the elderly, because it is duration rather than dose requirement that changes with age.