Six drugs that all do the same thing
— and are chosen for everything else about them.

Onset and duration are measured at roughly twice the ED95 for every agent, so the columns can be read against each other. Duration is the time to recovery of the first twitch to a quarter of its control height.

Rocuronium is the fastest of the six because it is the least potent, for the reason lesson 1 sets out. Pancuronium is the outlier at the other end: long-acting, and essentially reserved now for cases where that is wanted. The four intermediate agents are separated less by duration than by what clears them, which is the next section.

A comparison table is the right shape for seeing how the agents differ. It is the wrong shape for knowing a drug — for that you need its presentation, how it is supplied, what it does on injection and what makes it the one you would choose. What follows is each agent on its own terms.

Rocuronium

A monoquaternary aminosteroid developed from vecuronium, differing from it at four positions. Presented as a colourless solution of 50 mg in 5 mL, and stored refrigerated. Its defining property is low potency — an ED95 of 0.3 mg/kg, six times that of vecuronium — and from that follows the fast onset that is the reason it exists. Its name is a contraction of “rapid onset curonium”.

• Dose and onset. At 0.6 mg/kg, intubating conditions are reached within about 100–120 seconds. Raising the dose to 0.9–1.2 mg/kg brings that down to about 60 seconds, which is what makes it the alternative to suxamethonium for rapid sequence induction.
• Duration. Similar to vecuronium at an ordinary dose, but higher doses lengthen it substantially — see the figure above.
• Kinetics. Under 5% is metabolised. It is excreted largely unchanged in bile, less in urine, with some de-acetylated metabolites. Duration is prolonged in both hepatic and renal impairment.
• Other effects. Minimal cardiovascular action; a modest rise in heart rate at the large doses used for rapid intubation. No histamine release, which is why it is preferred in asthma.
• Distinguishing feature. The only agent with a specific reversal drug that works at any depth of block.

Vecuronium

The monoquaternary analogue of pancuronium, and conventionally described as a “clean” drug: no cardiovascular effect, no histamine release. Presented as 10 mg of freeze-dried powder with mannitol and sodium hydroxide, reconstituted in 5 mL of water — it is unstable in solution, which is why it comes as a powder when almost everything else in the class comes as a liquid.

• Dose and onset. 0.1 mg/kg gives satisfactory intubating conditions in about 90–120 seconds.
• Kinetics. Hepatic de-acetylation to 3-hydroxy, 17-hydroxy and 3,17-dihydroxy metabolites. The 3-hydroxy metabolite has significant relaxant activity of its own, but a very short half-life, so it is of little consequence when renal function is normal. Being monoquaternary it is more lipid-soluble than pancuronium, and a far greater proportion leaves in bile.
• Distinguishing feature, and its catch. “Clean” cuts both ways: having no vagolytic action of its own, vecuronium leaves an opioid- or propofol-induced bradycardia entirely unopposed. It also accumulates during infusion, and carries the association with critical illness myopathy.

Pancuronium

A bisquaternary aminosteroid, presented as a colourless solution of 4 mg in 2 mL and stored at 4 °C. The long-acting agent of the class, and now largely displaced by the intermediates.

• Dose and onset. 0.1 mg/kg gives intubating conditions within about 90–150 seconds.
• Kinetics. About a third is metabolised by hepatic de-acetylation; 3-hydroxypancuronium is half as potent as the parent drug, which matters because the parent drug is itself eliminated mainly in urine. Accumulation in renal impairment is the practical consequence.
• Distinguishing feature. The only agent that reliably causes a tachycardia, by two mechanisms: blockade of cardiac muscarinic receptors, and an indirect sympathomimetic effect from inhibiting noradrenaline reuptake at postganglionic nerve endings.

Atracurium

A benzylisoquinolinium compound, and a mixture of ten stereoisomers arising from four chiral centres. Presented as a colourless solution of 10 mg/mL in 2.5, 5 and 25 mL vials, stored at 4 °C — the refrigeration is not incidental, since Hofmann elimination proceeds at room temperature.

• Dose and onset. 0.5 mg/kg gives intubating conditions within about 90–120 seconds.
• Kinetics. Two organ-independent routes, covered in the next section.
• Distinguishing feature. Elimination that needs neither liver nor kidney — and, as the price, direct non-immunologic histamine release, which is worse with rapid injection and with larger doses.

Cisatracurium

One of the ten stereoisomers present in atracurium, isolated. Presented as a colourless solution of 2 or 5 mg/mL, stored at 4 °C. Three to four times more potent than atracurium and, for that reason, slower in onset.

• Dose and onset. 0.15–0.2 mg/kg — three to four times ED95, where every other agent in the class is intubated at about twice. The higher multiple is deliberate: the onset penalty of high potency is offset by raising the dose, and the dose can be raised precisely because histamine release is negligible.
• Kinetics. Predominantly Hofmann elimination. Unlike atracurium it does not undergo direct hydrolysis by plasma esterases. None of its metabolites has neuromuscular blocking activity.
• Distinguishing feature. Used safely in children from two years and in the elderly with minimal alteration in kinetics, and with no change in profile in end-stage renal or hepatic disease. It is the agent for a prolonged infusion in a patient whose organs cannot be relied on.

Mivacurium

A benzylisoquinolinium ester, structurally similar to atracurium, and the only short-acting non-depolariser. Presented as an acidic aqueous solution, pH 3.5–5.0, at 2 mg/mL in 5 and 10 mL ampoules, with a shelf life of 18 months below 25 °C.

• Composition. A chiral mixture of three stereoisomers: 58% trans-trans, 36% cis-trans and 6% cis-cis. The cis-cis isomer has about a tenth of the potency of the other two, is not metabolised enzymatically, and has a half-life ten times theirs — so the small fraction is the slow fraction.
• Kinetics. The two active isomers are metabolised by plasma cholinesterase, at 70–90% of the rate at which it metabolises suxamethonium. Duration is significantly prolonged in end-stage liver disease, chiefly through reduced enzyme activity.
• Distinguishing feature, and the reversal trap. Routine reversal with neostigmine may not be needed, given how quickly it is metabolised — and neostigmine also inhibits plasma cholinesterase, so it can prevent the very metabolism that would have ended the block. Edrophonium, which does not, is the more suitable anticholinesterase here.
• The patient to avoid it in. Anyone with an atypical plasma cholinesterase variant. The same genotype that gives suxamethonium apnoea prolongs mivacurium.

Two things are worth reading off that table rather than memorising it. Every volume of distribution is small — 0.15 to 0.27 L/kg — because a permanently charged molecule stays in extracellular fluid; and the percentage metabolised separates the two chemical families completely, 90–95% for the benzylisoquinoliniums against under 30% for the aminosteroids, which is the same fact as organ-independence stated a different way.

Hofmann elimination is a spontaneous, non-enzymatic degradation that proceeds at physiological pH and temperature. It needs no organ, no enzyme and no transporter, which is what makes atracurium and cisatracurium the agents of choice when hepatic and renal function are both unreliable. It is slowed by acidosis and by hypothermia, and is essentially arrested at pH 4 and 4 °C — which is why the drug is stored in a refrigerator and why a warm ampoule left out loses potency.

Ester hydrolysis moves in the opposite direction with pH: acidic conditions accelerate it. In the clinical range the two effects partly offset one another, and pH changes within that range probably do not alter the rate of ester hydrolysis appreciably.

Laudanosine is the product both routes share, and it is worth being precise about. It is a tertiary amine with no neuromuscular blocking activity of its own; it is a glycine antagonist; and it causes seizures in animals at concentrations far above anything reached clinically.

The point that matters is a pharmacokinetic one: unlike its parent drug, laudanosine is cleared by the kidney. So in renal failure it is the metabolite, not the atracurium, that accumulates — which is a consideration for a prolonged infusion in intensive care and not for a single dose in theatre.

Critical illness myopathy is the other extra-junctional effect, and the one most easily forgotten because it appears days after the drug has gone. It follows prolonged infusion, is associated with the aminosteroids and with concurrent corticosteroids, and produces a recovery measured in weeks rather than hours. The mechanism is not established.

The typical intubating dose is twice the ED95. Maintenance is roughly a quarter of the intubating dose, or about a tenth of the ED95 given as an infusion rate, titrated to a monitored endpoint rather than to the clock.

Priming exploits the margin of safety. A subparalysing dose — about 20% of the ED95, which is the same as about 10% of the intubating dose — is given 2 to 4 minutes before the main dose. It occupies part of the receptor reserve without producing detectable weakness, so the main dose has less reserve to overcome and onset is accelerated by 30 to 60 seconds, allowing intubation at about 90 seconds.

Notice that the changes pull in two directions and must be handled separately. Onset is slower, because cardiac output and circulation time are lower; duration is longer, because hepatic and renal clearance are both reduced. Neither is a reason to change the mg/kg dose. Both are reasons to monitor rather than dose by the clock.

Every property in this lesson exists to answer a clinical question, and the properties are worth little until they are paired with the decision they govern. Read the comparison this way round:

1. Physicochemical → distribution. All are highly polar and permanently charged, so all are confined to extracellular fluid. That is why none has a central effect, why none crosses the placenta meaningfully, and why hypovolaemia raises the effective concentration of any of them.
2. Metabolism → choice in organ failure. The benzylisoquinoliniums are cleared in plasma, independently of liver and kidney; the aminosteroids are not. This single line decides the agent for a patient with failing organs.
3. Potency → dose → onset → duration. ED95 fixes the dose, the dose fixes the gradient, the gradient fixes the onset — and a larger dose lengthens the duration. Speed is bought, never free.
4. Chemistry → side effects. Benzylisoquinolinium means possible histamine release, so avoid in asthma and inject slowly. Aminosteroid means the association with critical illness myopathy on prolonged infusion.
5. Structure → reversibility. All are antagonised by an anticholinesterase. Only the aminosteroids are bound by sugammadex, because it is the steroid nucleus that fits its cavity.

Held that way, the table stops being six columns to memorise and becomes five chains of reasoning, each ending in something you would actually do.