Atracurium, cisatracurium and mivacurium

Overview

Atracurium, cisatracurium and mivacurium are the three benzylisoquinolinium non-depolarising neuromuscular blockers in contemporary anaesthetic use. They are structurally a single chemical family — built on two linked isoquinoline rings — and are pharmacologically distinct from the aminosteroid non-depolarisers (rocuronium, vecuronium, pancuronium). Together they span the modern non-depolarising spectrum from a short-acting agent (mivacurium) to two intermediate agents defined by organ-independent elimination (atracurium and cisatracurium).[1]

The family is held together by four ideas that examiners return to repeatedly. First, all three are competitive antagonists at the postsynaptic nicotinic receptor and produce flaccid paralysis without depolarisation. Second, atracurium and cisatracurium are defined by organ-independent elimination (Hofmann elimination plus ester hydrolysis), which is why they are preferred in hepatic and renal failure and for prolonged intensive-care infusion. Third, the family shares a characteristic adverse-effect cluster — histamine release (atracurium, mivacurium) and the laudanosine metabolite — that cisatracurium was specifically designed to avoid. Fourth, none of the three is reversed by sugammadex, which sets the whole family apart from rocuronium and vecuronium.[1][3]

Mechanism

All three benzylisoquinolines are competitive antagonists at the postsynaptic nicotinic (muscle-type, N_M) acetylcholine receptor at the neuromuscular junction. They bind the receptor without activating it, so acetylcholine is displaced and unable to gain access; there is no receptor activation, no depolarisation and no fasciculation, and the resulting paralysis is flaccid. This is the defining pharmacological distinction from suxamethonium, a depolarising agent that first activates the receptor (producing fasciculation) and then keeps it depolarised.[1]

Because the block is competitive, it can be overcome by raising the concentration of acetylcholine at the junction — the basis of reversal with an anticholinesterase such as neostigmine. It cannot, however, be overcome by sugammadex, which selectively encapsulates the aminosteroids and has no affinity for the benzylisoquinoline structure.[1] On a train-of-four stimulus the block shows the classic non-depolarising pattern of fade — the fourth twitch smaller than the first — and it can be potentiated by aminoglycosides and other drugs that reduce acetylcholine release, a property shared across the ligand class at the nicotinic receptor.[5]

Organ-independent elimination

The defining pharmacokinetic feature of atracurium and cisatracurium is that their elimination is independent of the liver and kidney. Removal from the plasma occurs by two complementary pathways that do not require either organ.[1]

The first is Hofmann elimination, a non-enzymatic spontaneous degradation in which the molecule fragments at physiological pH and temperature. It is a chemical property of the molecule rather than an enzyme-mediated process, and it is accelerated by alkalosis and warmth and slowed by acidosis and hypothermia. The fragment that results is laudanosine (see below). The second is ester hydrolysis by non-specific plasma esterases (not butyrylcholinesterase), which cleave the ester bonds of the parent molecule independently of hepatic or renal function.[1]

The clinical consequence is the central exam point: because elimination does not depend on hepatic metabolism or renal excretion, atracurium and cisatracurium are the non-depolarisers of choice in hepatic failure, renal failure, and for prolonged infusion in the intensive-care unit, where accumulation of an organ-dependent agent would otherwise be a major concern. Their duration is largely predictable in organ failure, which is not true of the aminosteroids.[1][3]

Laudanosine

Laudanosine is a tertiary amine metabolite generated by Hofmann elimination of both atracurium and cisatracurium. It is pharmacologically active at the central nervous system: it crosses the blood-brain barrier and, in sufficiently high concentrations, produces cerebral excitation and seizures. This is the principal long-term concern of the family, and it is the reason atracurium is no longer the first-choice infusion relaxant for truly prolonged intensive-care paralysis.[1]

Laudanosine accumulates in three situations: in renal failure, because the kidney contributes to laudanosine clearance even though the parent drug is organ-independently eliminated; in the elderly, in whom clearance is reduced; and with prolonged high-dose infusion, particularly of atracurium. The relevance of laudanosine is correspondingly lower for cisatracurium, because cisatracurium is the more potent stereoisomer and a lower dose produces the same block and therefore less laudanosine for an equivalent clinical effect.[2][1]

Histamine release

Atracurium and mivacurium cause dose-dependent histamine release from mast cells on rapid bolus injection. The clinical picture is the familiar histamine syndrome — flushing, hypotension, tachycardia and bronchospasm — and it is dose-related and injection-rate-dependent; slowing the injection and dividing the dose reduce it. It is a particular concern in cardiovascular instability and in asthma, where histamine-mediated bronchospasm or hypotension may be poorly tolerated.[1]

Cisatracurium is the exception. It is a stereoisomer of atracurium — specifically the 1R-cis, 1R-prime-cis isomer — and this stereochemistry confers negligible histamine release at clinically used doses. This single property, combined with its greater potency (lower laudanosine burden), is the basis of cisatracurium's displacement of atracurium from cardiac and intensive-care practice.[3][6]

Atracurium

Atracurium is an intermediate-onset, intermediate-duration benzylisoquinoline. Onset of intubating conditions is about 2 to 3 minutes and clinical duration is roughly 30 to 45 minutes at a standard intubating dose. Its elimination is the organ-independent combination of Hofmann elimination and ester hydrolysis described above, so its duration is predictable in hepatic and renal failure and it does not accumulate in organ failure in the way the aminosteroids can.[1]

Its disadvantages are exactly the two family traits discussed above: it releases histamine on rapid bolus (with the attendant hypotension and bronchospasm risk) and it generates laudanosine, which accumulates in renal failure, the elderly and prolonged infusion. Atracurium was historically the mainstay of intensive-care paralysis and of balanced anaesthesia in organ failure, and it retains a place where a cheap, organ-independent intermediate relaxant is wanted. In most centres, however, it has been superseded for cardiac and prolonged intensive-care use by cisatracurium, and for routine intubation by rocuronium.[1][3]

Cisatracurium

Cisatracurium is the 1R-cis, 1R-prime-cis stereoisomer of atracurium, and it is the benzylisoquinoline of choice for cardiac surgery and modern intensive-care paralysis. It retains the organ-independent elimination of atracurium (Hofmann elimination plus ester hydrolysis) so it remains predictable in hepatic and renal failure, but it differs in two decisive ways. First, it has negligible histamine release at clinical doses, which makes it haemodynamically stable even on rapid bolus — the property that established it in cardiac anaesthesia, where histamine-mediated vasodilation and bronchospasm must be avoided.[3] Second, it is roughly three to four times more potent than atracurium, so a lower dose produces the same block and generates less laudanosine, further reducing the cerebral-excitation concern.[1]

Onset is slightly slower than atracurium (a consequence of higher potency, which generally trades onset for potency among non-depolarisers) and duration is intermediate. The principal modern use is prolonged infusion for paralysis in the intensive-care unit and for muscle relaxation in cardiac surgery, where cardiovascular stability and organ-independent elimination are both decisive. Comparative work in cardiac populations and in balanced anaesthesia supports its use as a haemodynamically stable, organ-independent alternative to the aminosteroids.[3][6]

Mivacurium

Mivacurium is the shortest-acting non-depolarising neuromuscular blocker in clinical use. Onset is about 2 to 3 minutes and clinical duration is roughly 15 to 20 minutes — substantially shorter than the intermediate agents. Its defining pharmacokinetic feature is its route of elimination: mivacurium is hydrolysed by plasma butyrylcholinesterase (also called pseudocholinesterase or plasma cholinesterase) — the same enzyme that metabolises suxamethonium. Hydrolysis by this enzyme is rapid, which is the basis of mivacurium's short duration.[4]

The direct consequence is that mivacurium is prolonged in butyrylcholinesterase deficiency, whether inherited or acquired. Inherited deficiency is produced by a spectrum of genotype-phenotype variants at the butyrylcholinesterase gene, and even heterozygous individuals can show a markedly prolonged block; acquired deficiency occurs in liver disease, late pregnancy, malignancy, and after organophosphate exposure.[7][4] In a homozygously deficient patient mivacurium produces a block lasting many hours, because there is no pharmacological reversal — sugammadex does not bind it, and exogenous butyrylcholinesterase is the only specific therapy, with management otherwise supportive (sedation, ventilation, and monitoring until the drug dissipates by slow non-specific pathways). Mivacurium also releases histamine on rapid bolus, like atracurium. Clinically it has been largely displaced by sugammadex-reversible rocuronium, but its butyrylcholinesterase dependence and its short duration remain high-yield exam material.[4][7]

Reversal

The benzylisoquinolines are reversed by acetylcholinesterase inhibition with neostigmine, given with a muscarinic anticholinergic (glycopyrrolate or atropine) to offset the muscarinic effects of cholinesterase inhibition (bradycardia, salivation, bronchoconstriction). By inhibiting acetylcholinesterase, neostigmine raises synaptic acetylcholine until it outcompetes the blocker at the receptor. Neostigmine reverses all three agents in the family, and it requires evidence of spontaneous recovery — it should be given only once a quantitative train-of-four ratio is approaching normal, because giving it against a profound block cannot achieve full reversal and may paradoxically deepen it.[1]

The crucial negative point is that sugammadex does NOT reverse any of the three benzylisoquinolines. Sugammadex is a modified gamma-cyclodextrin whose hydrophobic cavity selectively encapsulates the aminosteroids rocuronium and (less avidly) vecuronium; it has no affinity for the benzylisoquinoline structure. So for atracurium, cisatracurium and mivacurium the reversibility advantage of the aminosteroid-sugammadex pair is entirely absent, and reversal depends on neostigmine and spontaneous recovery.[1] For mivacurium, recovery is normally by butyrylcholinesterase hydrolysis; in deficiency, recovery is awaited (or hastened with exogenous butyrylcholinesterase), not achieved with sugammadex.

Neuromuscular monitoring

Quantitative train-of-four monitoring is the standard of care for any non-depolarising block and is essential for safe use of the benzylisoquinolines. Four supramaximal stimuli are delivered at 0.5-second intervals and the ratio of the fourth to the first twitch (the TOF ratio) is measured; a ratio of 0.9 or above is the target for safe extubation. Fade — the fourth twitch being smaller than the first — is the hallmark of a competitive block.[1]

Monitoring is especially important for atracurium and cisatracurium in intensive care, where infusion rate is titrated to a target depth (typically one to two twitches on train-of-four), and for mivacurium, where it confirms the rapid spontaneous recovery that is the hallmark of normal butyrylcholinesterase function — or its failure to recover, which is the bedside clue to butyrylcholinesterase deficiency.[1]

Adverse effects

The adverse-effect profile of the family is the second most examined area after its elimination. Histamine release (atracurium, mivacurium; negligible with cisatracurium) produces flushing, hypotension, tachycardia and bronchospasm on rapid bolus. Laudanosine neurotoxicity (atracurium greater than cisatracurium) is a concern in renal failure, the elderly and prolonged infusion. Prolonged blockade in butyrylcholinesterase deficiency is the specific hazard of mivacurium.[1][4]

Anaphylaxis is a class risk that must never be overlooked. Neuromuscular blockers as a class are among the leading causes of perioperative anaphylaxis, an IgE-mediated reaction presenting within minutes with hypotension, bronchospasm, erythema and cardiovascular collapse, and treated first-line with intravenous adrenaline. The benzylisoquinolines share this risk with the aminosteroids; the histamine-release reaction of atracurium or mivacurium is distinct from true IgE anaphylaxis but can mimic it, so any cardiovascular collapse after a benzylisoquinoline bolus must be treated as anaphylaxis until proven otherwise.[8]

Benzylisoquinolines versus aminosteroids

The comparison with the aminosteroid non-depolarisers (rocuronium, vecuronium, pancuronium) is one of the highest-yield exam structures, because the two families differ on three axes simultaneously.[1]

Reversibility. The aminosteroids are selectively encapsulated by sugammadex and can be reversed rapidly even from a profound block; the benzylisoquinolines are not sugammadex-reversible and rely on neostigmine plus spontaneous recovery. Elimination. Atracurium and cisatracurium are organ-independent (Hofmann plus esterase), which the aminosteroids are not — rocuronium is hepatobiliary and renal, vecuronium is hepatobiliary, and both can accumulate in organ failure. Histamine. Atracurium and mivacurium release histamine on rapid bolus; the aminosteroids generally do not, which is why rocuronium is cardiovascularly stable. The single property that cuts across the families is anaphylaxis, which is a risk for both.[1][8]

Clinical use and current place in practice

In contemporary practice the three benzylisoquinolines occupy distinct, partly overlapping niches. Cisatracurium is the modern benzylisoquinoline of choice for cardiac surgery and for prolonged paralysis in the intensive-care unit, where its cardiovascular stability, organ-independent elimination and low laudanosine burden are decisive.[3][6] Atracurium retains a place as a cheap, organ-independent intermediate relaxant for balanced anaesthesia in organ failure, but has been largely displaced from cardiac and prolonged intensive-care use by cisatracurium. Mivacurium has been largely displaced by sugammadex-reversible rocuronium for short-duration paralysis, because rocuronium is sugammadex-reversible and mivacurium is not, and because mivacurium is unpredictably prolonged in butyrylcholinesterase deficiency.[4]

What examiners expect candidates to articulate is the underlying logic: atracurium and cisatracurium are chosen when organ-independent elimination is wanted (hepatic or renal failure, prolonged infusion); cisatracurium is chosen over atracurium when histamine release or laudanosine is a concern (cardiac, elderly, intensive care); mivacurium is chosen only when a short non-depolarising block without sugammadex is acceptable; and none of the three is reversed by sugammadex.[1][3]

[1] [1]

Red flags

[1]

References

1. [1]Radkowski P, et al. Neuromuscular Blocking Agents in Anesthesia: A Narrative Review of Contemporary Challenges and Reversal Approaches J Clin Med, 2026.PMID 42123245
2. [2]Radkowski P, et al. Use of Neuromuscular Blocking Agents in Elderly Patients: A Narrative Review in Geriatric Medicine Int J Gen Med, 2025.PMID 41399428
3. [3]Roy VC, et al. The Use of Cisatracurium in Cardiac Surgery Turk J Anaesthesiol Reanim, 2025.PMID 40677119
4. [4]Kempff-Andersen S, et al. Butyrylcholinesterase activity and prolonged duration of action of mivacurium in elderly patients (≥80 years): A secondary analysis of a clinical trial Eur J Anaesthesiol, 2026.PMID 42298973
5. [5]Rybka H, et al. In silico assessment of neuromuscular blocking agents and fluoroquinolones as ligands of the Mas-related G protein-coupled receptor X2 Pharmacol Rep, 2026.PMID 41385156
6. [6]He ZY, et al. Comparison of propofol-remifentanil target-controlled infusion with lidocaine versus neuromuscular blockade for laryngoscopy Minerva Anestesiol, 2026.PMID 42267885
7. [7]Snak de Souza CD, et al. Genotype-phenotype relationships in butyrylcholinesterase deficiency: a systematic review Br J Anaesth, 2026.PMID 42120224
8. [8]Zofia Lisiecka M, et al. Allergic reactions to anaesthetics in surgery: current challenges and perspectives Drug Metab Pers Ther, 2026.PMID 42229044