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Nondepolarising neuromuscular blocking drugs


Nondepolarising neuromuscular blocking drugs have been used in anaesthetic practice for 60 years and are increasingly used in critical care

Roger Knaggs
PhD MRPharmS

Specialist Pharmacist
Anaesthesia and Pain Management

Queen’s Medical Centre Campus
Nottingham University Hospitals NHS Trust

Following the isolation of curare and the first successful use, in 1942, of a standardised mixture of alkaloids from the plant Chondrodendron tormentosum to allow muscle relaxation during anaesthesia, neuromuscular blocking (NMB) drugs have become firmly established in anaesthetic practice.[1] Previously,
only inhalation agents had been available. In order to achieve sufficient muscle relaxation it was necessary to deepen anaesthesia, which brought adverse cardiac and respiratory effects and made certain surgical procedures difficult. Today, NMB drugs are widely used in both anaesthesia and critical care in combination with other drugs to provide the triad of balanced anaesthesia (narcosis, analgesia and muscle relaxation).

Mechanism of action
NMB drugs are used to provide skeletal muscle relaxation during anaesthesia or critical care by preventing transmission at the neuromuscular junction. There are two distinct mechanisms by which neuromuscular transmission can be altered. Nondepolarising NMB drugs are competitive antagonists at the postjunctional nicotinic acetylcholine (ACh) receptor of the neuromuscular junction. Nondepolarising NMB drugs are highly ionised at physiological pH, containing at least one quaternary
ammonium group. Over the years many different nondepolarising NMB drugs have been used clinically (see Table 1). The structural requirements, conformation and action required for neuromuscular blockade have been reviewed.[2]

Depolarising NMB drugs cause depolarisation by mimicking the action of nicotinic ACh at the receptor but are not rapidly metabolised by acetylcholinesterase. The only depolarising NMB drug used clinically today is succinylcholine (formerly called suxamethonium).

Individual agents
Tubocurarine, the prototypical nondepolarising NMB agent, was first isolated in 1935. However, it is no longer commercially available, at least in the UK. Its name derives from the early classification of curare according to means of storage (with ‘tubo-‘ referring to tubular bamboo canes). Use of tubocurarine commonly caused histamine release and ganglion blockade, with physiological consequences being vasodilatation and hypotension. Anaphylactoid reactions occurred, with bronchospasm, urticaria and hypotension, caused by stimulation of histamine release from mast cells, although incidence was uncommon.

Similar in structure to the older pancuronium, vecuronium is a monoquaternary aminosteroid NMB drug. Vecuronium causes minimal histamine release and ganglion or vagal blockade over a large dose range and hence has minimal effect on blood pressure and pulse. However, it may lead to unopposed vagal stimulation, causing bradycardia. Reversal of the muscle-relaxant effect is particularly fast and may not require the use of acetylcholinesterase inhibitors (see below).

Rocuronium also has an aminosteroid structure with a similar lack of cardiovascular effects. The onset of action is rapid[3] and typically produces good intubating conditions within 60 seconds. It has been suggested that rocuronium may be the drug of choice where succinylcholine is contraindicated.[4] Elimination is predominately via the liver, and the pharmacokinetic handling of rocuronium is altered in renal and hepatic disease, but to a lesser extent than vecuronium.

Intubation is possible within two minutes of administration of mivacurium, with little effect on cardiovascular stability. Histamine release is also uncommon, although this may occur at high doses if given rapidly. Mivacurium is largely metabolised by plasma cholinesterase, so its action may be greatly prolonged in patients with cholinesterase deficiency.[5] The NMB effect is more easily reversed than with some other commonly used NMB drugs, such as vecuronium or atracurium. Onset of action and recovery are faster following administration in children than adults.

The development of atracurium, with work led by John Stenlake at the University of Strathclyde in Glasgow, UK, started in the 1950s, but it took until 1980 for a commercially available formulation to be marketed.[6] Atracurium may cause histamine release, resulting in anaphylactoid reactions. Normally this is not problematic, but severe reactions have also been reported. At body temperature and physiological pH, atracurium undergoes Hofmann elimination – spontaneous degradation to laudanosine.[7] It took a long time for researchers to realise that this was the rate-determining step in metabolism.

This novel elimination mechanism means that recovery from a single dose is fast, and that complete skeletal muscle paralysis may be maintained for long periods by administering small incremental doses. Recovery time is unaffected by the number of increments. As metabolism is independent of the liver or kidney, atracurium is often considered the drug of choice in cases of renal or hepatic impairment.

Cisatracurium, a stereo-isomer of atracurium that results in less histamine release, is now available. A greater proportion of cisatracurium is metabolised by Hofmann elimination, and because of greater potency a smaller dose than atracurium is required to produce skeletal muscle relaxation.


Monitoring of neuromuscular blockade
Ideally, monitoring of neuromuscular blockade with a nerve stimulator should be performed whenever a nondepolarising NMB drug is used.[8] This is particularly indicated:

  • During prolonged anaesthesia, when repeated bolus doses of NMB are required.
  • When infusions of NMB are used (including critical care).
  • In patients with concurrent hepatic or renal impairment.
  • In patients with neuromuscular disorders.

Reversal of effects
The muscle-relaxant effect of nondepolarising NMB drugs can be reversed by administering an anticholinesterase drug such as neostigmine. This prolongs the effect of ACh within the synaptic cleft of the neuromuscular junction, potentiating its effect. Neostigmine potentiates the effect of ACh wherever it acts as neurotransmitter, including within the autonomic nervous system, thus producing bradycardia, salivation, sweating and bronchospasm. These cholinergic effects may be reduced by simultaneous administration of an antimuscarinic drug such as
atropine or glycopyrronium. Neostigmine takes at least two minutes to have an initial effect, and recovery from neuromuscular blockade is maximal within approximately five minutes.

Sugammadex, a compound with novel mechanism of action and in the late stages of clinical development, will be commercially available soon. Sugammadex exerts its effect by forming very tight water-soluble complexes with aminosteroid neuromuscular blocking drugs such as rocuronium and vecuronium and has no effect on acetylcholinesterase.[9]

Neuromuscular blocking drugs have an integral place in modern anaesthetic practice. Although the mechanism of action of nondepolarising NMBs is identical, there are differences in pharmacokinetic profile and side-effects. Together with the procedure undertaken, these will determine the choice of NMB used by an anaesthetist.

1. Hunter JM. Muscle function and neuromuscular blockade. In: Aitkenhead AR , Rowbotham DJ, Smith G, editors. Textbook of anaesthesia. 5th ed. Edinburgh: Churchill Livingstone; 2007.
2. Lee C. Br J Anaesth 2001;87:755-69.
3. Atherton DPL, Hunter JM. Clin Pharmacokinet 1999;36:169-89.
4. Khuenl-Brady KS, Sparr H. Clin Pharmacokinet 1996;31:174-83.
5. Belmont MR, Rubin LA , Lien CA , Tjan J, Saravese JJ. Anaesth Pharmacol Rev 1995;31:156-67.
6. Stenlake JB. Pharm J 2001;267:430-31.
7. Alston TA . Anesth Analg 2003;96:622-5.
8. Brull SJ, Silverman DG. Sem Anaesth Periop Med 2002;21:104-14.
9. Naguib M. Anesth Analg 2007;104:575-81.

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