Neuromuscular Blockers

Neuromuscular blockers enable light levels of anaesthesia to be employed (with adequate relaxation of the muscles of the abdomen and diaphragm) by specific blockade of the neuromuscular junction. They also relax the vocal cords and allow the passage of a tracheal tube.

Vecuronium and atracurium are generally used for maintenance of paralysis in general anaesthesia because of their slow onset of action. However, rocuronium has been shown to be as effective as suxamethonium in rapid-sequence induction anaesthesia without its contraindications or adverse reactions.¹

Neuromuscular blocking agents induce paralysis of skeletal muscle by blocking the action of the neurotransmitter acetylcholine (Ach) at the junction of the nerve ending and the motor end plate (neuromuscular junction - NMJ).

Their action occurs in two phases:

• Phase I - This consists of an initial brief depolarisation of post-junctional membrane skeletal muscle, causing contraction. Fasciculations are seen and repolarisation is inhibited.
• Phase II - This is a desensitisation blockade.

After the drug has been present for a period of time, the motor end plate loses its sensitivity and depolarisation cannot occur. This is desensitisation and can continue for several minutes, even after the drug is no longer present.

There are two main types of neuromuscular blocking agents:

• Depolarising:
  • These depolarise the NMJ by binding to the nicotinic receptor without being broken down by acetylcholinesterase.
    • They produce what appears to be a "persistent" depolarisation of the NMJ.
    • They cause depolarisation by mimicking the effect of Ach but without being rapidly hydrolysed by acetylcholinesterase.
    • Propagation of an action potential is prevented by the area of inexcitability that occurs around the Ach receptors.
  • There is an initial depolarisation, causing fasciculations, followed by desensitisation of the receptor. Fasciculations can be prevented by pre-treatment with a competitive agent.
  • Suxamethonium (succinylcholine) is the main agent in this class.
  • They have a rapid onset and short duration of action and are broken down by plasma cholinesterase.
• Non-depolarising:
  • These drugs comprise:
    • The aminosteroid group - pancuronium, rocuronium, and vecuronium
    • The benzylisoquinolinium group - atracurium, cisatracurium, gallamine, and mivacurium
  • They compete with acetylcholine at the nicotinic receptor of the NMJ and hence prevent the transmission of nerve impulses to the muscle fibres. The blockade is competitive, hence muscle paralysis occurs gradually. They are poorly lipid soluble and poorly protein bound.
  • Non-depolarising muscle relaxants have a slower onset of action than suxamethonium. These drugs can be classified by their duration of action as:
    • Short-acting i.e. 15 - 30 minutes
    • Intermediate-acting i.e. 30 - 40 minutes
    • Long-acting i.e. 60 - 120 minutes, although duration of action is dose-dependent
  • Drugs with a shorter or intermediate duration of action, such as atracurium and vecuronium, are more widely employed than those with a longer duration of action such as pancuronium.
  • Non-depolarising muscle relaxants have no sedative or analgesic effects and are not considered to be a triggering factor for malignant hyperthermia.
  • For patients in intensive care who require tracheal intubation and mechanical ventilation, a non-depolarising muscle relaxant is chosen according to its onset of effect, duration of action and side-effects.
  • Rocuronium, with a rapid onset of effect, may facilitate intubation.
  • Atracurium or cisatracurium may be suitable for long-term muscle relaxation since their duration of action is not dependent on elimination by the liver or the kidneys.
  • They also inhibit release of acetylcholine at the presynaptic receptors.

Mainly used in rapid-sequence induction anaesthesia to allow intubation. Also used to control fits after electroconvulsive therapy (ECT).

• Suxamethonium should be given after anaesthetic induction, because paralysis is usually preceded by painful muscle fasciculations.
• While tachycardia occurs with single use, bradycardia may occur with repeated doses in adults and with the first dose in children.

Premedication with atropine reduces bradycardia as well as the excessive salivation associated with suxamethonium use.

Prolonged paralysis may occur in dual block, which occurs with high or repeated doses of suxamethonium.

• It is caused by the development of a non-depolarising block following the initial depolarising block.
• Edrophonium can be used to confirm the diagnosis of dual block. Individuals with myasthenia gravis are resistant to suxamethonium but can develop dual block resulting in delayed recovery.
• Prolonged paralysis may also occur in those with low or atypical plasma cholinesterase.
• Assisted ventilation should be continued until muscle function is restored.

Administration²

• Intravenous 1-2 mg/kg, with muscle relaxation occurring within 1 min and lasting 5-10 min.
• Paralysis can be maintained by repeat administration of approximately 25% of original dose, up to 6-8 mg/kg.
• Intramuscular 3 mg/kg, but slower and less reliable effect.

Adverse reactions

• Bradycardia is more common in children. Usually occurs with >1 dose and is prevented by atropine administration.
• Hyperkalaemia may involve increases of 0.2-0.4mmol/l, but in cases of burns, paraplegia and severe muscle damage, this can be much higher.
• Raised intraocular and intracranial pressure is a short term effect, but means that it is best avoided in patients with these pre-existing conditions.
• Prolonged paralysis occurs in patients with defective plasma cholinesterase or given gentamicin or tetracycline.
• Anaphylaxis of varying severity can occur, which may cause severe bronchospasm or cardiac arrest (1 in 4,000 inductions).
• Malignant hyperpyrexia can occur in those with a genetic predisposition.³
• Myalgia postoperatively is caused by fasciculations at induction.

Contraindications

• Extensive burns after first 24 hours
• Paraplegia due to spinal injury - this applies between days 10 and 100 after damage
• Hyperkalaemia
• Severe injury to muscle tissue
• Previous malignant hyperpyrexia

Cautions

• Allergic cross-reactivity between neuromuscular blocking agents has been reported. Caution is advised in cases of hypersensitivity to these drugs.
• Their activity is prolonged in patients with myasthenia gravis and in hypothermia, therefore lower doses are required.
• Resistance may develop in patients with burns who may require increased doses; low plasma cholinesterase activity in these patients requires dose titration for mivacurium.

Adverse effects

• Histamine release:
  Benzylisoquinolinium non-depolarising muscle relaxants (except cisatracurium) are associated with histamine release which can cause skin flushing, hypotension, tachycardia, bronchospasm and rarely, anaphylactoid reactions. Most aminosteroid muscle relaxants produce minimal histamine release. The effects of histamine release are:
  • Bronchospasm
  • Dilatation of peripheral blood vessels - decreased blood pressure
  • Excessive secretions
  • Anticoagulant effect
• Other side-effects:
  • Pancuronium has vagolytic and sympathomimetic side-effects which can cause tachycardia and hypertension.
  • Rocuronium in high doses produces mild vagolytic activity.
  • Gallamine is rarely used because it has a less predictable response and it should be avoided in patients with renal impairment.

NB: Literature review suggests that there is no increase in congenital anomalies at birth in women who underwent anaesthesia during pregnancy. However, first trimester anaesthesia exposure does increase the risk of spontaneous abortion and lower birth weight.⁷

• Blockade is potentiated with general inhalational anaesthetics and antibiotics e.g. gentamycin (decreases Ach release) and tetracyclines (chelate calcium and decrease Ach release).
• Blockade is reduced with anticholinesterase agents. This results in increased Ach levels at the NMJ, which antagonises the effects of competitive agents.