A lot of surgery, especially of the abdomen, requires that voluntary muscle tone and reflex contraction be inhibited. This can be attained by deep general anaesthesia, regional nerve blockade, or by using neuromuscular blocking drugs. Deep general anaesthesia causes cardiovascular depression, respiratory complications, and slow recovery. Regional nerve blocks may be difficult to do or contraindicated, for example if there is a haemostatic defect. Selective relaxation of voluntary muscle with neuromuscular blocking drugs allows surgery under light general anaesthesia with analgesia; it also facilitates tracheal intubation, quick induction and quick recovery. But it requires mechanical ventilation and technical skill. Neuromuscular blocking agents should be given only after induction of anaesthesia.
Neuromuscular blocking agents first attracted scientific notice because of their use as arrow poisons by the natives of South America, who used the most famous of all, curare, for killing food animals5 as well as enemies. In 1811 Sir Benjamin Brodie smeared 'woorara paste' on wounds of guinea-pigs and noted that death could be delayed by inflating the lungs through a tube introduced into the trachea. Though he did not continue until complete recovery, he did suggest that the drug might be of use in tetanus.
Despite attempts to use curare for a variety of diseases including epilepsy, chorea and rabies, the lack of pure and accurately standardised preparations, as well as the absence of convenient techniques of mechanical ventilation if overdose occurred, prevented it from gaining any firm place in medical practice until 1942, when these difficulties were removed.
Drugs acting at the myoneural junction produce complete paralysis of all voluntary muscle so that movement is impossible and mechanical ventilation is needed. It is plainly important that a paralysed patient should be in a state of full analgesia and unconscious during surgery.6 Using modern anaes-
5 Curare was obtained from several sources but most commonly from the vine Chondrodenron tomentosum. The explorers Humboldt and Bonpland in South America (1799-1804) reported that an extract of its bark was concentrated as a far-like mass and used to coat arrows. The potency was designated 'one tree' if a monkey, struck by a coated arrow, could only make one leap before dying. A more dilute ('three tree') from was used to paralyse animals so that they could be captured alive - an early example of a dose-response relationship.
thetic techniques and monitoring, awareness while paralysed for a surgical procedure is extremely rare. In the UK, general anaesthesia using volatile agents should always be monitored with agent analysers, which measure and display the end-tidal concentration of volatile agent. In the past, misguided concerns about the effect of volatile anaesthetics on the newborn led many anaesthetists to use little, if any, volatile agent when giving general anaesthesia for caesarean section. Under these conditions some mothers were conscious and experienced pain while paralysed and therefore unable to move. Despite its extreme rarity nowadays, fear of awareness under anaesthesia is still a leading cause of anxiety in patients awaiting surgery.
When an impulse passes down a motor nerve to voluntary muscle it causes release of acetylcholine from the nerve endings into the synaptic cleft. This activates receptors on the membrane of the motor endplate, a specialised area on the muscle fibre, opening ion channels for momentary passage of sodium which depolarises the endplate and initiates muscle contraction.
6 The introduction of tubocurarine into surgery made it desirable to decide once and for all whether the drug altered consciousness. Doubts were resolved in a single experiment.
A normal subject was slowly paralysed (curarised) after arranging a detailed and complicated system of communication. Twelve minutes after beginning the slow infusion of curare, the subject, having artificial respiration, could move only his head. He indicated that the experience was not unpleasant, that he was mentally clear and did not want an endotracheal tube inserted. After 22 min, communication was possible only by slight movement of the left eyebrow and after 35 min paralysis was complete and direct communication lost. An airway was inserted. The subject's eyelids were then lifted for him and the resulting inhibition of alpha rhythm of the electroencephalogram suggested that vision and consciousness were normal. After recovery, aided by neostigmine, the subject reported that he had been mentally 'clear as a bell' throughout, and confirmed this by recalling what he had heard and seen. The insertion of the endotracheal airway had caused only minor discomfort, perhaps because of the prevention of reflex muscle spasm. During artificial respiration he had 'felt that (he) would give anything to be able to take one deep breath' despite adequate oxygenation. Smith S M et al 1947 Anesthesiology 8:1. Note: a randomised controlled trial is not required for this kind of investigation.
Neuromuscular blocking agents used in clinical practice interfere with this process. Natural substances that prevent the release of acetylcholine at nerve endings exist, e.g. Clostridium botulinum toxin (see p. 429) and some venoms.
There are two principal mechanisms by which drugs used clinically interfere with neuromuscular transmission:
1. By competition with acetylcholine (atracurium, cisatracurium, mivacurium, pancuronium, rocuro-nium, vecuronium). These drugs are competitive antagonists of acetylcholine. They do not cause depolarisation themselves but protect the endplate from depolarisation by acetylcholine. The result is a flaccid paralysis.
Reversal of this type of neuromuscular block can be achieved with anticholinesterase drugs, such as neostigmine, which prevent the destruction by cholinesterase of acetylcholine released at nerve endings, allow the concentration to build up and so reduce the competitive effect of a blocking agent.
2. By depolarisation of the motor endplate (suxamethonium). Such agonist drugs activate the acetylcholine receptor on the motor endplate and at their first application voluntary muscle contracts but, as they are not destroyed immediately, like acetylcholine, the depolarisation persists.
It might be expected that this prolonged depolarisation would result in muscles remaining contracted but this is not so (except in chickens). With prolonged administration a depolarisation block changes to a competitive block (dual block). Because of the uncertainty of this situation a competitive blocking agent is preferred for anything other than short procedures.
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