08.03 Neuromuscular Blockers
There are two types of neuromuscular blockers, non-depolarizing (which are competitive antagonists) and depolarizing antagonists. The non-depolarizing (competitive) antagonists have no effect alone, but prevent Ach binding to NM-receptors. The first non-depolarizing antagonist was tubocurarine. Tubocurarine was known as curare and was used on in arrow heads to immobilize animals. Newer examples of non-depolarizing neuromuscular blockers include mivacurium, vecuronium, and rocuronium. Tubocararine is long acting, and difficult to fully reverse. The long acting non-depolarizing agents have been replaced by intermediate (vecuronium) and short-acting neuromuscular blockers (mivacurium). Vecuronium and mivacurium have a clinical duration of 60-90 minutes and 12-18 minutes, respectively, whereas rocuronium has a rapid onset (1-2 minutes) and intermediate duration (30-60 minutes).
The depolarizing neuromuscular blocker is succinylcholine (also known as suxamethonium), which initial causes depolarization/agonism with small contractions of the skeletal muscle. This is followed by causing persistent depolarization, which prevents the activation by acetylcholine and the skeletal muscle remains flaccid (relaxed). The effects of succinylcholine usually last for 5 minutes as it is rapidly metabolised by pseudocholinesterase. One in 3000 people are deficient in pseudocholinesterase, and in these people the effects of succinylcholine lasts for 20 h, as it is slowly metabolised.
The neuromuscular blockers are used to cause paralysis of skeletal muscle. The last muscles to be affected are the intercostal and diaphragm muscles. This means that there can be paralysis of other skeletal muscles without paralysis of respiration, which is good as paralysis of respiration can be deadly. The neuromuscular blockers are quaternary N+ compounds. As discussed in eChapter 1, quaternary N+ compounds are poorly absorbed after oral administration, and are used intravenously.
The main clinical use of neuromuscular blockers is an adjuvant in surgical anaesthesia to cause relaxation of skeletal muscle. The neuromuscular blockers are also used to cause relaxation of skeletal muscle in intensive care. The use of neuromuscular blockers is limited to anesthesiologists or other clinicians with extensive training in their use, and the choice of agent depends on duration of paralysis required.
The neuromuscular blockers have to be given to cause relaxation of muscles in arms and legs, without paralysing respiration muscle. When too much neuromuscular blocker has been given, it is essential to understand the interaction with anti-cholinesterases. Non-depolarizing/competitive reversible antagonism can be overcome by increasing the concentrations of acetylcholine in the synapse with an anti-cholinesterase (e.g. neostigmine). Ach will compete with non-depolarising agent for receptor and displace it, and thus decrease the effect of the antagonist. Depolarizing antagonism cannot be overcome by increasing the concentrations of acetylcholine in the synapse with an anti-cholinesterase. Ach will cause further depolarisation and make the block worse.