How does neuromuscular blockers work

Neuromuscular blocking drugs NMBDs act at several sites at the neuromuscular junction, but their main effects are as agonists and antagonists at postjunctional nicotinic receptors. Succinylcholine is the only available depolarizing NMBD; it has several undesirable side-effects.

Less potent non-depolarizing NMBDs have a more rapid onset of action, comparable with succinylcholine. Aminosteroid NMBDs depend on organ function for metabolism and excretion. They can have active metabolites. Benzylisoquinolinium compounds undergo organ-independent degradation but tend to release histamine.

A short-acting non-depolarizing NMBD with a rapid onset and short duration of effect is required to replace succinylcholine. Many NMBDs e. These bisquaternary amines are more potent than monoquaternary amines e. However, at physiological pH, and especially in acidotic conditions, the tertiary amine can become protonated and therefore positively charged, increasing the potency of monoquaternary NMBDs. This factor has clinical significance; the effect of such NMBDs is potentiated in acidotic patients.

The two quaternary ammonium groups are separated by a bridging structure that is lipophilic and varies in size. The bridging structure varies with different series of NMBDs and is a major determinant of their potency. NMBDs are classified as depolarizing and non-depolarizing drugs according to their action at the postjunctional nicotinic receptor. Depolarizing drugs are agonists at ACh receptors.

Succinylcholine is the only depolarizing NMBD in clinical use. It is effectively two ACh molecules joined through the acetate methyl groups. When voltage-sensitive sodium channels sense membrane depolarization as a result of activation of the ACh receptors , they first open Fig. The membrane potential must be reset before the sodium channels can be reactivated Fig.

This is a very rapid process with ACh 1 ms , as it is hydrolysed by acetylcholinesterase AChE within the synaptic cleft. However, succinylcholine is not metabolized by AChE, so a prolonged activation of the ACh receptors is produced.

The sodium receptors at the end-plate and the perijunctional zone remain inactivated Fig. The muscle becomes flaccid. A Sketch of the sodium channel. The bars v and t represent parts of the molecule that act as gates.

Gate v is voltage-dependent, and gate t is time-dependent. This state is maintained as long as the surrounding membrane is depolarized. The channel reverts to the resting state a when the membrane repolarizes. B Several states of nicotinic acetylcholine receptors. Upper left to right : resting; resting with agonist bound to recognition sites but channel not yet opened; and active with open channel allowing ion flow.

Lower left to right : desensitized without agonist; desensitized with agonist bound to recognition site. Both are non-conducting. All conformations are in dynamic equilibrium. Reproduced, with permission of Elsevier, from Standaert FG.

Neuromuscular physiology and pharmacology. In: Miller RD ed Anesthesia , 4th edn. New York: Churchill Livingstone, ; — Depolarization block is also called Phase I or accommodation block and is often preceded by muscle fasciculation. This is probably the result of the prejunctional action of succinylcholine, stimulating ACh receptors on the motor nerve, causing repetitive firing and release of neurotransmitter. Recovery from Phase I block occurs as succinylcholine diffuses away from the neuromuscular junction, down a concentration gradient as the plasma concentration decreases.

It is metabolized by plasma cholinesterase previously called pseudocholinesterase. Prolonged exposure of the neuromuscular junction to succinylcholine can result in i desensitization block or ii Phase II block. Desensitization occurs when ACh receptors are insensitive to the channel-opening effects of agonists, including ACh itself. Receptors are in a constant state of transition between resting and desensitized states, whether or not agonists are present Fig.

Agonists do promote the transition to a desensitized state or trap receptors in that state, as desensitized receptors have a high affinity for them. Normally, ACh is hydrolysed so rapidly that it has no potential for causing desensitization. Desensitization block may be a safety mechanism that prevents overexcitation of the neuromuscular junction. Phase II block differs from desensitization block.

It occurs after repeated boluses or a prolonged infusion of succinylcholine. In patients with atypical plasma cholinesterase, Phase II block can develop after a single dose of the drug.

The block is characterized by fade of the train-of-four TOF twitch response, tetanic fade and post-tetanic potentiation, which are all features of competitive block.

After the initial depolarization, the membrane potential gradually returns towards the resting state, even though the neuromuscular junction is still exposed to the drug. Neurotransmission remains blocked throughout. Possible explanations for the development of Phase II block include presynaptic block reducing the synthesis and mobilization of ACh; postjunctional receptor desensitization; and activation of the sodium—potassium ATPase pump by initial depolarization of the postsynaptic membrane, which repolarizes it.

Inhalation anaesthetic drugs accelerate the onset of Phase II block. Anticholinesterase drugs can be used to antagonize it, but the response is difficult to predict.

Therefore, it is advisable to allow spontaneous recovery. The dose of succinylcholine required for tracheal intubation in adults is 1. This dose produces profound block within 60 s, which is faster than any other NMBD presently available Table 1. Neuromuscular block starts to recover within 3 min and is complete within 12—15 min.

Plasma cholinesterase has an enormous capacity to hydrolyse succinylcholine, such that only a small fraction of the injected dose actually reaches the neuromuscular junction. Succinylcholine has several undesirable side-effects which limit its use.

It stimulates muscarinic and nicotinic receptors as does ACh. Normal muscle releases enough potassium during succinylcholine-induced depolarization to raise serum potassium by 0. Although this is usually insignificant in patients with normal baseline potassium levels, a life-threatening potassium elevation is possible in patients with burn injury, massive trauma, neurological disorders, and several other conditions.

Doxacurium, pancuronium, vecuronium, and pipecuronium are partially excreted by the kidneys, and their action is prolonged in patients with renal failure. Cirrhotic liver disease and chronic renal failure often result in an increased volume of distribution and a lower plasma concentration for a given dose of water-soluble drugs, such as muscle relaxants. On the other hand, drugs dependent on hepatic or renal excretion may demonstrate prolonged clearance.

Thus, depending on the drug, a greater initial dose—but smaller maintenance doses—might be required in these diseases. Atracurium and cisatracurium undergo degradation in plasma at physiological pH and temperature by organ-independent Hofmann elimination. The resulting metabolites a monoquaternary acrylate and laudanosine have no intrinsic neuromuscular blocking effects.

Hypertension and tachycardia may occur in patients given pancuronium. These cardiovascular effects are caused by the combination of vagal blockade and catecholamine release from adrenergic nerve endings.

Long-term administration of vecuronium to patients in intensive care units has resulted in prolonged neuromuscular blockade up to several days , possibly from accumulation of its active 3-hydroxy metabolite, changing drug clearance, or the development of a polyneuropathy.

Rocuronium 0. Skeletal muscle relaxation can be produced by deep inhalational anesthesia, regional nerve block, or neuromuscular blocking agents commonly called muscle relaxants. In , Harold Griffith published the results of a study using an extract of curare a South American arrow poison during Your MyAccess profile is currently affiliated with '[InstitutionA]' and is in the process of switching affiliations to '[InstitutionB]'.

This div only appears when the trigger link is hovered over. In the acute setting, the use of NMBAs can lead to increased ICU stay, prolonged mechanical ventilation, venous thromboembolism, skin tearing and ulcerations, infection, corneal damage, and anaphylaxis. Long-term administration can lead to immobility or increased recovery time because of impaired neuromuscular transmission and muscular weakness.

The pharmacist can play a highly important role in the regulation and use of NMBAs across a wide range of clinical-practice sites. By understanding the mechanism of action, therapeutic indications, supporting literature, and clinical side effects of this high-alert class of medications, the pharmacist can have an invaluable effect on patient care and patient safety.

Clinical practice guidelines for sustained neuromuscular blockade in the adult critically ill patient. Crit Care Med. Current therapeutic uses, pharmacology, and clinical considerations of neuromuscular blocking agents for critically ill adults.

Ann Pharmacother. Succinylcholine: a new approach to muscular relaxation in anesthesiology. N Engl J Med. Naguib M, Lien CA.

Pharmacology of muscle relaxants and their antagonists. Philadelphia, PA: Churchill Livingstone; Anectine succinylcholine package insert. Rocuronium package insert. Nimbex cisatracurium package insert. Airway management in the emergency department; a one-year study of tracheal intubations. Ann Emerg Med.

Rapid-sequence intubation at an emergency medicine residency: success rate and adverse events during a two-year period. Acad Emerg Med. Complications of emergency intubation with and without paralysis. Am J Emerg Med. The dose of succinylcholine required for excellent endotracheal intubating conditions.

Anesth Analg. Greenberg SB, Vender J. The use of neuromuscular blocking agents in the ICU: where are we now? Rocuronium versus succinylcholine for rapid sequence induction intubation. Cochrane Database Syst Rev. Effect of neuromuscular blocking agents on gas exchange in patients presenting with acute respiratory distress syndrome.

Neuromuscular blocking agents decrease inflammatory response in patients presenting with acute respiratory distress syndrome. Neuromuscular blockers in early acute respiratory distress syndrome. Neuromuscular blocking agents in acute respiratory distress syndrome: a systemic review and meta-analysis of randomized controlled trials.

However, because they are not metabolized by acetylcholinesterase, the binding of this drug to the receptor is prolonged resulting in an extended depolarization of the muscle end-plate.

As the muscle relaxant continues to bind to the ACh receptor, the end plate cannot repolarize, resulting in a phase I block. The ACh receptor can also undergo conformational and ionic changes after a period of time, resulting in a phase II block.

Nondepolarizing muscle relaxants act as competitive antagonists.