Neuromuscular-blocking drug

Type of paralyzing anesthetic including lepto- and pachycurares

Presynaptic terminal

Sarcolemma

Synaptic vesicle

Nicotinic acetylcholine receptor

Mitochondrion

Neuromuscular-blocking drugs, or Neuromuscular blocking agents (NMBAs), block transmission at the neuromuscular junction,^[1] causing paralysis of the affected skeletal muscles. This is accomplished via their action on the post-synaptic acetylcholine (Nm) receptors.

In clinical use, neuromuscular block is used adjunctively to

This class of medications helps to reduce patient movement, breathing, or ventilator dyssynchrony and allows lower insufflation pressures during laparoscopy.[3]^[4] It has several indications for use in the intense care unit. It can help reduce hoarseness in voice as well as injury to the vocal cord during intubation. In addition, it plays an important role in facilitating mechanical ventilation in patients with poor lung function.

Patients are still aware of pain even after full

• Pachycurares, which are bulky molecules with nondepolarizing activity
• Leptocurares, which are thin and flexible molecules that tend to have depolarizing activity.[5]

It is also common to classify them based on their chemical structure.

• Acetylcholine, suxamethonium, and decamethonium

• Aminosteroids

• Non-depolarizing blocking agents: These agents constitute the majority of the clinically relevant neuromuscular blockers. They act by competitively blocking the binding of ACh to its receptors, and in some cases, they also directly block the
  ionotropic activity of the ACh receptors.^[7]
• Depolarizing blocking agents: These agents act by
  muscle fiber
  . This persistent depolarization makes the muscle fiber resistant to further stimulation by ACh.

This drug needs to block about 70–80% of the ACh receptors for neuromuscular conduction to fail, and hence for effective blockade to occur. At this stage, end-plate potentials (EPPs) can still be detected, but are too small to reach the threshold potential needed for activation of muscle fiber contraction.

The speed of onset depends on the potency of the drug, greater potency is associated with slower onset of block. Rocuronium, with an ED₉₅ of 0.3 mg/kg IV has a more rapid onset than Vecuronium with an ED₉₅ of 0.05mg/kg.^[12] Steroidal compounds, such as rocuronium and vecuronium, are intermediate-acting drugs while Pancuronium and pipecuronium are long-acting drugs.^[12]

In larger clinical dose, some of the blocking agent can access the pore of the ion channel and cause blockage. This weakens neuromuscular transmission and diminishes the effect of

Under continuous exposure to succinylcholine, the initial end plate depolarization is reduced, and repolarisation process is initiated.[14] As a result of the widespread sustained depolarization the synapses ultimately begin repolarization. Once repolarized, the membrane is still less susceptible to additional depolarization (phase II block).^[14]

The prototypical depolarizing blocking drug is

• Non-depolarizing blockers are reversed by acetylcholinesterase inhibitor drugs since non-depolarizing blockers are competitive antagonists at the ACh receptor so can be reversed by increases in ACh.
• The depolarizing blockers already have ACh-like actions, so these agents have prolonged effect under the influence of acetylcholinesterase inhibitors. Administration of depolarizing blockers initially produces fasciculations (a sudden twitch just before paralysis occurs). This is due to depolarization of the muscle. Also, post-operative pain is associated with depolarizing blockers.

The tetanic fade is the failure of muscles to maintain a fused tetany at sufficiently high frequencies of electrical stimulation.

• Non-depolarizing blockers have this effect on patients, probably by an effect on presynaptic receptors.^[16]
• Depolarizing blockers do not cause the tetanic fade. However, a clinically similar manifestation called Phase II block occurs with repeated doses of suxamethonium.

This discrepancy is diagnostically useful in case of intoxication of an unknown neuromuscular-blocking drug.^[16]

Physiology at the Neuromuscular Junction

Neuromuscular blocking agents exert their effect by modulating the signal transmission in skeletal muscles. An action potential is, in other words, a depolarisation in neurone membrane due to a change in membrane potential greater than the threshold potential leads to an electrical impulse generation. The electrical impulse travels along the pre-synaptic neurone axon to synapse with the muscle at the neuromuscular junction (NMJ) to cause muscle contraction.^[17]

When the action potential reaches the axon terminal, it triggers the opening of the

The neurotransmitter, acetylcholine(ACh) binds to the nicotinic receptors on the motor end plate, which is a specialised area of the muscle fibre's post-synaptic membrane. This binding causes the nicotinic receptor channels to open and allow the influx of Na⁺ into the muscle fibre.[17]

Fifty percent of the released ACh is hydrolysed by acetylcholinesterase (AChE) and the remaining bind to the nicotinic receptors on the motor end plate. When ACh is degraded by AChE, the receptors are no longer stimulated and the muscle can be repolarised.^[17]

If enough Na⁺ enter the muscle fibre, it causes an increase in the membrane potential from its

Later, action potential reaches the sarcoplasmic reticulum which stores the Ca²⁺ needed for muscle contraction and causes Ca²⁺ to be released from the sarcoplasmic reticulum.^[17]

Mechanism of action

ammonium head and a site that binds to the blocking agent by donating a hydrogen bond.^[5]

Non-depolarizing agents A decrease in binding of acetylcholine leads to a decrease in its effect and neuron transmission to the muscle is less likely to occur. It is generally accepted that non-depolarizing agents block by acting as reversible competitive inhibitors. That is, they bind to the receptor as antagonists and that leaves fewer receptors available for acetylcholine to bind.^[5][18]

Depolarizing agents

Depolarizing agents produce their block by binding to and activating the ACh receptor, at first causing muscle contraction, then paralysis. They bind to the receptor and cause depolarization by opening channels just like acetylcholine does. This causes repetitive excitation that lasts longer than a normal acetylcholine excitation and is most likely explained by the resistance of depolarizing agents to the enzyme acetylcholinesterase. The constant depolarization and triggering of the receptors keeps the endplate resistant to activation by acetylcholine. Therefore, a normal neuron transmission to muscle cannot cause contraction of the muscle because the endplate is depolarized and thereby the muscle paralysed.^[5][18]

Binding to the

nicotinic receptor

Shorter molecules like acetylcholine need two molecules to activate the receptor, one at each receptive site. Decamethonium congeners, which prefer straight line conformations (their lowest energy state), usually span the two receptive sites with one molecule (binding inter-site). Longer congeners must bend when fitting receptive sites.

The greater energy a molecule needs to bend and fit usually results in lower potency.[19]

Structural and conformational action relationship

Conformational study on

SAR studies do not specify environmental factors on molecules. Computer-based conformational searches assume that the molecules are in vacuo, which is not the case in vivo. Solvation models take into account the effect of a solvent on the conformation of the molecule. However, no system of solvation can mimic the effect of the complex fluid composition of the body.^[20]

The division of

onium head distance in the longer muscle relaxant chains may quantify their ability to bend and fit its receptive sites.^[19] Using computers it is possible to calculate the lowest energy state conformer and thus most populated and best representing the molecule. This state is referred to as the global minimum. The global minimum for some simple molecules can be discovered quite easily with certainty. Such as for decamethonium the straight line conformer is clearly the lowest energy state. Some molecules, on the other hand, have many rotatable bonds and their global minimum can only be approximated.^[20]

Molecular length and rigidity

Neuromuscular blocking agents need to fit in a space close to 2 nanometres, which resembles the molecular length of decamethonium.^[19] Some molecules of decamethonium congeners may bind only to one receptive site. Flexible molecules have a greater chance of fitting receptive sites. However, the most populated conformation may not be the best-fitted one. Very flexible molecules are, in fact, weak neuromuscular inhibitors with flat dose-response curves. On the other hand, stiff or rigid molecules tend to fit well or not at all. If the lowest-energy conformation fits, the compound has high potency because there is a great concentration of molecules close to the lowest-energy conformation. Molecules can be thin but yet rigid.^[20] Decamethonium for example needs relatively high energy to change the N-N distance.^[19]

In general, molecular rigidity contributes to potency, while size affects whether a muscle relaxant shows a

lipophilic surface pointed towards the synapse enhances this effect by repelling cations. The importance of this effect varies between different muscle relaxants and classifying depolarizing from non-depolarizing blocks is a complex issue. The onium heads are usually kept small and the chains connecting the heads usually keep the N-N distance at 10 N or O atoms. Keeping the distance in mind the structure of the chain can vary (double bonded, cyclohexyl, benzyl, etc.)^[20]

Succinylcholine has a 10-atom distance between its N atoms, like decamethonium. Yet it has been reported that it takes two molecules, as with acetylcholine, to open one nicotinic ion channel. The conformational explanation for this is that each acetylcholine moiety of succinylcholine prefers the gauche (bent, cis) state. The attraction between the N and O atoms is greater than the onium head repulsion. In this most populated state, the N-N distance is shorter than the optimal distance of ten carbon atoms and too short to occupy both receptive sites. This similarity between succinyl- and acetyl-choline also explains its acetylcholine-like side-effects.^[20]

Comparing molecular lengths, the pachycurares

Gallamine despite having low bulk and rigidity is the most potent in its class, and it measures 1.9 nm.^[6][19] Based on this information one can conclude that the optimum length for neuromuscular blocking agents, depolarizing or not, should be 2 to 2.1 nm.^[20]

The CAR for long-chain bisquaternary tetrahydroisoquinolines like atracurium, cisatracurium, mivacurium, and doxacurium is hard to determine because of their bulky onium heads and large number of rotatable

laudexium and decamethylene bisatropium, which prefer a straight conformation.^[20]

Beers and Reich's law

It has been concluded that acetylcholine and related compounds must be in the

nicotinic. They showed that the distance from the centre of the quaternary N atom to the van der Waals extension of the respective O atom (or an equivalent H-bond acceptor) is a determining factor. If the distance is 0.44 nm, the compound shows muscarinic properties—and if the distance is 0.59 nm, nicotinic properties dominate.^[22]

)

Rational design

Pancuronium remains one of the few muscle relaxants logically and rationally designed from structure-action / effects relationship data. A

M2-receptors and therefore affect the vagus nerve, leading to hypotension and tachycardia. This muscarinic blocking effect is related to the acetylcholine moiety on the A ring on pancuronium. Making the N atom on the A ring tertiary, the ring loses its acetylcholine moiety, and the resulting compound, vecuronium, has nearly 100 times less affinity to muscarin receptors while maintaining its nicotinic affinity and a similar duration of action. Vecuronium is, therefore, free from cardiovascular effects.^[5] The D ring shows excellent properties validating Beers and Reich's rule with great precision. As a result, vecuronium has the greatest potency and specificity of all mono-quaternary compounds.^[20]

Potency

Two functional groups contribute significantly to aminosteroidal neuromuscular blocking potency, it is presumed to enable them to bind the receptor at two points. A bis-quaternary two point arrangement on A and D-ring (binding inter-site) or a D-ring acetylcholine moiety (binding at two points intra-site) are most likely to succeed. A third group can have variable effects.^[20] The quaternary and acetyl groups on the A and D ring of pipecuronium prevent it from binding intra-site (binding to two points at the same site). Instead, it must bind as bis-quaternary (inter-site).^[6] These structures are very dissimilar from acetylcholine and free pipecuronium from nicotinic or muscarinic side-effects linked to acetylcholine moiety. Also, they protect the molecule from hydrolysis by cholinesterases, which explain its nature of kidney excretion. The four methyl-groups on the quaternary N atoms make it less lipophilic than most aminosteroids. This also affects pipecuroniums metabolism by resisting hepatic uptake, metabolism, and biliary excretion. The length of the molecule (2.1 nm, close to ideal) and its rigidness make pipecuronium the most potent and clean one-bulk bis-quaternary. Even though the N-N distance (1.6 nm) is far away from what is considered ideal, its onium heads are well-exposed, and the quaternary groups help to bring together the onium heads to the anionic centers of the receptors without chirality issues.^[20]

Adding more than two onium heads in general does not add to potency. Though the third onium head in gallamine seems to help position the two outside heads near the optimum molecular length, it can interfere unfavorably and gallamine turns out to be a weak muscle relaxant, like all multi-quaternary compounds. Considering acetylcholine a quaternizing group larger than methyl and an acyl group larger than acetyl would reduce the molecule's potency. The charged N and the

carbonyl O atoms are distanced from structures they bind to on receptive sites and, thus, decrease potency. The carbonyl O in vecuronium for example is thrust outward to appose the H-bond donor of the receptive site. This also helps explain why gallamine, rocuronium, and rapacuronium are of relatively low potency.^[20]

In general, methyl quaternization is optimal for potency but, opposing this rule, the trimethyl derivatives of gallamine are of lower potency than gallamine. The reason for this is that gallamine has a suboptimal N-N distance. Substituting the ethyl groups with methyl groups would make the molecular length also shorter than optimal.

Methoxylation

of tetrahydroisoquinolinium agents seems to improve their potency. How methoxylation improves potency is still unclear. Histamine release is a common attribute of benzylisoquinolinium muscle relaxants. This problem generally decreases with increased potency and smaller doses. The need for larger doses increases the degree of this side-effect. Conformational or structural explanations for histamine release are not clear.^[20]

Pharmacokinetics

Metabolism and Hofmann elimination

atracurium the main idea was to make use of Hofmann elimination of the muscle relaxant in vivo. When working with bisbenzyl-isoquinolinium types of molecules, inserting proper features into the molecule such as an appropriate electron withdrawing group then Hofmann elimination should occur at conditions in vivo. Atracurium, the resulting molecule, breaks down spontaneously in the body to inactive compounds and being especially useful in patients with kidney or liver failure. Cis-atracurium is very similar to atracurium except it is more potent and has a weaker tendency to cause histamine release.^[5]

Structure relations to onset time

The effect of structure on the

succinylcholine or rocuronium are usually preferable.^[20]

Elimination

Muscle relaxants can have very different metabolic pathways and it is important that the drug does not accumulate if certain elimination pathways are not active, for example in kidney

failure.

Medical Use

Endotracheal intubation

Administration of neuromuscular blocking agents (NMBA) during

endotracheal intubation.^[12] This can decrease the incidence of postintubation hoarseness and airway injury.^[12]

Short-acting neuromuscular blocking agents are chosen for endotracheal intubation for short procedures (< 30minutes), and neuromonitoring is required soon after intubation.

succinylcholine, rocuronium or vecuronium if sugammadex is available for rapid reversal block.^[12]

Any short or intermediate acting neuromuscular blocking agents can be applied for endotracheal intubation for long procedures (≥ 30 minutes).

cisatracurium.^[12] The choice among these NMBA depends on availability, cost and patient parameters that affect drug metabolism

.

Intraoperative relaxation can be maintained as necessary with additional dose of nondepolarizing NMBA.[12]

Among all NMBA, Succinylcholine establish the most stable and fastest intubating conditions, thus is considered as the preferred NMBA for rapid sequence induction and intubation (RSII).^[12] Alternatives for succinylcholine for RSII include high dose rocuronium (1.2mg/kg which is a 4 X ED95 dose), or avoidance of NMBAs with a high dose remifentanil intubation.^[12]

Facilitation of surgery

Nondepolarizing NMBAs can be used to induce muscle relaxation that improves surgical conditions, including

thoracic procedures.^[12] It can reduce patient movement, muscle tone, breathing or coughing against ventilator and allow lower insufflation pressure during laparoscopy.^[12] Administration of NMBAs should be individualized according to patient’s parameters. However, many operations can be performed without the need to apply any NMBAs as adequate anesthesia during surgery can achieve many of the theoretical benefits of neuromuscular blockage.^[12]

Adverse effects

Since these drugs may cause

diaphragm

, mechanical ventilation should be at hand to provide respiration.

In addition, these drugs may exhibit

muscarinic receptors.^[11] If nicotinic receptors of the autonomic ganglia or adrenal medulla are blocked, these drugs may cause autonomic symptoms. Also, neuromuscular blockers may facilitate histamine release, which causes hypotension, flushing

, and tachycardia.

Succinylcholine may also trigger malignant hyperthermia in rare cases in patients who may be susceptible.

In depolarizing the musculature, suxamethonium may trigger a transient release of large amounts of

allergic reactions.^[12] As a result, it is contraindicated for patients with susceptibility to malignant hyperthermia, denervating conditions

, major burns after 48 hours, and severe hyperkalemia.

For nondepolarizing NMBAs except vecuronium, pipecuronium, doxacurium, cisatracurium, rocuronium and rapacuronium, they produce certain extent of cardiovascular effect.

systemic vascular resistance, which is unique in nondeploarizing NMBAs.^[14]

Certain drugs such as

fluoroquinolones also have neuromuscular blocking action as their side-effect.^[26]

Interactions

Some drugs enhance or inhibit the response to NMBAs which require the dosage adjustment guided by monitoring.

Combination of NMBAs

In some clinical circumstances, succinylcholine may be administered before and after a nondepolarising NMBA or two different nondepolarising NMBAs are administered in sequence.^[12] Combining different NMBAs can result in different degrees of neuromuscular block and management should be guided with the use of a neuromuscular function monitor.

The administration of nondepolarising neuromuscular blocking agent has an antagonistic effect on the subsequent depolarising block induced by succinylcholine.^[12] If a nondepolarising NMBA is administered prior to succinycholine, the dose of succinylcholine must be increased.

The administration of succinylcholine on the subsequent administration of a nondepolarising neuromuscular block depends on the drug used. Studies have shown that administration of succinylcholien before a nondepolarising NMBA does not affect the potency of mivacurium or rocuronium.^[12] But for vecuronium and cisatracurium, it speeds up the onset, increases the potency and prolongs the duration of action.^[12]

Combining two nondepolarising NMBAs of the same chemical class (e.g. rocuronium and vecuronium) produces an additive effect, while combining two nondepolarising NMBAs of different chemical class (e.g. rocuronium and cisatracurium) produces a synergistic response.^[12]

Inhaled anesthetics

Inhaled anesthetics inhibit nicotinic acetylcholine receptors (nAChRs) and potentiate neuromuscular blockage with nondepolarising NMBAs.

volatile anesthetic (desflurane > sevoflurane > isoflurane > nitrous oxide), the concentration and the duration of exposure.^[12]

Antibiotics

polymyxins and clindamycin potentiate neuromuscular blockage by inhibiting ACh release or desensitisation of post-synpatic nAChRs to ACh.^[12] This interaction happens mostly during maintenance of anesthesia. As antibiotics typically are given after a dose of NMBA, this interaction needs to be considered when re-dosing NMBA.^[12]

Anti-seizure drugs

Patients receiving chronic treatment are relatively resistance to nondepolarising NMBAs due to the accelerated clearance.^[12]

Lithium

Lithium is structurally similar to other cations such as sodium, potassium, magnesium and calcium, this causes lithium to activate potassium channels which inhibit neuromuscular transmission.^[12] Patients who take lithium can have a prolonged response to both depolarising and nondepolarising NMBAs.

Antidepressants

Sertraline and amitriptyline inhibit butyrylcholinesterase and cause prolonged paralysis.^[12] Mivacurium causes prolonged paralysis for patients chronically taking sertraline.^[12]

Local anesthetics (LAs)

LAs may enhance the effects of depolarisation and nondepolarising NMBAs through pre and post-synaptic interactions at the NMJ.^[12] It may result in blood levels high enough to potentiate NMBA-induced neuromuscular block.^[12] Epidurally administered levobupivacaine and mepivacaine potentiate amino-steroidal NMBAs and delay recovery from neuromuscular blockade.^[12]

Estimating effect

Methods for estimating the degree of neuromuscular block include valuation of muscular response to stimuli from surface electrodes, such as in the

intensive care.^[28]

Reversal

The effect of non-depolarizing neuromuscular-blocking drugs may be reversed with acetylcholinesterase inhibitors, neostigmine, and edrophonium, as commonly used examples. Of these, edrophonium has a faster onset of action than neostigmine, but it is unreliable when used to antagonize deep neuromuscular block.^[29] Acetylcholinesterase inhibitors increase the amount of acetylcholine in the neuromuscular junction, so a prerequisite for their effect is that the neuromuscular block is not complete, because in case every acetylcholine receptor is blocked then it does not matter how much acetylcholine is present.

selective relaxant binding agent (SRBA).^[30]

History

Curare is a crude extract from certain South American plants in the genera Strychnos and Chondrodendron, originally brought to Europe by explorers such as Walter Raleigh^[31] Edward Bancroft, a chemist and physician in the 16th century brought samples of crude curare from South America back to the Old-World. The effect of curare was experimented with by Sir Benjamin Brodie when he injected small animals with curare, and found that the animals stopped breathing but could be kept alive by inflating their lungs with bellows. This observation led to the conclusion that curare can paralyse the respiratory muscles. It was also experimented by Charles Waterton in 1814 when he injected three donkeys with curare. The first donkey was injected in the shoulder and died afterward. The second donkey had a tourniquet applied to the foreleg and was injected distal to the tourniquet. The donkey lived while the tourniquet was in place but died after it was removed. The third donkey after injected with curare appeared to be dead but was resuscitated using bellows. Charles Waterton's experiment confirmed the paralytic effect of curare.

It was known in the 19th century to have a

quaternary ammonium heads.^[9][33]

Neurologist

Intocostrin

.

At the same time in Montreal,

Harold Randall Griffith and his resident Enid Johnson at the Homeopathic Hospital administered curare to a young patient undergoing appendectomy

. This was the first use of NMBA as muscle relaxant in anesthesia.

The 1940s, 1950s and 1960s saw the rapid development of several synthetic NMBA.

Nobel Prize in medicine in 1957. Suxamethonium showed different blocking effect in that its effect was achieved more quickly and augmented a response in the muscle before block. Also, tubocurarine effects were known to be reversible by acetylcholinesterase inhibitors, whereas decamethonium and suxamethonium block were not reversible.^[9][5]

Another compound

neurons and receptors

.

Outdated treatment

FDA orange book

.

See also

• Ganglionic blocker
• Cholinergic blocking drugs

References

1. ^ "Dorlands Medical Dictionary:neuromuscular blocking agent".^{[permanent dead link]}
2. doi:10.1213/XAA.0000000000001334
3. doi:10.1213/XAA.0000000000001334
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8. ^ Neuromuscular+Nondepolarizing+Agents at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
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15. ^ Neuromuscular+Depolarizing+Agents at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
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17. ^ ^{a b c d e f} "Neuromuscular Junction | Structure, Function, Summary & Clinical". The Human Memory. 2019-11-26. Retrieved 2020-04-22.
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External links

• Neuromuscular+blocking+agents at the U.S. National Library of Medicine Medical Subject Headings (MeSH)