text:
Neuromuscular-blocking drug
From Wikipedia, the free encyclopedia
Jump to: navigation, search
Global view of a neuromuscular junction:
1. Axon
2. Motor end-plate
3. Muscle fiber
4. Myofibril
Detailed view of a neuromuscular junction:
1. Presynaptic terminal
2. Sarcolemma
3. Synaptic vesicle
4. Nicotinic acetylcholine receptor
5. Mitochondrion
Neuromuscular-blocking drugs block neuromuscular transmission at the neuromuscular junction,[1] causing paralysis of the affected skeletal muscles. This is accomplished either by acting presynaptically via the inhibition of acetylcholine (ACh) synthesis or release or by acting postsynaptically at the acetylcholine receptors of the motor nerve end-plate. While some drugs act presynaptically (such as botulinum toxin and tetanus toxin), those of current clinical importance work postsynaptically.
In clinical use, neuromuscular block is used adjunctively to anesthesia to produce paralysis, firstly to paralyze the vocal cords, and permit intubation of the trachea, and secondly to optimize the surgical field by inhibiting spontaneous ventilation, and causing relaxation of skeletal muscles. Because the appropriate dose of neuromuscular-blocking drug may paralyze muscles required for breathing (i.e., the diaphragm), mechanical ventilation should be available to maintain adequate respiration.
Patients are still aware of pain even after full conduction block has occurred; hence, general anesthetics and/or analgesics must also be given to prevent anesthesia awareness.
Quaternary ammonium muscle relaxants are quaternary ammonium salts used as drugs for muscle relaxation, most commonly in anesthesia. It is necessary to prevent spontaneous movement of muscle during surgical operations. Muscle relaxants inhibit neuron transmission to muscle by blocking the nicotinic acetylcholine receptor. What they have in common, and is necessary for their effect, is the structural presence of quaternary ammonium groups, usually two. Some of them are found in nature and others are synthesized molecules.[2][3]
Contents
[hide]
1 Nomenclature
2 Classification
2.1 Non-depolarizing blocking agents
2.2 Depolarizing blocking agents
2.3 Comparison of drugs
3 Mechanism of action
4 Structural and conformational action relationship
4.1 Molecular length and rigidity
4.2 Beers and Reich's law
4.3 Rational design
4.4 Potency
5 Pharmacokinetics
6 Adverse effects
7 Estimating effect
8 Reversal
9 History
10 See also
11 References
12 External links
Nomenclature[edit]
Neuromuscular blocking drugs are often classified into two broad classes:
Pachycurares, which are bulky molecules with nondepolarizing activity
Leptocurares, which are thin and flexible molecules that tend to have depolarizing activity.[3]
It is also common to classify them based on their chemical structure.
Acetylcholine, suxamethonium, and decamethonium
Suxamethonium was synthesised by connecting two acetylcholine molecules and has the same number of heavy atoms between methonium heads as decamethonium. Just like acetylcholine, succinylcholine, decamethonium and other polymethylene chains, of the appropriate length and with two methonium, heads have small trimethyl onium heads and flexible links. They all exhibit a depolarizing block.
Aminosteroids
Main article: Aminosteroid
Pancuronium, vecuronium, rocuronium, rapacuronium, dacuronium, malouètine, duador, dipyrandium, pipecuronium, chandonium (HS-310), HS-342 and other HS- compounds are aminosteroidal agents. They have in common the steroid structural base, which provides a rigid and bulky body. Most of the agents in this category would also be classified as non-depolarizing.
Tetrahydroisoquinoline derivatives
Compounds based on the tetrahydroisoquinoline moiety such as atracurium, mivacurium, and doxacurium would fall in this category. They have a long and flexible chain between the onium heads, except for the double bond of mivacurium. D-tubocurarine and dimethyltubocurarine are also in this category. Most of the agents in this category would be classified as non-depolarizing.
Gallamine and other chemical classes
Gallamine is a trisquaternary ether with three ethonium heads attached to a phenyl ring through an ether linkage. Many other different structures have been used for their muscle relaxant effect such as alcuronium (alloferin), anatruxonium, diadonium, fazadinium (AH8165) and tropeinium.
Novel NMB agents
In recent years much research has been devoted to new types of quaternary ammonium muscle relaxants. These are asymmetrical diester isoquinolinium compounds and bis-benzyltropinium compounds that are bistropinium salts of various diacids. These classes have been developed to create muscle relaxants that are faster and shorter acting. Both the asymmetric structure of diester isoquinolinium compounds and the acyloxylated benzyl groups on the bisbenzyltropiniums destabilizes them and can lead to spontaneous breakdown and therefore possibly a shorter duration of action.[4]
Classification[edit]
These drugs fall into two groups:
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.[5]
Depolarizing blocking agents: These agents act by depolarizing the sarcolemma of the skeletal muscle fiber. This persistent depolarization makes the muscle fiber resistant to further stimulation by ACh.
Non-depolarizing blocking agents[edit]
A neuromuscular non-depolarizing agent is a form of neuromuscular blocker that does not depolarize the motor end plate.[6]
The quaternary ammonium muscle relaxants belong to this class.
Mind Map showing a summary of Neuromuscular nondepolarizing agent
Below are some more common agents that act as competitive antagonists against acetylcholine at the site of postsynaptic acetylcholine receptors.
Tubocurarine, found in curare of the South American plant Pareira, Chondrodendron tomentosum, is the prototypical non-depolarizing neuromuscular blocker. It has a slow onset (>5 min) and a long duration of action (30 mins). Side-effects include hypotension, which is partially explained by its effect of increasing histamine release, a vasodilator,[7] as well as its effect of blocking autonomic ganglia.[8] It is excreted in the urine.
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.
Comparison of non-depolarizing neuromuscular blocking agents
Agent
Time to onset
(seconds) Duration
(minutes)
Side effects
Clinical use
Storage
Rapacuronium (Raplon)
Mivacurium (Mivacron) 90 12–18[9]
hypotension (transiently), by release of histamine[9]
No longer manufactured secondary to marketing, manufacturing, and financial concerns refrigerated
Atracurium (Tracrium) 90 30 min or less[9]
hypotension, transiently,[9] by release of histamine
Toxic metabolite called laudanosine, greater accumulation in individuals with renal failure
widely[9] refrigerated
Doxacurium (Nuromax) long[9]
hypotension, transiently,[9] by release of histamine
Toxic metabolite called laudanosine, greater accumulation in individuals with renal failure
Cisatracurium (Nimbex) 90 60–80 does not cause release of histamine refrigerated
Vecuronium (Norcuron) 60 30–40[9] Few,[9] may cause prolonged paralysis[9] and promote muscarinic block widely[9] non-refrigerated
Rocuronium (Zemuron) 75 45–70[citation needed] may promote muscarinic block non-refrigerated
Pancuronium (Pavulon) 90 180 or more[citation needed]
tachycardia (slight)[9]
(no hypotension)[9]
widely[9] non-refrigerated
Tubocurarine (Jexin) 300 or more[9] 60–120[9]
hypotension (by ganglion-block and histamine release)[9]
Bronchoconstriction (by histamine release)[9]
rarely[9]
gallamine (Flaxedil) 300 or more[9] 60–120[9]
tachycardia
Pipecuronium 90 180 or more[citation needed]
tachycardia (slight)[9]
(no hypotension)[9]
non-refrigerated
Depolarizing blocking agents[edit]
A depolarizing neuromuscular blocking agent is a form of neuromuscular blocker that depolarizes the motor end plate.[10]
An example is succinylcholine.
Mind Map showing a summary of Neuromuscular depolarizing agent
Depolarizing blocking agents work by depolarizing the plasma membrane of the muscle fiber, similar to acetylcholine. However, these agents are more resistant to degradation by acetylcholinesterase, the enzyme responsible for degrading acetylcholine, and can thus more persistently depolarize the muscle fibers. This differs from acetylcholine, which is rapidly degraded and only transiently depolarizes the muscle.
There are two phases to the depolarizing block. During phase I (depolarizing phase), they cause muscular fasciculations (muscle twitches) while they are depolarizing the muscle fibers. Eventually, after sufficient depolarization has occurred, phase II (desensitizing phase) sets in and the muscle is no longer responsive to acetylcholine released by the motoneurons. At this point, full neuromuscular block has been achieved.
The prototypical depolarizing blocking drug is succinylcholine (suxamethonium). It is the only such drug used clinically. It has a rapid onset (30 seconds) but very short duration of action (5–10 minutes) because of hydrolysis by various cholinesterases (such as butyrylcholinesterase in the blood). Succinylcholine was originally known as diacetylcholine because structurally it is composed of two acetylcholine molecules joined with a methyl group. Decamethonium is sometimes, but rarely, used in clinical practice.
Comparison of drugs[edit]
The main difference is in the reversal of these two types of neuromuscular-blocking drugs.
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.[11]
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.[11]
Mechanism of action[edit]
Fig.1 A simple illustration of how two acetylcholine molecules bind to its receptive sites on the nicotinic receptor
Quaternary muscle relaxants bind to the nicotinic acetylcholine receptor and inhibit or interfere with the binding and effect of ACh to the receptor. Each ACh-receptor has two receptive sites and activation of the receptor requires binding to both of them. Each receptor site is located at one of the two α-subunits of the receptor. Each receptive site has two subsites, an anionic site that binds to the cationic ammonium head and a site that binds to the blocking agent by donating a hydrogen bond.[3]
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.[3][12]
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.[3][12]
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.[13]
Structural and conformational action relationship[edit]
Conformational study on neuromuscular blocking drugs is relatively new and developing. Traditional 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.[14]
The division of muscle relaxants to rigid and non-rigid is at most qualitative. The energy required for conformational changes may give a more precise and quantitative picture. Energy required for reducing onium head distance in the longer muscle relaxant chains may quantify their ability to bend and fit its receptive sites.[13] 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.[14]
Molecular length and rigidity[edit]
Fig.2 A simple illustration of how decamethonium binds to the nicotinic receptor. The onium heads bind to two separate subunits of the ion-channel
Neuromuscular blocking agents need to fit in a space close to 2 nanometres, which resembles the molecular length of decamethonium.[13] Some molecules of decamtehonium 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.[14] Decamethonium for example needs relatively high energy to change the N-N distance.[13]
In general, molecular rigidity contributes to potency, while size affects whether a muscle relaxant shows a polarizing or a depolarizing effect.[4] Cations must be able to flow through the trans-membrane tube of the ion-channel to depolarize the endplate.[14] Small molecules may be rigid and potent but unable to occupy or block the area between the receptive sites.[4] Large molecules, on the other hand, may bind to both receptive sites and hinder depolarizing cations independent of whether the ion-channel is open or closed below. Having 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.)[14]
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.[14] Comparing molecular lengths, the pachycurares dimethyltubocurarine and d-tubocurarine both are very rigid and measure close to 1.8 nm in total length. Pancuronium and vecuronium measure 1.9 nm, whereas pipecuronium is 2.1 nm. The potency of these compounds follows the same rank of order as their length. Likewise, the leptocurares prefer a similar length. Decamethonium, which measures 2 nm, is the most potent in its category, whereas C11 is slightly too long. Gallamine despite having low bulk and rigidity is the most potent in its class, and it measures 1.9 nm.[4][13] 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.[14]
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 bonds and groups. These agents must follow the same receptive topology as others, which means that they do not fit between the receptive sites without bending.[13] Mivacurium for example has a molecular length of 3.6 nm when stretched out, far from the 2 to 2.1 nm optimum. Mivacurium, atracurium, and doxacurium have greater N-N distance and molecular length than d-tubocurarine even when bent. To make them fit, they have flexible connections that give their onium heads a chance to position themselves beneficially. This bent N-N scenario probably does not apply to laudexium and decamethylene bisatropium, which prefer a straight conformation.[14]
Beers and Reich's law[edit]
It has been concluded that acetylcholine and related compounds must be in the gauche (bent) configuration when bound to the nicotinic receptor.[15]) Beers and Reich's studies on cholinergic receptors in 1970 showed a relationship affecting whether a compound was muscarinic or 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.[16])
Rational design[edit]
Pancuronium remains one of the few muscle relaxants logically and rationally designed from structure-action / effects relationship data. A steroid skeleton was chosen because of its appropriate size and rigidness. Acetylcholine moieties were inserted to increase receptor affinity. Although having many unwanted side-effects, a slow onset of action and recovery rate it was a big success and at the time the most potent neuromuscular drug available. Pancuronium and some other neuromuscular blocking agents block 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.[3] 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.[14]
Potency[edit]
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.[14] 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).[4] 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.[14]
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.[14] 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.[14]
Pharmacokinetics[edit]
Metabolism and Hofmann elimination
Fig.3 A simple illustration of how vecuronium binds to the nicotinic receptor. Its D-ring binds to the receptor at two points and the lipophillic side of the molecule repels cations from flowing through the ion-channel
Deacetylating vecuronium at position 3 results in a very active metabolite.[17] In the case of rapacuronium the 3-deacylated metabolite is even more potent than rapacuronium. As long as the D-ring acetylcholine moiety is unchanged they retain their muscle relaxing effect. Mono-quaternary aminosteroids produced with deacylation in position 17 on the other hand are generally weak muscle relaxants.[14] In the development of 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.[3]
Structure relations to onset time
The effect of structure on the onset of action is not very well known except that the time of onset appears inversely related to potency.[18] In general mono-quaternary aminosteroids are faster than bis-quaternary compounds, which means they are also of lower potency. A possible explanation for this effect is that drug delivery and receptor binding are of a different timescale. Weaker muscle relaxants are given in larger doses so more molecules in the central compartment must diffuse into the effect compartment, which is the space within the mouth of the receptor, of the body. After delivery to the effect compartment then all molecules act quickly.[19] Therapeutically this relationship is very inconvenient because low potency, often meaning low specificity can decrease the safety margin thus increasing the chances of side-effects. In addition, even though low potency usually accelerates onset of action, it does not guaranty a fast onset. Gallamine, for example, is weak and slow. When fast onset is necessary then succinylcholine or rocuronium are usually preferable.[14]
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.
Adverse effects[edit]
Since these drugs may cause paralysis of the diaphragm, mechanical ventilation should be at hand to provide respiration.
In addition, these drugs may exhibit cardiovascular effects, since they are not fully selective for the nicotinic receptor and hence may have effects on muscarinic receptors.[8] 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.
In depolarizing the musculature, suxamethonium may trigger a transient release of large amounts of potassium from muscle fibers. This puts the patient at risk for life-threatening complications, such as hyperkalemia and cardiac arrhythmias.
Certain drugs such as aminoglycoside antibiotics and polymyxin and some fluoroquinolones also have neuromuscular blocking action as their side-effect.[20]
Estimating effect[edit]
Methods for estimating the degree of neuromuscular block include valuation of muscular response to stimuli from surface electrodes, such as in the train-of-four test, wherein four such stimuli are given in rapid succession. With no neuromuscular blockade, the resultant muscle contractions are of equal strength, but gradually decrease in case of neuromuscular blockade.[21] It is recommended during use of continuous-infusion neuromuscular blocking agents in intensive care.[22]
Reversal[edit]
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.[23] 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.
Sugammadex is a newer drug for reversing neuromuscular block by rocuronium in general anaesthesia. It is the first selective relaxant binding agent (SRBA).[24]
History[edit]
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[25] It was known in the 19th century to have a paralysing effect, due in part to the studies of scientists like Claude Bernard.[26] D-tubocurarine a mono-quaternary alkaloid was isolated from Chondrodendron tomentosum in 1942, and it was shown to be the major constituent in curare responsible for producing the paralysing effect. At that time, it was known that curare and, therefore, d-tubocurarine worked at the neuromuscular junction. The isolation of tubocurarine and its marketing as the drug Intocostrin led to more research in the field of neuromuscular-blocking drugs. Scientists figured out that the potency of tubocurarine was related to the separation distance between the two quaternary ammonium heads.[2][27]
Further research led to the development of synthesized molecules with different curariform effects, depending on the distance between the quaternary ammonium groups. One of the synthesized bis-quaternaries was decamethonium a 10-carbon bis-quaternary compound. Following research with decamethonium, scientists developed suxamethonium, which is a double acetylcholine molecule that was connected at the acetyl end. The discovery and development of suxamethonium lead to a 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.[2][3]
Another compound malouétine that was a bis-quaternary steroid was isolated from the plant Malouetia bequaertiana and showed curariform activity. This led to the synthetic drug pancuronium, a bis-quaternary steroid, and subsequently other drugs that had better pharmacological properties.[2][28] Research on these molecules helped improve understanding of the physiology of neurons and receptors.
See also[edit]
Ganglionic blocker
References[edit]
Jump up ^ "Dorlands Medical Dictionary:neuromuscular blocking agent".
^ Jump up to: a b c d Raghavendra, T. (2002). "Neuromuscular blocking drugs: discovery and development". Journal of the Royal Society of Medicine. 95 (7): 363–367. doi:10.1258/jrsm.95.7.363. PMC 1279945  . PMID 12091515.
^ Jump up to: a b c d e f g h W. C. Bowman (2006). "Neuromuscular block". British Journal of Pharmacology. 147 (S1): S277–S286. doi:10.1038/sj.bjp.0706404. PMC 1760749  . PMID 16402115.
^ Jump up to: a b c d e Lee, C. (2001). "Structure, conformation and action of neuromuscular blocking drugs". British Journal of Anaesthesia. 87 (5): 755–769. doi:10.1093/bja/87.5.755. PMID 11878528.
Jump up ^ Bufler J, Wilhelm R, Parnas H, Franke C, Dudel J (1996). "Open channel and competitive block of the embryonic form of the nicotinic receptor of mouse myotubes by (+)-tubocurarine". J. Physiol. 495 (Pt 1): 83–95. doi:10.1113/jphysiol.1996.sp021575. PMC 1160726  . PMID 8866353.
Jump up ^ Neuromuscular Nondepolarizing Agents at the US National Library of Medicine Medical Subject Headings (MeSH)
Jump up ^ Inada E, Philbin DM, Machaj V, et al. (1986). "Histamine antagonists and d-tubocurarine-induced hypotension in cardiac surgical patients". Clin. Pharmacol. Ther. 40 (5): 575–80. doi:10.1038/clpt.1986.226. PMID 2429800.
^ Jump up to: a b Ostergaard D, Engbaek J, Viby-Mogensen J (1989). "Adverse reactions and interactions of the neuromuscular blocking drugs". Medical toxicology and adverse drug experience. 4 (5): 351–68. doi:10.1007/bf03259917. PMID 2682131.
^ Jump up to: a b c d e f g h i j k l m n o p q r s t u v w Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. p. 151. ISBN 0-443-07145-4. OCLC 51622037.
Jump up ^ Neuromuscular Depolarizing Agents at the US National Library of Medicine Medical Subject Headings (MeSH)
^ Jump up to: a b Flower, Rod; Rang, Humphrey P.; Dale, Maureen M.; Ritter, James M. (2007). Rang & Dale's pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-06911-5.
^ Jump up to: a b Brunton LL, Lazo JS, Parker KL (2006). "Goodman & Gilman's The pahrmacological basis of Therapeutics". New York: McGraw-Hill. pp. 220–223. ISBN 0071624422.
^ Jump up to: a b c d e f Lee, C.; Jones, T. (2002). "Molecular conformation–activity relationship of decamethonium congeners". British Journal of Anaesthesia. 88 (5): 692–699. doi:10.1093/bja/88.5.692. PMID 12067008.
^ Jump up to: a b c d e f g h i j k l m n o Lee, Chingmuh (2003). "Conformation, action and mechanism of action of neuromuscular blocking muscle relaxants". Pharmacology and Therapeutics. 98 (2): 143–169. doi:10.1016/S0163-7258(03)00030-5.
Jump up ^ Spivak CE, Waters JA, Aronstam RS (1 July 1989). "Binding of semirigid nicotinic agonists to nicotinic and muscarinic receptors". Molecular Pharmacology. 36 (1): 177–184. PMID 2747625.
Jump up ^ Beers, W.H; E. Reich (1970). "Structure and Activity of Acetylcholine". Nature. 228 (5275): 917–922. Bibcode:1970Natur.228..917B. doi:10.1038/228917a0.
Jump up ^ Caldwell JE, Szenohradszky J, Segredo V, Wright PM, McLoughlin C, Sharma ML, Gruenke LD, Fisher DM, Miller RD (1 September 1994). "The pharmacodynamics and pharmacokinetics of the metabolite 3- desacetylvecuronium (ORG 7268) and its parent compound, vecuronium, in human volunteers". American Society for Pharmacology and Experimental Therapeutics. 270 (3): 1216–1222. PMID 7932174.
Jump up ^ Kopman AF, Klewicka MM, Kopman DJ, Neuman GG (1999). "Molar potency is predictive of the speed of onset of neuromuscular block for agents of intermediate, short and ultrashort duration". Anesthesiology. 90 (2): 425–431. doi:10.1097/00000542-199902000-00016. PMID 9952148.
Jump up ^ Donati, F.; Claude Meistelman (2005). "A kinetic-dynamic model to explain the relationship between high potency and slow onset time for neuromuscular blocking drugs". Journal of pharmacokinetics and Pharmacodynamics. 19 (5): 537–552. doi:10.1007/BF01062962. PMID 1783991.
Jump up ^ Paradelis, A. G.; Triantaphyllidis, C.; Logaras, G. (1976). "Neuromuscular Blocking Activity of Aminoglycoside Antibiotics". Pharmacology of Antibiotics. p. 359. doi:10.1007/978-1-4684-3123-0_51. ISBN 978-1-4684-3125-4.
Jump up ^ thefreedictionary.com > train-of-four Citing: Mosby's Medical Dictionary, 8th edition.
Jump up ^ Strange, C.; Vaughan, L.; Franklin, C.; Johnson, J. I. M. (1997). "Comparison of Train-of-Four and Best Clinical Assessment during Continuous Paralysis". American Journal of Respiratory and Critical Care Medicine. 156 (5): 1556–1561. doi:10.1164/ajrccm.156.5.9701079. PMID 9372675.
Jump up ^ Shorten, G. D.; Ali, H. H.; Goudsouzian, N. G. (1993). "Neostigmine and edrophonium antagonism of moderate neuromuscular block induced by pancuronium or tubocurarine". British journal of anaesthesia. 70 (2): 160–162. doi:10.1093/bja/70.2.160. PMID 8435259.
Jump up ^ Naguib M (2007). "Sugammadex: another milestone in clinical neuromuscular pharmacology". Anesth Analg. 104 (3): 575–81. doi:10.1213/01.ane.0000244594.63318.fc. PMID 17312211.
Jump up ^ Taylor, P. (1990). Goodman and Gilman's The Pharmacological Basis of Therapeutics, 8th ed. A. G. Gilman et al. (eds.). New York: Pergamon Press. p. 167. ISBN 0071052704.
Jump up ^ Bernard, C (1857). "25th lesson". Leçons sur les effets des substances toxiques et médicamenteuses (in French). Paris: J.B. Baillière. pp. 369–80.
Jump up ^ Nedergaard, O. A. (2003). "Curare: Flying death". Pharmacology & toxicology. 92 (4): 154–5. doi:10.1034/j.1600-0773.2003.920402.x. PMID 12753415.
Jump up ^ McKenzie, A. G. (2000). "Prelude to pancuronium and vecuronium". Anaesthesia. 55 (6): 551–556. doi:10.1046/j.1365-2044.2000.01423.x. PMID 10866718.
External links[edit]
Neuromuscular blocking agents at the US National Library of Medicine Medical Subject Headings (MeSH)
[show]
v
t
e
Pharmacomodulation
Types
♦ Enzyme: Inducer
Inhibitor
♦ Ion channel: Opener
Blocker
♦ Receptor: Agonist
Partial agonist
Antagonist
Inverse agonist
Positive allosteric modulator (PAM)
Negative allosteric modulator (NAM)
♦ Transporter [Reuptake vs Efflux]: Enhancer (RE)
Inhibitor (RI)
Releaser (RA)
♦ Miscellaneous: Precursor
Cofactor
Classes
Enzyme
see Enzyme inhibition
Ion channel
Calcium channel blocker (CCB)
Potassium channel blocker (PCB)
Sodium channel blocker (SCB)
Potassium channel opener (PCO)
Receptor &
transporter
BA/M
Adrenergic
Adrenergic receptor agonist (α
β (1
2))
Adrenergic receptor antagonist (α (1
2)
β)
Norepinephrine reuptake inhibitor (NRI)
Dopaminergic
Dopamine receptor agonist
Dopamine receptor antagonist
Dopamine reuptake inhibitor (DRI)
Histaminergic
Histamine receptor agonist
Histamine receptor antagonist (H1
H2
H3)
Serotonergic
Serotonin receptor agonist
Serotonin receptor antagonist (5-HT3)
Serotonin reuptake inhibitor (SRI)
AA
GABAergic
GABA receptor agonist
GABA receptor antagonist
GABA reuptake inhibitor (GRI)
Glutamatergic
Glutamate receptor agonist (AMPA)
Glutamate receptor antagonist (NMDA)
Glutamate reuptake inhibitor
Cholinergic
Acetylcholine receptor agonist (Muscarinic
Nicotinic)
Acetylcholine receptor antagonist (Muscarinic
Nicotinic (Ganglionic
Muscular))
Cannabinoidergic
Cannabinoid receptor agonist
Cannabinoid receptor antagonist
Endocannabinoid enhancer (eCBE)
Endocannabinoid reuptake inhibitor (eCBRI)
Opioidergic
Opioid modulator
Opioid receptor agonist
Opioid receptor antagonist
Enkephalinase inhibitor
Other
Adenosine reuptake inhibitor (AdoRI)
Angiotensin II receptor antagonist
Endothelin receptor antagonist
NK1 receptor antagonist
Vasopressin receptor antagonist
Miscellaneous
Cofactor (see Enzyme cofactors)
Precursor (see Amino acids)
[show]
v
t
e
Skeletal muscle relaxants (M03)
Peripherally acting
(primarily antinicotinic,
NMJ block)
Non-depolarizing
Curare alkaloids
Alcuronium
Dimethyltubocurarine
Tubocurarine
4° ammonium agents
ultra-short duration: Gantacurium
short duration: Mivacurium
Chandonium
intermediate duration: Atracurium
Cisatracurium
Fazadinium
Rocuronium
Vecuronium
long duration: Doxacurium
Dimethyltubocurarine
Pancuronium
Pipecuronium
Laudexium
Gallamine
unsorted: Hexafluronium (Hexafluorenium)
Depolarizing
Choline derivatives: Suxamethonium (Succinylcholine)
Polyalkylene derivatives: Hexamethonium
ACh release inhibitors
Botulinum toxin
Centrally acting
Carbamic acid esters
Carisoprodol
Cyclarbamate
Difebarbamate
Febarbamate
Meprobamate
Phenprobamate
Styramate
Tybamate
Benzodiazepines
Bromazepam
Diazepam
Clonazepam
Flunitrazepam
Lorazepam
Nitrazepam
Temazepam
Tetrazepam
Nonbenzodiazepines
Eszopiclone
Thienodiazepines
Etizolam
Quinazolines
Methaqualone
Anticholinergics
(Antimuscarinics)
Cyclobenzaprine
Orphenadrine
Other
Arbaclofen placarbil
Baclofen
Chlormezanone
Chlorphenesin
Chlorzoxazone
Donepezil
Eperisone
Fenyramidol
Flopropione
Gabapentin
GHB
Inaperisone
Lanperisone
Mephenesin
Mephenoxalone
Metaxalone
Methocarbamol
Phenibut
Pregabalin
Pridinol
Promoxolane
Quinine
Silperisone
Thiocolchicoside
Tizanidine
Tolperisone
Zoxazolamine
Directly acting
Dantrolene
[show]
v
t
e
Acetylcholine metabolism and transport modulators
Enzyme
(modulators)
ChAT
Inhibitors: 1-(-Benzoylethyl)pyridinium
2-(α-Naphthoyl)ethyltrimethylammonium
3-Chloro-4-stillbazole
4-(1-Naphthylvinyl)pyridine
Acetylseco hemicholinium-3
Acryloylcholine
AF64A
B115
BETA
CM-54,903
N,N-Dimethylaminoethylacrylate
N,N-Dimethylaminoethylchloroacetate
AChE
Inhibitors: Reversible: Carbamates: Aldicarb
Aminocarb
Bendiocarb
Bufencarb
Carbaryl
Carbendazim
Carbetamide
Carbofuran
Carbosulfan
Chlorbufam
Chloropropham
Dimetilan
Ethienocarb
Ethiofencarb
Fenobucarb
Formetanate
Formparanate
Methiocarb
Methomyl
Metolcarb
Miotine
Oxamyl
Phenmedipham
Pinmicarb
Pirimicarb
Propamocarb
Propham
Propoxur
Thiofanox; Stigmines: Distigmine
Eptastigmine
Ganstigmine
Neostigmine
Phenserine
Physostigmine
Pyridostigmine
Quilostigmine
Rivastigmine
Terestigmine; Others: Acotiamide
Ambenonium
Caffeine
Donepezil
EA-3990
EA-4056
Edrophonium
Galantamine
Huperzine A
Ipidacrine
Itopride
Ladostigil
Minaprine
T-1123
Tacrine
Zanapezil
Irreversible: Organophosphates: Acephate
Anatoxin-a(S)
Azinphos-ethyl
Azinphos-methyl
BAY-29952
Bensulide
Cadusafos
Carbophenothion
Chlorethoxyfos
Chlorfenvinphos
Chlorpyrifos
Chlorpyrifos-methyl
Coumaphos
Cyanophos
Cyclosarin
Demephion
Demeton
Demeton-S-methyl
Dialifor
Diazinon
Dichlorvos
Dicrotophos
Diisopropyl fluorophosphate
Diisopropylphosphate
Dimefox
Dimethoate
Dimethyl 4-(methylthio)phenyl phosphate
Dioxathion
Disulfoton
EA-3148
Echothiophate
Endothion
Ethion
Ethoprop
Fenamiphos
Fenitrothion
Fenthion
Fonofos
Formothion
Fosthiazate
GV
Hexaethyl tetraphosphate
Isofluorophate
Isoxathion
Leptophos
Malaoxon
Malathion
Methamidophos
Methidathion
Methyl phenkapton
Metrifonate
Mevinphos
Monocrotophos
Naled
Novichok agent
Omethoate
Oxydemeton-methyl
Paraoxon
Parathion
Parathion-methyl
Phorate
Phosalone
Phosfolan
Phosmet
Phosphamidon
Phoxim
Pirimiphos-methyl
Profenofos
Prothoate
Sarin
Soman
Tabun
Tebupirimfos
Temefos
Terbufos
Tetrachlorvinphos
Triazofos
Tribufos
Trichlorfon
Trichloronate
Tricresyl phosphate
VE
VG
VM
VR
VX; Others: Demecarium
Fasciculins (green mamba toxins) (1, 2, 3, 4)
Onchidal (Onchidella binneyi)
Unsorted: α-Pinene
α-Viniferin
Affinine
Affinisine
Arisugacin A
Bulbocapnine
Conodurine
Coronaridine
Corydaline
Corynoline
Crimidine
Cyclanoline
Cymserine
Harmaline
Kobophenol A
Lactucopicrin
Lycorine
Phosacetim
Rosmarinic acid
Stercuronium iodide
Taspine
Tetrahydrocannabinol
Ungeremine
Ungiminorine
Reactivators: Asoxime chloride
Methoxime
Obidoxime
Pralidoxime
Trimedoxime bromide
BChE
Inhibitors: Affinine
Affinisine
Conodurine
Cymserine
Ladostigil
Profenamine (ethopropazine)
Rivastigmine
Tacrine
ZINC-12613047
Many of the other AChE inhibitors listed above
Transporter
(modulators)
CHT
Inhibitors: Hemicholinium-3 (hemicholine)
Triethylcholine
Enhancers: Coluracetam
VAChT
Inhibitors: Vesamicol
Release
(modulators)
Inhibitors
SNAP-25 inactivators: Botulinum toxin (A, C, E)
VAMP inactivators: Botulinum toxin (B, D, F, G)
Others: Bungarotoxins (β-bungarotoxin, γ-bungarotoxin)
Enhancers
LPHN agonists: α-Latrotoxin
Others: Atracotoxin (e.g., robustoxin, versutoxin)
Crotoxin
See also: Receptor/signaling modulators • Muscarinic acetylcholine receptor modulators • Nicotinic acetylcholine receptor modulators
[show]
v
t
e
Nicotinic acetylcholine receptor modulators
nAChRs
Agonists
(and PAMs)
5-HIAA
A-84,543
A-366,833
A-582,941
A-867,744
ABT-202
ABT-418
ABT-560
ABT-894
Acetylcholine
Altinicline
Anabasine
Anatoxin-a
AR-R17779
Bephenium hydroxynaphthoate
Butinoline
Butyrylcholine
Carbachol
Choline
Cotinine
Cytisine
Decamethonium
Desformylflustrabromine
Dianicline
Dimethylphenylpiperazinium
Epibatidine
Epiboxidine
Ethanol (alcohol)
Ethoxysebacylcholine
EVP-4473
EVP-6124
Galantamine
GTS-21
Ispronicline
Ivermectin
JNJ-39393406
Levamisole
Lobeline
MEM-63,908 (RG-3487)
Morantel
Nicotine (tobacco)
NS-1738
PHA-543,613
PHA-709,829
PNU-120,596
PNU-282,987
Pozanicline
Pyrantel
Rivanicline
RJR-2429
Sazetidine A
SB-206553
Sebacylcholine
SIB-1508Y
SIB-1553A
SSR-180,711
Suberyldicholine
Suxamethonium (succinylcholine)
Suxethonium (succinyldicholine)
TC-1698
TC-1734
TC-1827
TC-2216
TC-5214
TC-5619
TC-6683
Tebanicline
Tribendimidine
Tropisetron
UB-165
Varenicline
WAY-317,538
XY-4083
Antagonists
(and NAMs)
18-MAC
18-MC
α-Neurotoxins (e.g., α-bungarotoxin, α-cobratoxin, α-conotoxin, many others)
ABT-126
Alcuronium
Allopregnanolone
Amantadine
Anatruxonium
AQW051
Atracurium
Barbiturates (e.g., pentobarbital, sodium thiopental)
BNC-210
Bungarotoxins (e.g., α-bungarotoxin, κ-bungarotoxin)
Bupropion
BW-A444
Candocuronium iodide (chandonium iodide)
Chlorisondamine
Cisatracurium
Coclaurine
Coronaridine
Curare
Cyclopropane
Dacuronium bromide
Decamethonium
Dehydronorketamine
Desflurane
Dextromethorphan
Dextropropoxyphene
Dextrorphan
Diadonium
DHβE
Dihydrochandonium
Dimethyltubocurarine (metocurine)
Dioscorine
Dipyrandium
Dizocilpine (MK-801)
Doxacurium
Encenicline
Enflurane
Erythravine
Esketamine
Fazadinium
Gallamine
Gantacurium chloride
Halothane
Hexafluronium
Hexamethonium (benzohexonium)
Hydroxybupropion
Hydroxynorketamine
Ibogaine
Isoflurane
Ketamine
Kynurenic acid
Laudanosine
Laudexium (laudolissin)
Levacetylmethadol
Levomethadone
Malouetine
ME-18-MC
Mecamylamine
Memantine
Methadone
Methorphan (racemethorphan)
Methyllycaconitine
Metocurine
Mivacurium
Morphanol (racemorphan)
Neramexane
Nitrous oxide
Norketamine
Pancuronium bromide
Pempidine
Pentamine
Pentolinium
Phencyclidine
Pipecuronium bromide
Progesterone
Promegestone
Radafaxine
Rapacuronium bromide
Reboxetine
Rocuronium bromide
Sevoflurane
Stercuronium iodide
Surugatoxin
Thiocolchicoside
Toxiferine
Tramadol
Trimetaphan camsilate (trimethaphan camsylate)
Tropeinium
Tubocurarine
Vanoxerine
Vecuronium bromide
Xenon
Precursors
(and prodrugs)
Acetyl-coA
Adafenoxate
Choline (lecithin)
Citicoline
Cyprodenate
Dimethylethanolamine
Glycerophosphocholine
Meclofenoxate (centrophenoxine)
Phosphatidylcholine
Phosphatidylethanolamine
Phosphorylcholine
Pirisudanol
See also: Receptor/signaling modulators • Muscarinic acetylcholine receptor modulators • Acetylcholine metabolism/transport modulators
Retrieved from "https://en.wikipedia.org/w/index.php?title=Neuromuscular-blocking_drug&oldid=809642264"
Categories:
Muscle relaxants
Neuromuscular blockers
Hidden categories:
CS1 French-language sources (fr)
All articles with unsourced statements
Articles with unsourced statements from March 2010
Navigation menu
Personal tools
Not logged in
Talk
Contributions
Create account
Log in
Namespaces
Article
Talk
Variants
Views
Read
Edit
View history
More
Search
Navigation
Main page
Contents
Featured content
Current events
Random article
Donate to Wikipedia
Wikipedia store
Interaction
Help
About Wikipedia
Community portal
Recent changes
Contact page
Tools
What links here
Related changes
Upload file
Special pages
Permanent link
Page information
Wikidata item
Cite this page
Print/export
Create a book
Download as PDF
Printable version
Languages
Català
Español
Polski
Português
中文
Edit links
This page was last edited on 10 November 2017, at 13:30.
Text is available under the Creative Commons Attribution-ShareAlike License; additional terms may apply. By using this site, you agree to the Terms of Use and Privacy Policy. Wikipedia® is a registered trademark of the Wikimedia Foundation, Inc., a non-profit organization.
Privacy policy
About Wikipedia
Disclaimers
Contact Wikipedia
Developers
Cookie statement
Mobile view
Enable previews

values: mw-page-base noprint

values: mw-head-base noprint

values: firstHeading firstHeading en

values: siteSub noprint

values: jump-to-nav mw-jump

attrs: href class

values:
/wiki/Muscle_fiber
mw-redirect
Muscle fiber

values:
/wiki/Acetylcholine_receptors
mw-redirect
Acetylcholine receptors

values:
/wiki/Tetanus_toxin
mw-redirect
Tetanus toxin

values:
/wiki/Conduction_block
mw-redirect
Conduction block

values:
/wiki/General_anesthetic
mw-redirect
General anesthetic

values:
/wiki/Quaternary_ammonium_salt
mw-redirect
Quaternary ammonium salt

values:
/wiki/Quaternary_ammonium
mw-redirect
Quaternary ammonium

values:
/wiki/Muscle_relaxants
mw-redirect
Muscle relaxants

values: Edit section: Non-depolarizing blocking agents

values:
/wiki/Neuromuscular_blocker
mw-redirect
Neuromuscular blocker

values:
/wiki/Motor_end_plate
mw-redirect
Motor end plate

values:
/wiki/Competitive_antagonist
mw-redirect
Competitive antagonist

values:
/wiki/Duration_of_action
mw-redirect
Duration of action

values: This claim needs references to reliable sources. (March 2010)

values:
noprint Inline-Template Template-Fact
white-space:nowrap;

values: Edit section: Depolarizing blocking agents

values:
/wiki/Nicotinic_receptor
mw-redirect
Nicotinic receptor

values: Edit section: Structural and conformational action relationship

values:
/wiki/Structure-activity_relationship
mw-redirect
Structure-activity relationship

values: Edit section: Molecular length and rigidity

values:
/wiki/Chemical_group
mw-redirect
Chemical group

values: Decamethylene bisatropium (page does not exist)

values:
/wiki/Muscarinic_receptor
mw-redirect
Muscarinic receptor

values:
/wiki/Diaphragm_(anatomy)
mw-redirect
Diaphragm (anatomy)

values:
/wiki/Cardiac_arrhythmia
mw-redirect
Cardiac arrhythmia

values:
/wiki/Intensive_care
mw-redirect
Intensive care

values:
/wiki/Selective_relaxant_binding_agent
mw-redirect
Selective relaxant binding agent

values:
/wiki/Nobel_Prize_in_medicine
mw-redirect
Nobel Prize in medicine

values: Malouetia bequaertiana (page does not exist)

values: Journal of the Royal Society of Medicine

values:
nofollow
external text
//doi.org/10.1258%2Fjrsm.95.7.363

attrs: alt src title width height srcset data-file-width data-file-height

values:
/wiki/PubMed_Identifier
mw-redirect
PubMed Identifier

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/12091515

values:
nofollow
external text
//doi.org/10.1038%2Fsj.bjp.0706404

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/16402115

values:
nofollow
external text
//doi.org/10.1093%2Fbja%2F87.5.755

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/11878528

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/8866353

values:
nofollow
external text
//doi.org/10.1038%2Fclpt.1986.226

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/2429800

values:
nofollow
external text
//doi.org/10.1007%2Fbf03259917

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/2682131

values:
nofollow
external text
//www.worldcat.org/oclc/51622037

values:
nofollow
external text
//doi.org/10.1093%2Fbja%2F88.5.692

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/12067008

values:
/wiki/Pharmacology_and_Therapeutics
mw-redirect
Pharmacology and Therapeutics

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/2747625

values:
nofollow
external text
//doi.org/10.1038%2F228917a0

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/7932174

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/9952148

values: Journal of pharmacokinetics and Pharmacodynamics (page does not exist)

values:
nofollow
external text
//doi.org/10.1007%2FBF01062962

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/1783991

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/9372675

values:
nofollow
external text
//doi.org/10.1093%2Fbja%2F70.2.160

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/8435259

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/17312211

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/12753415

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/10866718

values: -moz-column-width: 30em; -webkit-column-width: 30em; column-width: 30em; list-style-type: decimal;

values:
/wiki/Positive_allosteric_modulator
mw-redirect
Positive allosteric modulator

values:
/wiki/Negative_allosteric_modulator
mw-redirect
Negative allosteric modulator

values:
/wiki/Releasing_agent
mw-redirect
Releasing agent

values:
/wiki/Histamine_antagonist
mw-redirect
Histamine antagonist

values:
/wiki/Serotonin_antagonist
mw-redirect
Serotonin antagonist

values:
/wiki/GABA_agonist
mw-redirect
GABA agonist

values:
/wiki/GABA_antagonist
mw-redirect
GABA antagonist

values:
/wiki/Excitatory_amino_acid_agonist
mw-redirect
Excitatory amino acid agonist

values:
/wiki/Excitatory_amino_acid_antagonist
mw-redirect
Excitatory amino acid antagonist

values: Excitatory amino acid reuptake inhibitor

values:
/wiki/Template:Amino_acids
mw-redirect
Template:Amino acids

values: nowraplinks collapsible collapsed navbox-inner

values: navigation navbox Pharmacomodulation padding:3px

values:
/wiki/Neuromuscular-blocking_drugs
mw-redirect
Neuromuscular-blocking drugs

values:
/wiki/Neuromuscular_depolarizing_agent
mw-redirect
Neuromuscular depolarizing agent

values: nowraplinks collapsible autocollapse navbox-inner

values: Template:Acetylcholine metabolism and transport modulators

values: Template talk:Acetylcholine metabolism and transport modulators

values: 1-(-Benzoylethyl)pyridinium (page does not exist)

values: 2-(α-Naphthoyl)ethyltrimethylammonium (page does not exist)

values: 3-Chloro-4-stillbazole (page does not exist)

values: 4-(1-Naphthylvinyl)pyridine (page does not exist)

values: Acetylseco hemicholinium-3 (page does not exist)

values: (E)-1-Methyl-4-(1-naphthylvinyl)-1,2,3,6-tetrahydropyridine (page does not exist)

values: (2-Benzoylethyl)trimethylammonium (page does not exist)

values: N,N-Dimethylamino-2-ethoxyimino-2-adamantane (page does not exist)

values: N,N-Dimethylaminoethylacrylate (page does not exist)

values: N,N-Dimethylaminoethylchloroacetate (page does not exist)

values:
/wiki/Transporter_modulator
mw-redirect
Transporter modulator

values:
/wiki/Neurotransmitter_release
mw-redirect
Neurotransmitter release

values:
/wiki/Release_inhibitor
mw-redirect
Release inhibitor

values:
/wiki/Botulinum_toxin_A
mw-redirect
Botulinum toxin A

values:
/wiki/Release_enhancer
mw-redirect
Release enhancer

values: Template:Muscarinic acetylcholine receptor modulators

values: Template:Nicotinic acetylcholine receptor modulators

values: Template talk:Nicotinic acetylcholine receptor modulators

values:
/wiki/Nicotinic_acetylcholine_receptors
mw-redirect
Nicotinic acetylcholine receptors

values:
/wiki/Receptor_agonist
mw-redirect
Receptor agonist

values:
/wiki/Positive_allosteric_modulators
mw-redirect
Positive allosteric modulators

values: Ethoxysebacylcholine (page does not exist)

values:
/wiki/Negative_allosteric_modulators
mw-redirect
Negative allosteric modulators

values: Dihydro-beta-erythroidine (page does not exist)

values: Category:CS1 French-language sources (fr)

values: Category:All articles with unsourced statements

values: Category:Articles with unsourced statements from March 2010

values: Discussion about edits from this IP address [ctrl-alt-n]

values: A list of edits made from this IP address [ctrl-alt-y]

values: You are encouraged to create an account and log in; however, it is not mandatory

values: You're encouraged to log in; however, it's not mandatory. [ctrl-alt-o]

values:
/wiki/Neuromuscular-blocking_drug
View the content page [ctrl-alt-c]
c

values: Discussion about the content page [ctrl-alt-t]

values: p-namespaces navigation vectorTabs p-namespaces-label

values:
p-variants
navigation
vectorMenu emptyPortlet
p-variants-label

values: Past revisions of this page [ctrl-alt-h]

values: p-views navigation vectorTabs p-views-label

values:
p-cactions
navigation
vectorMenu emptyPortlet
p-cactions-label

values:
mw-wiki-logo
/wiki/Main_Page
Visit the main page

values:
/wiki/Main_Page
Visit the main page [ctrl-alt-z]
z

values: Featured content – the best of Wikipedia

values: Find background information on current events

values:
/wiki/Special:Random
Load a random article [ctrl-alt-x]
x

values: portal navigation p-navigation p-navigation-label

values: Guidance on how to use and edit Wikipedia

values: About the project, what you can do, where to find things

values: A list of recent changes in the wiki [ctrl-alt-r]

values: portal navigation p-interaction p-interaction-label

values: List of all English Wikipedia pages containing links to this page [ctrl-alt-j]

values: Recent changes in pages linked from this page [ctrl-alt-k]

values:
/wiki/Wikipedia:File_Upload_Wizard
Upload files [ctrl-alt-u]
u

values: A list of all special pages [ctrl-alt-q]

values: Permanent link to this revision of the page

values: Link to connected data repository item [ctrl-alt-g]

values: Printable version of this page [ctrl-alt-p]

values: Depolaryzujące środki zwiotczające – Polish

values: 神经肌肉阻滞药 – Chinese

values: mediawiki ltr sitedir-ltr mw-hide-empty-elt ns-0 ns-subject page-Neuromuscular-blocking_drug rootpage-Neuromuscular-blocking_drug skin-vector action-view