neuromuscular-blocking drug neuromuscular-blocking drug neuromuscular-blocking drugs block neuromuscular transmission at the neuromuscular junction, causing paralysis of the affected skeletal muscles. this is accomplished via their action on the post-synaptic acetylcholine (nm) receptors. global view of a neuromuscular junction: axonmotor end-platemuscle fibermyofibril detailed view of a neuromuscular junction: presynaptic terminalsarcolemmasynaptic vesiclenicotinic acetylcholine receptormitochondrion for similar term named cholinesterase–blocking drug, see cholinesterase inhibitor. 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. nomenclature 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. 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. classification 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. 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 a neuromuscular non-depolarizing agent is a form of neuromuscular blocker that does not depolarize the motor end plate. the quaternary ammonium muscle relaxants belong to this class. 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. 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, as well as its effect of blocking autonomic ganglia. 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) bronchospasm withdrawn due to bronchospasm risk mivacurium (mivacron) 90 12–18 hypotension (transiently), by release of histamine no longer manufactured secondary to marketing, manufacturing, and financial concerns refrigerated atracurium (tracrium) 90 30 min or less hypotension, transiently, by release of histamine toxic metabolite called laudanosine, greater accumulation in individuals with renal failure widely refrigerated doxacurium (nuromax) long hypotension, transiently, by release of histamine harmful metabolite called laudanosine (lowering seizure threshold); greater accumulation in individuals with renal failure cisatracurium (nimbex) 90 60–80 does not cause release of histamine refrigerated vecuronium (norcuron) 60 30–40 few, may cause prolonged paralysis and promote muscarinic block widely non-refrigerated rocuronium (zemuron) 75 45–70 may promote muscarinic block non-refrigerated pancuronium (pavulon) 90 180 or more tachycardia (slight) (no hypotension) widely non-refrigerated tubocurarine (jexin) 300 or more 60–120 hypotension (by ganglion-block and histamine release) bronchoconstriction (by histamine release) rarely gallamine (flaxedil) 300 or more 60–120 tachycardia non-refrigerated pipecuronium 90 180 or more tachycardia (slight) (no hypotension) non-refrigerated depolarizing blocking agents a depolarizing neuromuscular blocking agent is a form of neuromuscular blocker that depolarizes the motor end plate. 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 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. 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. mechanism of action fig.1 a simple illustration of how two acetylcholine molecules bind to its receptive sites on the nicotinic receptorquaternary 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. 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. 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. 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. structural and conformational action relationship 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. 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. 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. molecular length and rigidity fig.2 a simple illustration of how decamethonium binds to the nicotinic receptor. the onium heads bind to two separate subunits of the ion-channelneuromuscular blocking agents need to fit in a space close to 2 nanometres, which resembles the molecular length of decamethonium. 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.