decamethonium for example needs relatively high energy to change the n-n distance. in general, molecular rigidity contributes to potency, while size affects whether a muscle relaxant shows a polarizing or a depolarizing effect. cations must be able to flow through the trans-membrane tube of the ion-channel to depolarize the endplate. small molecules may be rigid and potent but unable to occupy or block the area between the receptive sites. 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.) 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. 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. 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. 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. 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. beers and reich's law it has been concluded that acetylcholine and related compounds must be in the gauche (bent) configuration when bound to the nicotinic receptor. 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.) rational design 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. 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. 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. 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). 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. 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. 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. pharmacokinetics 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-channeldeacetylating vecuronium at position 3 results in a very active metabolite. 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. 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. 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. 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. 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. 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 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. 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 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. estimating effect 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. it is recommended during use of continuous-infusion neuromuscular blocking agents in intensive care. 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. 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 and vecuronium in general anaesthesia. it is the first selective relaxant binding agent (srba). 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 it was known in the 19th century to have a paralysing effect, due in part to the studies of scientists like claude bernard. 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