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Atracurium besylate

[1]

is a neuromuscular-blocking drug or skeletal muscle relaxant in the category of non-

depolarizing neuromuscular-blocking drugs, used adjunctively in anesthesia to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation. Atracurium is classified as an intermediate-duration non-depolarizing neuromuscular-blocking agent.

History[edit]
Atracurium besylate was first synthesized in 1974 by George H. Dewar, a pharmacist and a medicinal chemistry doctoral candidate in John B. Stenlake's medicinal chemistry research group in the Department [2] of Pharmacy at Strathclyde University, Scotland. Dewar first named this compound "33A74" before its eventual emergence in the clinic as atracurium. Atracurium was the culmination of a rational approach to drug design to produce the first non-depolarizing non-steroidal skeletal muscle relaxant that undergoes chemodegradation in vivo. [3] The term chemodegradation was coined by Roger D. Waigh, PhD, also a pharmacist and a postdoctoral researcher in Stenlake's research group. Atracurium was licensed by Strathclyde University to The Wellcome Foundation [4] Ltd. UK, which developed the drug (then known as BW 33A ) and its introduction to first human trials in [5][6] [7] 1979, and then eventually to its first introduction (as a mixture of all ten stereoisomers ) into clinical anesthetic practice in the UK, in 1983, under the tradename of Tracrium. The premise to the design of atracurium and several of its congeners stemmed from the knowledge that a bisquaternary structure is essential forneuromuscular-blocking activity: ideally, therefore, a chemical entity devoid of this bis-quaternary structure via susceptibility to inactive breakdown products by enzymic-independent processes would prove to be invaluable in the clinical use of a drug with a predictable onset and duration of action. Hofmann elimination provided precisely this basis: It is a chemical process in which a suitably activated quaternary ammonium [8] compound can be degraded by the mildly alkaline conditions present at physiological pH and temperature. In effect, Hofmann elimination is a retro-Michael addition chemical process. It is important to note here that the physiological process of Hofmann elimination differs from the non-physiological Hofmanndegradation process: the latter is a chemical reaction in which a quaternary ammonium hydoxide solid salt is heated to 100 °C, or an aqueous solution of the salt is boiled. Regardless of which Hofmann process is referenced, the end-products in both situations will be the same: an alkene and a tertiary amine. The approach to utilizing Hofmann elimination as a means to promoting biodegradation had its roots in much earlier observations that the quaternaryalkaloid petaline (obtained from the Lebanese plant Leontice leontopetalum) readily underwent facile Hofmann elimination to a tertiary amine calledleonticine upon passage through a basic (as opposed [9] to an acidic) ion-exchange resin. Stenlake's research group advanced this concept by systematically synthesizing [10][11][12][13] [14] numerous quaternary ammonium β-aminoesters and β-aminoketones and evaluated them for skeletal [5][12] [2][15] muscle relaxant activity: one of these compounds, initially labelled as 33A74, eventually led to further clinical development, and came to be known as atracurium. Atracurium's limited clinical utility for the future was presaged with the marketing approval of cisatracurium in 1995 under the tradename of Nimbex. Cisatracurium is the R-cis R-cis isomer component of the ten stereoisomers that [7] comprise atracurium. The pharmacodynamic and adverse effects profile of cisatracurium proved to be superior to that of atracurium, which rapidly led to decline in the use of atracurium. The clinical development of cisatracurium was undertaken by Burroughs Wellcome Co. (and its parent The Wellcome Foundation Ltd.), from 1992 to 1994, and by the time of its approval for use in humans by the US Food and Drug Administration, Burroughs Wellcome Co. had merged with Glaxo Inc., and Nimbex was subsequently marketed worldwide byGlaxoWellcome Inc.
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Neuromuscular function parameters: definitions[edit]

ED95: the dose of any given neuromuscular-blocking agent required to produce 95% suppression of muscle twitch (e.g., the adductor pollicis) response with balanced anesthesia

Chapple and Clarke reported on the neuromuscular and cardiovascular effects of the breakdown products of atracurium and related substances in anesthetized cats. However. Laudanosine.3–0. Hughes and Payne described the [16] 14 preliminary pharmacology of atracurium in anesthethetized cats. the quaternary acid and metholaudanosine were devoid of neuromuscular blocking activity within the dose range 0. A C radiolabeled metabolism study in cats confirmed the lack of hepatic or renal involvement in the metabolism of atracurium: radioactivity eliminated in bile and urine was predominantly from metabolites rather than the unchanged parent [17] drug.v.provides a measure of the full recovery of neuromuscular function     Duration of action: definitions[edit] Neuromuscular-blocking agents can be classified in accordance to their duration of pharmacological action. They concluded that the metabolites were of low potencies. defined as follows: Classification of neuromuscular-blocking agents by duration of pharmacological action (minutes) Parameter Ultra-short Duration Short Duration Intermediate Duration Long Duration Clinical Duration (Time from injection to T25% recovery) 6-8 12-20 30-45 >60 Recovery Time (Time from injection to T95% recovery) Recovery Index (T25%-T75% recovery slope) <15 25-30 50-70 90-180 2-3 6 10-15 >30 Preclinical pharmacology[edit] Several publications describe the preclinical pharmacology of atracurium.essentially.5 –4 mg kg-1.6 mg kg-1 i. Clinical duration: difference in time between time of injection and time to 25% recovery from neuromuscular block Train-of-Four (TOF) response: stimulated muscle twitch response in trains of four when stimuli are applied in a burst of four as opposed to a single stimulus. equal depression in depolarising and fading response with nondepolarising blocker. and quite likely that the quantities present either as an impurity or formed after administration of therapeutic doses of atracurium (0. the difference in time between the time to recovery to 25% and time to recovery to 75% of baseline value T4:T1 ≥ 0.9: a 90% ratio of the fourth twitch to the first twitch in a TOF .provides a measure of the recovery of neuromuscular function T4:T1 ≥ 0.7: a 70% ratio of the fourth twitch to the first twitch in a TOF . [18] . dogs and rhesus monkeys.) would be of no pharmacological importance. 25%-75% recovery index: an indicator of the rate of skeletal muscle recovery .

On the other hand. with accumulation of clinical data over time. 2R. the quaternary acid. cis−trans. but only two are presented in the pharmaceutical preparation.hypotension. Hofmann elimination is a temperature. The initial in vitro studies appeared to indicate a major role for ester hydrolysis but. Although there are four stereocentres. Administration of the quaternary monoacrylate. [cis-cis isomers ≈ 58% cis-trans isomers ≈ 36% trans-trans isomers ≈ 6%]. while the facial flush may take around 3–4 [citation needed] minutes to dissipate. there is a plane of symmetry running through the centre of the diester bridge. Otherwise. the quaternary alcohol. (August 2012) The tetrahydroisoquinolinium class of neuromuscular blocking agents. and. Clinical pharmacology[edit] Atracurium is susceptible to degradation by Hofmann elimination and ester hydrolysis as components of the in [19][20] [19] vivo metabolic processes. metholaudanosine and the monoquaternary analogue at 4 mg kg1 doses resulted in a significant reduction in mean arterial pressure (by 30 –70 mm Hg). to a small extent. 1′R. in general. they reported that the quaternary monoacrylate. whereas significant vagal blockade occurred after 4 mg kg-1 of the quaternary monoacrylate. hypotension and a consequent [citation needed] reflextachycardia. It should be noted though that these sequelae are very transient effects: The total duration of the cardiovascular effects is no more than one to two minutes. reflex tachycardia and cutaneous flush [edit] This section needs additional citations for verification. 2′R at the four stereocentres. and the monoquaternary analogue. the preponderence of evidence indicated that Hofmann elimination at [20] physiological pH is the major degradation pathway vindicating the premise for the design of atracurium to undergo [21] an organ-independent metabolism. There are some exceptions to this rule. Most commonly. with increasing doses administered at the same rate. There are three cis-cis isomers (an enantiomeric pair and a meso structure). and therefore atracurium's rate of degradation in vivo is highly influenced by body pH and temperature: An increase in body pH favors the elimination [6][16] [21] process. the quaternary alcohol and the monoquaternary analogue produced a dose-dependent neuromuscular block. the histamine release following administration of these agents is associated with observable cutaneous flushing (facial face and arms. age. or by the status of renal or hepatic [28] function. laudanosine. excretion of the metabolite. and so 6 meso structures (structures that can be superimposed by having the opposite configuration then 180° rotation) are formed. Significant sympathetic blockade after preganglionic nerve stimulation was observed only with the monoquaternary analogue at a dose of 4 mg kg-1.5 :6. The pharmaceutical presentation is a mixture of all ten possible stereoisomers. The liberation of histamine is a dose-dependent phenomenon such that. This reduces the number from sixteen to ten. commonly). Because these effects are so transient. which could give 16 structures.. and three trans-trans isomers (an enantiomeric pair and a meso structure).and pH-dependent process.2 :1. Unsourced material may be challenged and removed. Adverse effects[edit] Histamine release . laudanosine. cisatracurium (trade name Nimbex). the breakdown process is [22] [23] [24][25][26][27] unaffected by the level of plasma esterase activity. One of the three cis-cis structures is marketed as a single-isomer preparation.within this dose range. atracurium itself is [23][26] dependent on hepatic and renal functions that tend to be less efficient in the elderly population. The beta-blocking drug Nebivolol has ten similar structures with 4 stereocentres and a plane of symmetry. obesity. there is no reason to administer adjunctive . The proportions of cis−cis. four cis-trans isomers (two enantiomeric pairs).g. Please help improve this article by adding citations to reliable sources. there is a greater propensity for eliciting histamine release and its ensuing [citation needed] sequelae. whereas a decrease in temperature slows down the process. cisatracurium (Nimbex) is one such agent that does not elicit histamine release even up to [citation needed] 5xED95 doses. the quaternary alcohol. e. and trans−trans isomers are in the ratio of 10. is associated [29] with histamine release upon rapid administration of a bolus intravenous injection. it has the configuration 1R.

fact and information pertaining to adverse events were distorted to suit taste. when observed. now subsumed into Merck & Co.rapacuronium (Raplon . which led to the latter's withdrawal of approval for clinical use worldwide. now subsumed into GlaxoSmithKline) and vecuronium (Norcuron .a steroidal neuromuscular-blocking agent marketed by Organon. There was complete failure to disseminate the true picture that not only are these effects transient but that the extent of the hypotensive effect and the reflex tachycardia are rarely of clinical significance and therefore did not require adjunctive therapy. However. because laudanosine is cleared primarily via renal excretion. vecuronium.Pulmonary compliance[edit] Bronchospasm has been reported on occasion with the use of atracurium. both for the public and for atracurium.. following its administration. and Organon. instead. this particular undesirable effect does not appear to be observed nearly as often as that seen with rapacuronium. The most common misinformation seeded into the minds of anesthesiologists was the failure to categorically state that the cardiovascular effects following histamine release were transient. Indeed. 2001 from clinical use (<2 years after its approval by the US [35] FDA on August 18. these ill-willed beguiling notions have persisted through the decades and become ingrained with each successive generation of newly qualified anesthesiologists and CRNAs (certified registered nurse anesthetists) to the extent that the mere mention of "benzylisoquinolines" (the erroneous but commonly used class name for tetrahydroisoquinolinium neuromuscularblocking agents) immediately conjures images ofhistamine release and generates serious anxiety. a tertiary amino alkaloid reported to be a modest CNS stimulant with [53] [54] epileptogenic activity and cardiovascular effects such a hypotension and bradycardia. and gallamine. 1999 . which had to be [34] withdrawn voluntarily during the week of March 19. The issue of bronchospasm acquired considerable prominence in the neuromuscular-blocking agents arena after the spectacular failure of a clinically introduced neuromuscular-blocking agent. much misinformation was deliberately disseminated regarding histamine release and its effects: this was particularly so in the 1980s and 1990s shortly after the near simultaneous competitive clinical introduction of atracurium (Tracrium a bistetrahydroisoquinolinium neuromuscular-blocking agent marketed by Burroughs Wellcome Co. were evident only at plasma concentrations 8 to 10 times greater than those observed in . Inc. Thus. including five "unexplained" fatalities. erroneous information was quickly and subtly disseminated very shortly after the clinical introduction of atracurium that the clinical use of atracurium was likely to result in a terrible tragedy because of [53] the significant clinical hazard by way of frank seizures induced by the laudanosine by-product . a cat study modelling anephric patients went so far as to corroborate that EEG changes. As part of the then fierce marketing battle between the competing pharmaceutical companies (Burroughs Wellcome Co. one of the major metabolites from this process is laudanosine.see NME Drug and New Biologic Approvals in 1999) after several serious events [36][37] [38] ofbronchospasm.a steroidal neuromuscular-blocking agent marketed by Organon. However. rapid initial investigations irrefutably failed to find any overt or EEG evidence for a [56][57] connection between atracurium administration and epileptogenic activity. as well as [47] [48][49] [50][51] [52] alcuronium. in the fierce battle to win market share for sales of the "steroidal" versus the terahydroisoquinolinium class of neuromuscular-blocking agents. tubocurarine and succinylcholine. the marketing focus was single-mindedly to regurgitate and emphasize that the tetrahydroisoquinolinium class elicited histamine release that could prove to be a danger to the cardiovascular stability of the patient during surgical procedures. Bronchospasm . and.the posited hypothesis being that the laudanosine produced from the chemodegradation of parent atracurium would cross the [55] blood–brain barrier in sufficiently high enough concentrations that lead to epileptogenic foci. pancuronium. now subsumed into Merck & Co.). and. [30][31][32][33] Laudanosine – Epileptic foci[edit] Because atracurium undergoes Hofmann elimination as a primary route of chemodegradation. Inc.) with their respective products.therapy to ameliorate either the cutaneousor the cardiovascular effects. Inc.). That is not to say that bronchospasm was an unknown phenomenon prior to rapacuronium: Occasional reports of bronchospasm have been [39][40][41] [42][43][44][45][46] noted also with the prototypical agents. Fortunately. as evidenced by the complete lack of any clinical literature advocating the need for adjunctive antihistamine use concomitantly with the administration of tetrahydroisoquinolinium neuromuscular-blocking agents. as a consequence.

owing to accumulation of cytosolic calcium caused by activation of acetylcholine receptor ion channels. were likely to cause acute excitement and seizures. Plasma concentrations of laudanosine generated are lower when [54] cisatracurium is used. following atracurium administration in an anephric patient. confirmed that. because of its identical structure to atracurium. the cat study predicted that. work by Cardone et al. Just over two decades later with uninterrupted clinical availability of atracurium. when introduced directly into the CNS. almost a decade later. Furthermore.humans during infusions of atracurium.. it is the steroidal neuromuscular-blocking agents pancuronium and vecuronium that. Laudanosine is also a metabolite of cisatracurium that. neither atracurium nor laudanosine caused such accumulation of intracellular calcium. Unlike the two steroidal agents. [58] . Thus.a prediction that correlated very well with a study in patients with renal failure and undergoing cadaveric renal [59] [60] transplantation. in fact. laudanosine accumulation and related CNS or cardiovascular toxicity were unlikely . there is now little doubt that laudanosine accumulation and related toxicity will likely ever be seen with the [54] doses of atracurium that are administered in clinical practice. undergoes chemodegradation via Hofmann elimination in vivo.