Atracurium Besylate 64228-79-1

History

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 of Pharmacy at the Strathclyde University, Scotland. Dewar first named this compound "33A74" also a pharmacist and a postdoctoral researcher in Stenlake's research group. Atracurium was licensed by Strathclyde University to The Wellcome Foundation Ltd. UK, which developed the drug (then known as BW 33A) and its introduction to first human trials in 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 bis-quaternary structure is essential for neuromuscular 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 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 Hofmann degradation 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 quaternary alkaloid petaline (obtained from the Lebanese plant Leontice leontopetalum) readily underwent facile Hofmann elimination to a tertiary amine called leonticine upon passage through a basic (as opposed to an acidic) ion-exchange resin. Stenlake's research group advanced this concept by systematically synthesizing numerous quaternary ammonium β-aminoesters and β-aminoketones and evaluated them for skeletal muscle relaxant activity: one of these compounds, 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 comprise atracurium. A ¹⁴C 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 drug. Chapple and Clarke reported on the neuromuscular and cardiovascular effects of the breakdown products of atracurium and related substances in anesthetized cats. They concluded that the metabolites were of low potencies, and quite likely that the quantities present either as an impurity or formed after administration of therapeutic doses of atracurium (0. 3-0. 6 mg kg-1 i. v. ) would be of no pharmacological importance. Laudanosine, the quaternary acid and metholaudanosine were devoid of neuromuscular blocking activity within the dose range 0. 5-4 mg kg-1. However, within this dose range, they reported that the quaternary monoacrylate, the quaternary alcohol and the monoquaternary analogue produced a dose-dependent neuromuscular block. Administration of the quaternary monoacrylate, laudanosine, the quaternary alcohol, metholaudanosine and the monoquaternary analogue at 4 mg kg-1 doses resulted in a significant reduction in mean arterial pressure (by 30-70 mm Hg). Significant sympathetic blockade after preganglionic nerve stimulation was observed only with the monoquaternary analogue at a dose of 4 mg kg-1, whereas significant vagal blockade occurred after 4 mg kg-1 of the quaternary monoacrylate, the quaternary acid, the quaternary alcohol and the monoquaternary analogue.

Clinical pharmacology

Atracurium is susceptible to degradation by Hofmann elimination and ester hydrolysis as components of the in vivo metabolic processes. The initial in vitro studies appeared to indicate a major role for ester hydrolysisHofmann elimination is a temperature- and pH-dependent process, 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 process, age, or by the status of renal or hepatic function. On the other hand, excretion of the metabolite, laudanosine, and, to a small extent, atracurium itself is dependent on hepatic and renal functions that tend to be less efficient in the elderly population. There are some exceptions to this rule, e. g, cisatracurium (Nimbex®) is one such agent that does not elicit histamine release even up to 5xED₉₅ doses. The liberation of histamine is a dose-dependent phenomenon such that, with increasing doses administered at the same rate, there is a greater propensity for elicting histamine release and its ensuing sequelae. Most commonly, the histamine release following administration of these agents is associated with observable cutaneous flushing (facial face and arms, commonly), hypotension and a consequent reflex tachycardia. It should be noted though that these sequelae are very transient effects: the total duration of the cardiovascular effects is no more that one to two minutes while the facial flush may take around 3-4 minutes to dissipate. Because these effects are so transient, there is no reason to administer adjunctive therapy to ameliorate either the cutaneous or cardiovascular effects. Thus, in the fierce battle to win market share for sales of the "steroidal" versus the terahydroisoquinolinium class of neuromuscular blocking agents, fact and information peratining to adverse events were distorted to suit taste, and, consequently, 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 bisterahydroisoquinolinium neuromuscular blocking agent marketed by Burroughs Wellcome Co. , now subsumed into GlaxoSmithKline) and vecuronium (Norcuron® - a steroidal neuromuscular blocking agent marketed by Organon, now subsumed into Merck & Co. Inc. ). 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, and, instead, 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. There was complete failure to disseminate the true picture that these effects were not only transient but that the extent of the hypotensive effect and the reflex tachycardia were rarely of clinical significance and therefore did not require adjuntive therapy, 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. Unfortunately, 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 neuromuscular blocking agents) immediately conjures images of histamine release and generates serious anxiety.

Bronchospasm - Pulmonary compliance

Bronchospasm has been reported on occasion with the use of atracurium. However, this particular undesirable effect does not appear to be observed nearly as often as that seen with rapacuronium which led to the latter's withdrawal of approval for clinical use worldwide. The issue of bronchospasm acquired considerable prominence in the neuromuscular blocking agents arena after the spectacular failure of a clinically introduced neuromuscular blocking agent, rapacuronium (Raplon® - a steroidal neuromuscular blocking agent marketed by Organon, now subsumed into Merck & Co. Inc. ), which had to be withdrawn voluntarily during the week of March 19, 2001 after several serious events of bronchospasm, including five "unexplained" fatalities, following its administration. That is not to say that bronchospasm was an unknown phenomenon prior to rapacuronium: occasional reports of bronchospasm have been noted also with the prototypical agents, tubocurarine and succinylcholine, as well as alcuronium, pancuronium, vecuronium, and gallamine.

Laudanosine - Epileptic foci

Because atracurium undergoes Hofmann elimination as a primary route of chemodegradation, not surprisingly one of the major metabolites from this process is laudanosine, a tertiary amino alkaloid reported to be a modest CNS stimulant with epileptogenic activity and cardiovascular effects such a hypotension and bradycardia. As part of the then fierce marketing battle between the competing pharmaceutical companies (Burroughs Wellcome Co. and Organon, Inc. ) with their respective products, 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 the significant clinical hazard by way of frank seizures induced by the laudanosine by-product. Indeed, because laudanosine is cleared primarily via renal excretion, a cat study modelling anephric patients went so far as to corroborate that EEG changes, when observed, were only evident at plasma concentrations eight to 10 times greater those observed in humans during infusions of atracurium. Thus, the cat study predicted that, following atracurium administration in an anephric patient, laudanosine accumulation and related CNS or cardiovascular toxicity were unlikely - a prediction that correlated very well with a study in patients with renal failure and undergoing cadaveric renal transplantation. Furthermore, almost a decade later, work by Cardone et al. confirmed that, in fact, it is the steroidal neuromuscular blocking agents pancuronium and vecuronium which, when introduced directly into the CNS, were likely to cause acute excitement and seizures owing to accumulation of cytosolic calcium caused by activation of acetylcholine receptor ion channels. Unlike the two steroidal agents, neither atracurium nor laudanosine caused such accumulation of intracellular calcium. Just over two decades later with uninterrupted clinical availability of atracurium, there is now little doubt that laudanosine accumulation and related toxicity will likely ever be seen with the doses of atracurium that are administered in clinical practice. Laudanosine is also a metabolite of cisatracurium which, because of its identical structure to atracurium, undergoes chemodegradation via Hofmann elimination in vivo. Plasma concentrations of laudanosine generated are lower when cisatracurium is used.