[1] Because atracurium undergoes Hofmann elimination as a primary route of chemodegradation, one of the major metabolites from this process is laudanosine, a tertiary amino alkaloid reported to be a modest CNS stimulant with epileptogenic activity[28] and cardiovascular effects such a hypotension and bradycardia.
[29] 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[28] - the posited hypothesis being that the laudanosine produced from the chemodegradation of parent atracurium would cross the blood–brain barrier in sufficiently high enough concentrations that lead to epileptogenic foci.
[34] Furthermore, almost a decade later, work by Cardone et al..[35] confirmed that, in fact, it is the steroidal neuromuscular-blocking agents pancuronium and vecuronium that, 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.
[36][37] The initial in vitro studies appeared to indicate a major role for ester hydrolysis[36] but, with accumulation of clinical data over time, the preponderance of evidence indicated that Hofmann elimination at physiological pH is the major degradation pathway[37] vindicating the premise for the design of atracurium to undergo an organ-independent metabolism.
[38] Otherwise, the breakdown process is unaffected by the level of plasma esterase activity, obesity,[41] age,[42] or by the status of renal[43][44][45][46] or hepatic function.
[47] 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.
The beta-blocking drug nebivolol has ten similar structures with 4 stereocentres and a plane of symmetry, but only two are presented in the pharmaceutical preparation.
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.
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.
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.
[55] Stenlake's research group advanced this concept by systematically synthesizing numerous quaternary ammonium β-aminoesters[56][57][58][59] and β-aminoketones[60] and evaluated them for skeletal muscle relaxant activity: one of these compounds,[52][58] initially labelled as 33A74,[48][61] eventually led to further clinical development, and came to be known as atracurium.