Cardiovascular The
tetrahydroisoquinolinium class of
neuromuscular blocking agents,
in general, is associated with
histamine release upon rapid administration of a bolus intravenous injection. There are some exceptions to this rule;
cisatracurium (Nimbex), for example, is one such agent that does not elicit histamine release even up to 5×ED95 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 eliciting 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. These sequelae are very transient effects: the total duration of the
cardiovascular effects is no more than 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 the cardiovascular effects.
Bronchospasm 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 prominence in the
neuromuscular-blocking agents arena after the withdrawal from clinical use of
rapacuronium (Raplon - a steroidal neuromuscular-blocking agent marketed by Organon) in 2001 after several serious events of bronchospasm, including five unexplained fatalities, following its administration. Bronchospasm was not 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.
Seizures Seizures rarely occur. 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 Fortunately, both for the public and for atracurium, rapid initial investigations irrefutably failed to find any overt or EEG evidence for a connection between atracurium administration and epileptogenic activity. 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 evident only at plasma concentrations 8 to 10 times greater than 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
kidney 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 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. Unlike the two steroidal agents, neither atracurium nor laudanosine caused such accumulation of intracellular calcium. Just over two decades later with availability of atracurium, there is little doubt that laudanosine accumulation and related toxicity will likely never be seen with the doses of atracurium that are generally used. Laudanosine is also a
metabolite of
cisatracurium that, 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. == Pharmacokinetics ==