Histamine release—hypotension, reflex tachycardia and cutaneous flushing<unk>  is not associated with histamine release when administered as a rapid bolus (95) according to one small study in healthy human volunteers. At 0.54 mg/kg (just under 3xED95 dose), one of four volunteers experienced histamine release with associated hypotension (30% maximum decrease in blood pressure and 13% maximum increase in heart rate) but no cutaneous flushing. At the highest administered dose of 0.72 mg/kg, three of four volunteers experienced histamine release with associated hypotension (17% to 34% maximum decrease in blood pressure and 16% to 25% increase in heart rate) and cutaneous flushing. These effects were transient and lasted no more than two minutes and did not require any adjunctive treatment to address the changes in blood pressure or heart rate. 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, e.g., cisatracurium (Nimbex) is one such agent that does not elicit histamine release even up to 5xED95 bolus doses or continuous infusions. On the other hand, histamine liberation is not a domain exclusive to the tetrahydroisoquinolinium agents: in vitro data confirm that the aminosteroidal agents also have the potential to evoke histamine release, though the mechanisms of mast cell activation may differ. Indeed, histamine release has been reported with administration of pancuronium. 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—(note: half-life of plasma histamine is ~2 minutes). 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 pertaining to adverse events were distorted to suit partisan 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 bis-benzyltetrahydroisoquinolinium (BBTHIQ) 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: 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 adjunctive 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 marketing 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, cardiovascular instability and generates unnecessary anxiety. Bronchospasm—pulmonary compliance Incidents of bronchospasm associated with intravenous administration of<unk>  have not been reported to date. Antagonistic action at the airway presynaptic parasympathetic M2 muscarinic receptors or allosteric potentiation of the post-synaptic acetylcholine M3 muscarinic receptors is thought to be the mechanism that precipitates airway constriction and bronchospam. Although neuromuscular blocking agents are designed to antagonize nicotinic acetylcholine receptors, they are also suspected to antagonize the muscarinic receptors. 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 from clinical use (<2 years after its approval by the US FDA on August 18, 1999—NME Drug and New Biologic Approvals in 1999) 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 atracurium, alcuronium, pancuronium, vecuronium, and gallamine. Recent data from studies in Guinea pigs confirm that<unk>  (as well as cisatracurium) is devoid of significant effects at airway muscarinic receptors and therefore, unlike rapacuronium (Raplon), not likely to cause bronchospasm at clinically relevant doses. Laudanosine—epileptic foci Administration of<unk>  has not been reported, to date, to result in any measured levels of laudanosine (a completely unlikely event, in any case). Laudanosine is a metabolite associated with other related neuromuscular blocking agents such as cisatracurium and atracurium and its detected presence is consequent to the in vivo Hofmann elimination of both these chemodegradable agents (cf. the initial 1985 editorial commentary by Frank G. Standaert, MD on the controversial laudanosine issue with atracurium, with more detailed information on the issue in the Wikipedia article on atracurium itself). The structural difference between<unk>  and these two agents (cisatracurium and atracurium)—in particular, the reverse positioning of the carboxyl ester and onium nitrogen groups—absolutely ensures that<unk>  will never undergo Hofmann elimination just as is the case with mivacurium and doxacurium.
Gantacurium chloride
Mivacurium chloride
Suxamethonium chloride
Alcuronium chloride
Cisatracurium besilate
Pancuronium bromide
Rocuronium bromide
Rapacuronium bromide