Atracurium is a bis-benzyltetrahydroisoquinolinium with isoquinolinium nitrogens connected by a diester-containing hydrocarbon chain. Its action is intermediate with a dose-dependent onset of action of approximately 5 minutes and duration of approximately 30 minutes in dogs (Jones, 1983). Repeated doses are generally not cumulative, so longer-term maintenance can be achieved via a constant-rate infusion (Playfor et al., 2000). Atracurium undergoes ester hydrolysis, Hofmann elimination reaction, and likely other nonhepatic routes for biotransformation, making the drug appropriate for use in hepatic or patients with renal insufficiency. In a Hofmann elimination reaction, a quaternary ammonium group is converted to a tertiary amine by cleavage of a carbon–nitrogen bond. This process does not require enzymatic activity. Hofmann elimination is both a pH and temperature-sensitive reaction in which higher pH and temperatures favor drug breakdown. Clinical consequences of this are important in that patient acidemia and hypothermia may hinder drug breakdown (Playfor et al., 2000). Additionally, the drug should be kept refrigerated and is supplied at a pH of 3.25–3.65 to slow degradation.

The marketed atracurium product has ten isomers. These isomers are separated into three geometric isomer groups that have been designated cis–cis, cis–trans, and trans–trans according to their configuration about the tetrahydroisoquinoline ring system (Wastila et al., 1996). Cisatracurium is the 1R cis-1’R cis isomer of atracurium and represents approximately 15% of the marketed atracurium product’s weight yet produces roughly 50% of atracurium’s neuromuscular blocking activity. Cisatracurium (Nimbex) is available as a stand-alone product separate from atracurium. Cisatracurium is metabolized by Hofmann elimination entirely. The presence of portosystemic shunt and hepatic insufficiency did not affect the rate of onset or duration of action of cisatracurium in dogs receiving 0.1 mg/kg IV followed by repeat doses of 0.03 mg/kg IV (Adams et al., 2006). In general, cisatracurium has a similar duration and clinical effects to atracurium.

Following intravenous injection, atracurium spontaneously decomposes into laudanosine and a quaternary monoacrylate. Laudanosine in high quantities is a CNS stimulant and may result in seizures, hypotension, and tachycardia (Chapple et al., 1987). Laudanosine, unlike atracurium, is dependent upon hepatic clearance, so theoretically laudanosine plasma concentrations may become elevated in patients with hepatic dysfunction. Practically, laudanosine-induced toxicity is unlikely in clinical patients unless atracurium is used in large doses and/or for prolonged periods (Chapple et al., 1987). Nonetheless, another aminosteroid may be selected to avoid this remote issue entirely.

d-Tubocurarine, the prototypical benzoisoquinolone NMB agent, is associated with histamine release and resulting hypotension. Although atracurium has the potential to result in histamine release, this requires several times the ED₉₅ dose (effective dose producing a 95% reduction in twitch height) before appreciable amounts of histamine are released, making problems such as hypotension and tachycardia rarely observed in clinical cases (Scott et al., 1986; Hackett et al., 1989). In isoflurane-anesthetized dogs, 0.2 mg/kg IV atracurium did not result in significant changes to intraocular pressure, mean arterial pressure, heart rate, or central venous pressure (McMurphy et al., 2004). A notable exception to atracurium and cisatracurium’s minimal cardiovascular profile may be in dogs with X-linked muscular dystrophy. Affected golden retrievers in one retrospective study that received 0.1 mg/kg cisatracurium had marked increases in heart rate (115 ± 64%) and blood pressure (33.5 ± 31%) that lasted 10 and 30 minutes, respectively (Staffieri et al., 2011).

Atracurium has been widely used with positive clinical success across a variety of species including, but not limited to, dogs, cats, and horses. In horses and dogs, the use of atracurium in conjunction with aminoglycoside antibiotics, specifically gentamycin, has been shown to augment neuromuscular blockade; however, this effect appears minimal and has not been reported to impact recovery quality (Hildebrand and Hill, 1994; Martinez et al., 1996). Atracurium has also been investigated for use in a urethral flushing solution in cats and dogs to help facilitate manual bladder expression in patients with spinal cord injuries and in obstructive urethral plugs (Galluzzi et al., 2012; Galluzzi et al., 2015).

Two additional benzylisoquinolinium compounds, mivacurium and doxacurium, are reported in the veterinary literature but are infrequently used in clinical practice today. Mivacurium (Mivacron) is a short-acting NMB agent in humans (15–20 minutes’ duration); however, this duration of effect appears markedly prolonged in dogs. Although mivacurium resulted in minimal hemodynamic changes, in dogs administered 0.05 mg/kg IV it appeared to have a long half-life and slow clearance under halothane anesthesia with duration of effect up to 151.0 ± 38.50 minutes (Smith et al., 1999a, 1999b). Clinical observations in cats suggest that mivacurium has a shorter duration of action compared to that in dogs. Mivacurium is unique amongst the benzylisoquinolinium compounds in that it is metabolized by plasma cholinesterases to a monoester and this attribute, as a result of interspecies differences in plasma cholinesterases, may explain its variable duration of action between species. At the time of writing, mivacurium is not currently available within the United States.

Doxacurium (Nuromax) has a slow onset of action and long duration (>50 minute) of effect in man. Doxacurium may result in an increased propensity for histamine release and cardiovascular side effects when compared to other benzylisoquinolinium compounds. Work in dogs would suggest that 2.1 μg/kg IV approximates an ED₅₀ while 3.5 μg/kg IV approximates an ED₉₅ with duration of action at 108 ± 31 minutes (Martinez et al., 1996). Due to increased cost, minimal reported advantage, and lack of availability and clinical experience, atracurium is typically selected over other available benzylisoquinolinium compound for veterinary patients.

Pancuronium (Pavulon) was the first aminosteroid to be introduced as a NMB agent. The drug has a dose-dependent onset of approximately 5 minutes and long duration of action, up to 60 minutes in the dog (Gleed and Jones, 1982). Because repeated doses have a cumulative effect, constant-rate infusions are avoided. A large proportion of pancuronium is excreted by the kidney. The remainder is metabolized via the liver, making the duration of action increased in patients with renal and hepatic dysfunction. In addition to exerting its effect on postsynaptic nicotinic receptors at the NMJ, pancuronium also has a vagolytic effect by blocking cardiac muscarinic action, which may result in an increase in heart rate. Decreases to systemic vascular resistance, pulmonary vascular resistance, and coronary and renal artery dilation via prostaglandin I₂ release have also been noted in the dog (Hackett et al., 1989; Sai, 1998). In dogs, cats, pigs, and horses doses between 0.06 and 0.12 mg/kg IV have been reported (Gleed and Jones, 1982; Hildebrand et al., 1989; Miller et al., 1978; Veres-Nyéki et al., 2012). Pancuronium is stable at room temperature for 6 months.

Removal of a single positively charged methyl group from pancuronium creates vecuronium, an aminosteroid NMB agent that is essentially devoid of cardiovascular effects (Morris et al., 1983; Jones, 1985b). This molecular modification has several other important clinical implications, including molecular instability in solution which necessitates vecuronium be kept as a lyophilized powder and only reconstituted immediately prior to administration with stability of only 24 hours once reconstituted. Additionally, vecuronium has a shorter duration of action than pancuronium and an increase in lipid solubility, which results in greater biliary elimination than with pancuronium (Hill et al., 1994). Vecuronium has a dose-dependent onset of action of approximately 5 minutes and generally an intermediate duration of action of approximately 30 minutes, making its clinical utility similar to atracurium.

Vecuronium undergoes both hepatic metabolism, biliary clearance from the liver as parent compound, and about 25% undergoes renal elimination. Patients with renal or hepatic insufficiency may experience prolonged recovery if increased doses of vecuronium are administered. Dogs with diabetes mellitus have been shown to have a shorter duration of effect from vecuronium based upon both tactile train-of-four (TOF) and electromyography (Clark et al., 2012). The potency and duration of vecuronium does not, however, appear to be altered in dogs with autosomal recessive centronuclear myopathy (Martin-Flores et al., 2015b). In horses, it appears that a dose greater than 0.1 mg/kg IV would be needed for complete neuromuscular blockade and that this effect would have a uniquely long duration in this species, lasting over 120 minutes (Martin-Flores et al., 2012a, 2012b). Additionally, one case report documents that a dosage of 0.5 mg/kg IV edrophonium failed to completely reverse prolonged vecuronium-induced neuromuscular blockade in anesthetized dog as judged by peripheral nerve stimulation (Martin-Flores et al., 2011).

Rocuronium bromide (Zemuron), another member of the aminosteroid NMB agent family, lacks the acetyl ester that is found in the steroid nucleus of pancuronium and vecuronium and is less potent but similar in molecular weight to vecuronium. Rocuronium has a more rapid onset compared with atracurium and vecuronium, but similar duration of action (Carson et al., 1990; Gyermek et al., 2002). Additionally, rocuronium appears to be largely devoid of cardiovascular side effects, including no significant histamine release (Hudson et al., 1998). The drug is eliminated primarily via hepatic clearance while a small fraction is eliminated via the kidney. Detectable levels of rocuronium metabolites are not found. Rocuronium is stable for 60 days at room temperature. Rocuronium at clinically relevant concentrations may also bias the accuracy of lithium dilution cardiac output monitoring by interacting with the LiDCO sensor (Ambrisko et al., 2013).

In cats, a dosage of 0.6 mg/kg IV rocuronium had an onset time of 46 ± 11 seconds, produced no change to subject heart rate, and took 20.7 ± 5.4 minutes for TOF ratios to return to 0.9, a level consistent with full recovery from neuromuscular blockade (Auer and Mosing, 2006; McGrath and Hunter, 2006). Sixty seconds after rocuronium administration in cats, paralysis of the internal laryngeal muscles and conditions suitable for endotracheal intubation occurred that were comparable to topical lidocaine (Moreno-Sala et al., 2013). In dogs, rocuronium at 0.3 mg/kg and 0.6 mg/kg IV resulted in an onset of neuromuscular blockade in 2 ± 0.9 minutes and 1.1 ± 0.6 minutes with total recovery occurring at 23.8 ± 6.6 minutes and 31.9 ± 6.5 minutes respectively (Auer, 2007). Following a loading dose of 0.5 mg/kg IV, rocuronium was found to be suitable for constant-rate infusion at 0.2 mg/kg/h for up to 146 minutes (Alderson et al., 2007). Doses of rocuronium as low as 0.03–0.075 mg/kg IV in isoflurane-anesthetized dogs resulted in a centralized globe position and acceptable conditions for ophthalmic procedures (Briganti et al., 2015). In horses undergoing ophthalmic surgery, a dose of 0.3 mg/kg IV rocuronium produced effective neuromuscular blockade in 2.3 ± 2 minutes with a central globe position in 31 ± 2.8 seconds and a clinical duration of 32 ± 18.6 minutes in all 20 horses studied (Auer and Moens, 2011).

Gantacurium represents a new class of nondepolarizing NMB agents called asymmetric mixed-onium chlorofumarates, which are structurally distinct from the traditional aminosteroids and benzylisoquinolinium compounds. Gantacurium has an ultrashort duration of action and is degraded in plasma by pH sensitive chemical hydrolysis and inactivation by cysteine adduction. It does not undergo Hofmann elimination. In dogs anesthetized with thiopental, nitrous oxide, and isoflurane, the ED₉₅ was 0.06 mg/kg IV with an onset time of 107 seconds and duration of action of 5.2 minutes (Heerdt et al., 2004). In cats following dexmedetomidine and propofol, IV gantacurium at 0.5 mg/kg abolished laryngospasm in 100% of cats and induced apnea for 3 ± 1.5 minutes (Martin-Flores et al., 2015a). At clinical doses, cats and dogs do not appear to have appreciable cardiovascular effects; however, in humans, transient cardiovascular side effects were observed at doses beginning at three times the ED₉₅ and were consistent with histamine release (Belmont et al., 2004). Recovery is accelerated with AChE inhibitors such as edrophonium. In humans, exogenous administration of cysteine can also accelerate the antagonism of gantacurium-induced neuromuscular blockade. Gantacurium is not stable in aqueous solution and, like vecuronium, is provided as a lyophilized powder that is reconstituted prior to administration.