By: Joseph DiPaola (PharmD Candidate c/o 2022), Nishanth Viswanath (PharmD Candidate c/o 2022)

           Neuromuscular blocking agents (NMBAs) are drugs that induce a physiological state of paralysis, and are used in a variety of surgical procedures, disease states, and situations in clinical pharmacy and anesthesiology. Practitioners have been successfully using NMBAs since 1995 after the publication of the first clinical guidelines by the Society of Critical Care Medicine. Advances in medicine have since encouraged their use as adjunctive agents in anesthetic procedures.¹ Though their use is widely restricted to critical care operations and surgical procedures, they are used heavily in emergency events and, as a result, it is imperative that clinicians in these respective fields understand their uses and implications with respect to clinical outcomes. 

Most notably, the emergency use of NMBAs is highlighted in the practice of Rapid Sequence Intubation (RSI), a form of endotracheal intubation used to provide ventilation during surgical procedures that involve rapid anesthesia, delayed gastric emptying, ileus, the use of opioids, gestation, or neurological/neuromuscular disorders due to their high risk of aspiration.² While conventional endotracheal intubation involves a large volume of air being displaced into a patient’s gastrointestinal tract, it is contingent on the assumption that the patient’s stomach contents are emptied via perioperative fasting or the use of prokinetic agents. RSI, by contrast, offers respiratory ventilation for the patient with a lesser risk of regurgitation or aspiration of stomach contents, making it convenient for use in emergency surgical procedures. Most RSI protocols will require the use of an induction agent such as propofol or etomidate (Amidate^®) to facilitate the loss of consciousness and a fast acting NMBA such as succinylcholine (Anectine^®) or rocuronium (Zeumuron^®) for muscle paralysis.² It is important to note that while RSI procedures most commonly warrant NMBA use, other intubating procedures such as laryngoscopies have been known to include neuromuscular blockade at the discretion of practitioners.³

NMBAs are broadly classified as either depolarizing or nondepolarizing agents, both of which prevent muscular contraction through the alteration of acetylcholine receptors in varied mechanisms. Depolarizing NMBAs work by agonizing nicotinic acetylcholine receptors on postsynaptic membranes, which then exhibit muscular contraction as expected, but eventually continue to induce complete paralysis as the muscle end plates are unable to repolarize.^1,4 This physiological status is known as phase 1 block.¹ After continued binding or exposure to higher concentrations of a depolarizing NMBA, the receptor may undergo conformational changes which render it partially dysfunctional even in response to normal acetylcholine levels.¹ This phenomenon is known as phase 2 block, and results in a longer recovery time and eventual neuromuscular weakness upon recovery or reversal.¹ To date the only available depolarizing NMBA is succinylcholine.¹ Though is it conventionally used and inexpensive, succinylcholine is associated with post-anesthetic muscle weakness and cardiac arrhythmias, and therefore, is not commonly used for prolonged periods of neuromuscular blockade.⁴ 

Nondepolarizing NMBAs contrast depolarizing NMBAs as they induce paralysis by competitively antagonizing nicotinic acetylcholine receptors.^1,4 Paralysis is seen sequentially, starting with fast twitch muscles in the eyes and larynx and then progressing to the limbs, trunk and diaphragm, while reversal occurs in the opposite order. Uniquely, nondepolarizing NMBAs do not have any effect on the conformation of acetylcholine receptors, rendering them useful for long term neuromuscular block via continuous infusion.¹ This, in a sense, makes them novel entities that contrast the emptying of ions at neuromuscular end plates which is seen with depolarizing NMBAs. 

Chemically, nondepolarizing NMBAs are further classified as either benzylisoquinolines or aminosteroids, which are both structurally related to acetylcholine.¹ The aminosteroids were first introduced with the approval of pancuronium (Pavulon^®) in 1964, which exhibits a slow onset of action but a long duration of action.¹ A notable drawback to pancuronium use, however, is its vagolytic effect induced by blockage of cardiac muscarinic receptors, which results in moderate tachycardia.¹ In response, vecuronium (Norcuron^®) was introduced soon after, being branded as an agent that lacked any vagolytic side effects and possessed a shorter time of onset and duration of action than pancuronium.¹ The release of rocuronium soon followed, which boasts the shortest time of onset and duration of action of the aminosteroids, but at higher doses can present mild vagolytic activity similar to pancuronium.¹ 

The benzylisoquinolines consist of a chain of methyl groups connecting two quaternary ammonium groups which allow for the variation of several stereoisomers with different metabolic rates, ranging from short to intermediate acting.¹ Structurally, they are ideal for the patient who may have renal or hepatic dysfunction since benzylisoquinoline NMBAs are degraded by plasma cholinesterases or Hoffman elimination, which is a phenomenon that causes quaternary salts to undergo degradation in slightly alkaline conditions.¹ The agents currently approved in this class and used in practice are mivacurium (Mivacron^®), atracurium (Tracrium^®), and cisatracurium (Nimbex^®), which exhibit an increasing duration of action in that order.⁴ Clinically, it is important to note that atracurium has the potential to cause seizures induced by a toxic metabolite called laudanosine.^4,5 In response to this, cisatracurium was marketed as the cis-cis isomer of atracurium which produces around a third of the amount of laudanosine as a byproduct when compared to atracurium, and is three times as potent.^1,6 Additionally, doses of both atracurium and mivacurium have exhibited post-marketing instances of varying histamine release, making some patients susceptible to hypersensitivities.^5,7  

Sugammadex (Bridion^®) and neostigmine methylsulfate (Bloxiverz^®) are postoperative critical care agents indicated for the reversal of nondepolarizing and depolarizing NMBAs after surgery and or intubation.^3,8,9 Neostigmine methylsulfate is an acetylcholinesterase inhibitor which has been conventionally used by clinicians as a principal reversal agent for neuromuscular blockade for many years. By allowing it to bypass degradation, neostigmine methylsulfate increases the competitive pressure of acetylcholine, causing it to resume binding to nicotinic receptors.⁴ However, if NMBA concentrations are too high, neostigmine methylsulfate is not able to overcome the antagonism regardless of the dose given.⁴ Since neostigmine methylsulfate works on both nicotinic and muscarinic acetylcholine receptors, concomitant administration of an antimuscarinic agent, such as atropine or glycopyrrolate, is required to offset instances of bronchospasm, bradycardia and post-operative nausea and vomiting.³

In 2015, the Food and Drug Administration (FDA) approved sugammadex, a novel selective relaxant binding agent (SRBA) for the reversal of neuromuscular blockade specifically induced by rocuronium or vecuronium.^3,4,8 Sugammadex is a modified gamma cyclodextrin that encapsulates rocuronium or vecuronium molecules in a 1:1 ratio, which allows for reversal of neuromuscular block of any degree, as opposed to neostigmine methylsulfate.⁸ Furthermore, as sugammadex has no effect on cholinergic receptors, an antimuscarinic agent does not need to be co-administered.^8,10 In a series of studies registered on the Cochrane Central Register of Controlled Trials, the times for reversal of rocuronium using sugammadex versus neostigmine methylsulfate registered as 6.6 times faster (1.96 versus 12.87 minutes) in moderate neuromuscular blockade, and 16.8 times faster than neostigmine methylsulfate (2.9 versus 48.8 minutes) in deep neuromuscular blockade on average.⁹ These trials, however, represented recovery of rocuronium induced neuromuscular block exclusively. While data exists for the reversal of vecuronium using sugammadex, it is important to note that sugammadex has an 2.5 times higher affinity for rocuronium than vecuronium (25,000,000 M versus 10,000,000 M) in neuromuscular blockade reversal.^10,11 Additionally, though it has a greater affinity for aminosteroid NMBAs, sugammadex may cause the plasma levels of endogenous and exogenous hormones or compounds that follow a structural similarity to aminosteroids to decrease during administration.^8,11  

When evaluating sugammadex as an alternative to traditionally used cholinesterase inhibitors, it is important to take sugammadex’s cost into consideration. Since sugammadex is only indicated for use in reversal of rocuronium and vecuronium, one of its main issues is that it cannot completely replace neostigmine methylsulfate on formularies.⁷ Additionally, the price of sugammadex is approximately 59.84 dollars/mL in a 2mL vial, while the price of neostigmine methylsulfate ranges from 0.72-5.40 dollars/mL in a 10mL vial.^10,12,13 However, though its use is slightly limited and its cost is exponentially larger compared to neostigmine methylsulfate, there is sound justification for sugammadex to be included on hospital formularies for certain situations.¹⁰ One such scenario where it is commonly seen is in RSI. While succinylcholine is commonly used as a first line agent in RSI, a trending option for institutions is to use rocuronium instead of succinylcholine as the first line agent. This has been supported by a Cochrane review, which found that the combination of rocuronium with sugammadex is potentially safer than succinylcholine due to a lower side effect profile.¹⁰ A rising issue, however, is inadequate training of anesthesiologists in sugammadex dosing calculations. This coupled with lower overall accessibility due to cost can delay administration of sugammadex by 6.7 minutes, on average, in an emergency scenario.¹⁰ Although these issues do not correspond to the drug itself, it is important to acknowledge that additional training is required to make the combination effective. 

While sugammadex does show a clear difference in recovery time when compared to neostigmine methylsulfate, this does not necessarily mean there is a reduction in length of hospital stay or cost to the patient. Most cost analyses available do not demonstrate a pharmacoeconomic advantage in adding sugammadex to formulary, as its use seems to increase costs by approximately 9.04 dollars per case.¹⁰ Even though sugammadex is more effective than neostigmine methylsulfate and other similar agents for the reversal of rocuronium and vecuronium, there is no consensus regarding whether it would be beneficial for an institution to add sugammadex to formulary. Such decisions are dependent on individual institutions taking budget, staffing, logistics, and other internal and external factors into account. 

NMBAs have been implicated in critical care events for many years and continue to show efficacy in many surgical procedures. The introduction of sugammadex in 2015 for reversal of steroidal NMBAs encourages the use of nondepolarizing NMBAs in surgical procedures, furthering patient safety and the predictability of paralytic agents. By understanding the uses and indications of NMBAs and the utilization of their reversal agents in practice, clinicians, including pharmacists, can provide an invaluable impact on patient safety and outcomes.

SOURCES:

1. Smetana KS, Roe NA, Deopker BA, Jones GM. Review of Continuous Infusion Neuromuscular Blocking Agents in the Adult Intensive Care Uni. Crit Care Nurs Q. 2017;40(4):323-343. Published 12/31/2017. Accessed 1/7/2020.
2. Sinclair RCF, Luxton MC. Rapid sequence induction. OUP Academic. https://academic.oup.com/bjaed/article/5/2/45/422107. Pub. 4/1/2005. Acc.1/7/2020.
3. Lundstrøm  LH, Duez  CHV, Nørskov  AK, Rosenstock  CV, Thomsen  JL, Møller  AM, Strande  S, Wetterslev  J. Avoidance versus use of neuromuscular blocking agents for improving conditions during tracheal intubation or direct laryngoscopy in adults and adolescents. Cochrane Database of Systematic Reviews 2017, Issue 5. Art. No.: CD009237. DOI: 10.1002/14651858.CD009237.pub2. Published 11/15/2018. Accessed 1/7/2020
4. Gustafson KA, Brown AS. Neuromuscular Blocking Agents: Use and Controversy in the Hospital Setting. US Pharmacist. 2017;42(1):16-20. Pub. 1/19/2017. Accessed 1/7/2020.
5. Atracurium besylate [package insert]. Hyderabad, India: Hospira Inc.; Revised August 2018.
6. NIMBEX® (cisatracurium besylate) [package insert]. North Chicago, IL: Abbvie Inc.; Revised October 2019.
7. MIVACRON® (mivacurium chloride) [package insert]. North Chicago, IL: Abbvie Inc. Revised July 2018.
8. BRIDION® (sugammadex) [package insert]. Whitehouse Station, NJ: Merck & Co Inc.; Revised December 2015.
9. BLOXIVERZ® (neostigmine methylsulfate) [package insert]. Chesterfield, MO: Eclat Pharmaceuticals; May 2013.
10. Hristovska  AM, Duch  P, Allingstrup  M, Afshari  A. Efficacy and safety of sugammadex versus neostigmine in reversing neuromuscular blockade in adults. Cochrane Database of Systematic Reviews 2017, Issue 8. Art. No.: CD012763. DOI: 10.1002/14651858.CD012763. Published 8/14/2017. Accessed 1/7/2020.
11. Fink H, Schaller. Sugammadex as a reversal agent for neuromuscular block: an evidence-based review. Core Evidence. September 2013:57. doi:10.2147/ce.s35675. Published 6/15/2013. Accessed 1/7/2020.
12. Neostigmine Methylsulfate. RED BOOK Online. Micromedex Healthcare Series [database online]. Greenwood Village, CO: Truven Health Analytics; 2020. 1/28/2020.
13. Sugammadex. RED BOOK Online. Micromedex Healthcare Series [database online]. Greenwood Village, CO: Truven Health Analytics; 2020. Accessed 1/28/2020

Published by Rho Chi Post