The role of sugammadex, a novel cyclodextrin compound in modern anesthesia practice: conventional neuromuscular physiology and clinical pharmacology

KEYWORDS:

• Sugammadex
• neuromuscular blockade
• rocuronium
• vecuronium
• reversal

1. Introduction

With nearly twenty million doses delivered in nearly sixty countries, sugammadex development represents a breakthrough in clinical pharmacology. This commentary emphasizes anatomy and physiology of the neuromuscular junction and an overview of the benefits of this rapidly acting neuromuscular blocker reversal agent. Efficacy of sugammadex has been well-established with most patients having a full reversal in 2–3 minutes. The side effects are limited with rare allergic reaction and bradycardia. This drug represents a step forward in clinical pharmacology, in anesthesia practice, and in the reversal of neuromuscular blockade with rocuronium bromide and vecuronium bromide in the operating room setting.

Sugammadex, indicated for the reversal of neuromuscular blockade induced by rocuronium bromide and vecuronium bromide in adults, represents a pharmacological advance with far ranging clinical implications. Sugammadex, a novel cyclodextrin compound, was FDA-approved in the USA in December 2015 and works through a different mechanism than neostigmine by directly binding and rapidly inactivating steroidal neuromuscular blocker agents [1]. Conventional reversal has included a combination of neostigmine, an acetylcholinesterase inhibitor, which is associated with nausea and vomiting, and glycopyrrolate, an antimuscarinic, which increases heart rate.

A basic understanding of neuromuscular physiology and pharmacology is required for all clinicians utilizing medications that have effects on neuromuscular function. Currently, special credentials are typically required for any clinician who wishes to administer neuromuscular blocker medications and are usually delineated under separate deep sedation and general anesthesia privileges. Documentation of airway management experience and competency in pharmacological and physiological considerations with neuromuscular blocking agents is now standard in the United States and elsewhere.

2. Basic neuromuscular junction anatomy and physiology

As a review of human physiology, the neuromuscular junction is comprised of several key components, including the presynaptic nerve terminal, synaptic cleft, and the post-synaptic nicotinic acetylcholine receptors on motor end-plates [2]. Action potentials propagated along the presynaptic neuron result in the release of acetylcholine into the synaptic cleft. These molecules then bind to two alpha subunits of the ionic post-junctional nicotinic acetylcholine receptors. Binding results in a conformational change in the ion channel prompting an influx of sodium and efflux of potassium. Dosing for neuromuscular blocker agents is typically based on an effective dose (ED) 95, which is the dose in which 95% twitch depression occurs in 50% of individuals [3]. For induction, one, two or three times the ED95 dose is typically administered and for maintenance dosing, the ED95 dosage is employed [3].

Acetylcholinesterase is located on the post-junctional fold and is responsible for the enzymatic break down of acetylcholine into choline and acetate. Choline is then taken back into the presynaptic terminal to be recycled and form more acetylcholine. By definition, neuromuscular blocking agents prevent nicotinic acetylcholine neuromuscular transmission.

3. Depolarizing neuromuscular blockers

Succinylcholine was first introduced in 1951 and is surprisingly still the only rapid acting depolarizing neuromuscular blocking agent clinically available for use. Its chemical structure mimics two connected acetylcholine molecules. Binding to motor end plate receptors results in a state of persistent depolarization via sodium influx. Muscle fasciculations will arise as a result of this depolarization, which is often observed after intravenous or intramuscular administration. Traditionally, 1.0 mg/kg of succinylcholine has been used for intubation, however, the ED95 of succinylcholine is less than 0.30mg/kg. Therefore, 1.0 mg/kg dose would be 3.5–4 times the ED95. Degradation is accomplished predominantely via plasma cholinesterases. The benefits of succinylcholine administration are often outweighed by its numerous adverse effects. These include but are not limited to hyperkalemia, ocular hypertension, increased intracranial pressure, myalgia, bradycardia, and the possibility for triggering malignant hypertension [2]. The aforementioned make succinylcholine far from an ideal muscle relaxant.

4. Non depolarizing neuromuscular blockers

Non-depolarizing neuromuscular blocking agents function by competitively inhibiting acetylcholine from binding to the alpha subunits of the post junctional receptor. This inhibition prevents muscle contraction as the ion channel conformation is not altered [2]. Non-depolarizing neuromuscular blockers are classified according to their chemical structure as either benzylisoquinolones or aminosteroids. Clinically relevant benzylisoquinolones include atracurium, cisatracurium, and mivacurium. Atracurium was first used in 1980 and is classified as an intermediate acting bisquaternary ammonium compound. Atracurium is metabolized via both Hoffman degradation and ester hydrolysis. Cisatracurium was first used in 1995 and has a longer duration of action relative to atracurium. Metabolism is primarily through Hoffman degradation. Mivacurium was first introduced in 1993 and is a short acting neuromuscular blocking agent. Metabolism is primarily via plasma cholinesterases. Mivacurium is available for regular clinical use, however, because of associated hypotension, bronchospasm, and tachycardia it is rarely used.

Clinically relevant aminosteroids include pancuronium, vecuronium, and rocuronium. Pancuronium is a long acting bisquaternary ammonium compound that was first used in 1967. This drug has fallen out of favor after recognition of its vagolytic properties, subsequent sympathetic stimulation, and excessive duration of action. Vecuronium and rocuronium are both monoquaternary aminosteroids with intermediate durations of actions. They were introduced for clinical use in 1983 and 1994 respectively. Metabolism and clearance of both are largely dependent on the hepatic and renal systems. These medications are both commonly used in present clinical practice in patients without evidence of renal or hepatic impairment.

As evident above, advancements in neuromuscular blocking agents have been limited.

5. The role of sugammadex and its clinical pharmacology

There are several studies comparing the effects of sugammadex to other reversal agents. One 2010 multicenter, randomized, controlled trial reported the geometric mean time to recovery of the train-of-four (TOF) ratio, which monitors the recovery from neuromuscular blockade, to 0.9 was significantly faster with sugammadex compared with neostigmine. Furthermore, the mean recovery times were also significantly shorter with sugammadex [4]. Another 2010 randomized, controlled trial reported that sugammadex achieved significantly faster recovery of neuromuscular function after rocuronium to a TOF of 0.9 compared to neostigmine [5]. Finally, a 2009 randomized, multicenter, safety-assessor-blinded, parallel group, active-controlled, PhaseIIIa trial showed that reversal of high-dose rocuronum-induced NMB with sugammadex was significantly faster than spontaneous recovery from 1 mg/kg succinylcholine [6].

Sugammadex has limitations and is not effective for reversing nonsteroidal neuromuscular blockers. 16 mg/kg of sugammadex is used in the failed rapid induction and intubation sequence when there is a ‘cannot-ventilate-cannot-intubate’ scenario when rocuronium is used. A dose of 16 mg/kg sugammadex is then used to reverse the 4 x ED95 (1.2 mg/kg) dose of rocuronium. Rapid-sequence induction with vecuronium, on the other hand, is never practiced anymore since the introduction of rocuronium.

There is a 0.3% reported incidence of allergic reaction and ‘rare’ incidence so low there is no known percentage of bradycardia that is responsive to atropine or glycopyrrolate.

In summary, Sugammadex, a novel cyclodextrin with an excellent efficacy and side effect potential, has been impactful in the transition to a quicker patient recovery in the post anesthesia care unit (PACU) with the potential for reduced adverse outcomes in our ever-challenging patient population.

Article Highlights

• Advancements in neuromuscular blocking agents have been limited

• Sugammadex, a novel cyclodextrin with an excellent efficacy and side effect potential, has been impactful in the transition to a quicker patient recovery in the post anesthesia care unit (PACU) with the potential for reduced adverse outcomes in our ever-challenging patient population.

• A basic understanding of neuromuscular physiology and pharmacology is required for all clinicians utilizing medications that have effects on neuromuscular function.

• Sugammadex has limitations and is not effective for reversing nonsteroidal neuromuscular blockers.

• There is a 0.3% reported incidence of allergic reaction and ‘rare’ incidence so low there is no known percentage of bradycardia that is responsive to atropine or glycopyrrolate.

Declaration of interest

A Kaye is on Speakers Bureau for Merck Pharmaceuticals. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

A reviewer on this manuscript has disclosed they have intellectual property assigned to Mayo Clinic (Rochester, MN); has received research funding from Merck & Co., Inc. (funds to Mayo Clinic) and is a consultant for Merck & Co., Inc. (Kenilworth, NJ); is a principal and shareholder in Senzime AB (publ) (Uppsala, Sweden); and a member of the Scientific Advisory Boards for ClearLine MD (Woburn, MA), The Doctors Company (Napa, CA), and NMD Pharma (Aarhus, Denmark). Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper had no funding.