Discovery, development, and clinical application of sugammadex sodium, a selective relaxant binding agent

Abstract

Neuromuscular blockade, induced by neuromuscular blocking agents, has allowed prescribed immobility, improved surgical exposure, optimal airway management conditions, and facilitated mechanical ventilation. However, termination of the effects of neuromuscular blocking agents has, until now, remained limited. A novel cyclodextrin encapsulation process offers improved termination of the paralytic effects of aminosteroidal non-depolarizing neuromuscular blocking agents. Sugammadex sodium is the first in a new class of drug called selective relaxant binding agents. Currently, in clinical trials, sugammadex, a modified gamma cyclodextrin, has shown consistent and rapid termination of neuromuscular blockade with few side effects. The pharmacology of cyclodextrins in general and sugammadex in particular, together with the results of current clinical research are reviewed. The ability of sugammadex to terminate the action of neuromuscular blocking agents by direct encapsulation is compared to the indirect competitive antagonism of their effects by cholinesterase inhibitors. Also discussed are the clinical implications that extend beyond fast, effective reversal, including numerous potential perioperative benefits.

Keywords: encapsulation; modified cyclodextrin; muscle relaxants; neuromuscular blockade reversal; selective relaxant binding agent (SRBA); sugammadex.

Figure 1

Crystal spectroscopy image of sugammadex encapsulating a rocuronium molecule. Reprinted with permission from Zhang M-Q. 2003. Drug-specific cyclodextrins: The future of rapid neuromuscular block reversal? Drugs Future, 28: 347–54. Copyright© 2003 Prous Scientific and Organon USA, a part of Schering-Plough Corporation.

Figure 2

Naturally occurring cyclodextrins. From left to right: alpha, beta, and gamma. Sites of modification for the creation of sugammadex are the peripheral 6th carbon hydroxyl groups on the gamma cyclodextrin. Reproduced with permission from Welliver M. 2007. Update for nurse anesthetists. Part 3. Cyclodextrin introduction to anesthesia practice: form, function, and application. AANA J, 75:289–96. Copyright© 2007 American Association of Nurse Anesthetists.

Figure 3

Structural arrangement of glucopyranose units in a gamma CD, showing primary and secondary rim hydroxyl groups. Reproduced with permission from Welliver M. 2007. Update for nurse anesthetists. Part 3. Cyclodextrin introduction to anesthesia practice: form, function, and application. AANA J, 75:289–96. Copyright© 2007 American Association of Nurse Anesthetists.

Figure 4

Sugammadex structure. Reproduced with permission from Welliver M. 2007. Update for nurse anesthetists. Part 3. Cyclodextrin introduction to anesthesia practice: form, function, and application. AANA J, 75:289–96. Copyright© 2007 American Association of Nurse Anesthetists.

Figure 5

Aqueous inclusion complex of sugammadex-rocuronium.

Figure 6

Encapsulation process: Sugammadex carboxyl groups interact with steroidal rings A, B, C, and D, drawing the aminosteroidal NMBA molecule into the cavity where additional non-covalent attractions hold the molecule securely in place.

Figure 7

Sugammadex encapsulates aminosteroidal NMBA molecules in the plasma causing a concentration gradient that favors the extraction of additional rocuronium molecules from the nicotinic junction into the plasma. Reproduced with permission from Harris AM, Welliver M, Redfern R, et al. 2007. Orthopaedic surgery implications of a novel encapsulation process that improves neuromuscular blockade and reversal. The Internet Journal of Orthopedic Surgery, 7(2). Copyright© ISPUB.com.