Sugammadex

Sugammadex

Clinical data
AHFS/Drugs.com	International Drug Names
[[Regulation of therapeutic goods |Template:Engvar data]]	EU EMA: by INN
Routes of administration	Intravenous
ATC code	V03AB35 (WHO)
Identifiers
CAS Number	343306-79-6 N
PubChem CID	6918584
ChemSpider	5293781 N
UNII	361LPM2T56
KEGG	D05940 Y
E number	{{#property:P628}}
ECHA InfoCard	{{#property:P2566}}
Chemical and physical data
Formula	C72H104Na8O48S8
Molar mass	2178 g/mol
3D model (JSmol)	Interactive image
SMILES [Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].O=C([O-])CCSC[C@H]8O[C@@H]7O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@@H]1CSCCC(=O)[O-])O[C@H]2[C@H](O)[C@@H](O)[C@H](O[C@@H]2CSCCC(=O)[O-])O[C@H]3[C@H](O)[C@@H](O)[C@H](O[C@@H]3CSCCC(=O)[O-])O[C@H]4[C@H](O)[C@@H](O)[C@H](O[C@@H]4CSCCC(=O)[O-])O[C@@H]9[C@H](O[C@H](O[C@H]5[C@H](O)[C@@H](O)[C@H](O[C@@H]5CSCCC(=O)[O-])O[C@H]6[C@H](O)[C@@H](O)[C@H](O[C@@H]6CSCCC([O-])=O)O[C@H]8[C@H](O)[C@H]7O)[C@H](O)[C@H]9O)CSCCC(=O)[O-]
InChI InChI=1S/C72H112O48S8.8Na/c73-33(74)1-9-121-17-25-57-41(89)49(97)65(105-25)114-58-26(18-122-10-2-34(75)76)107-67(51(99)43(58)91)116-60-28(20-124-12-4-36(79)80)109-69(53(101)45(60)93)118-62-30(22-126-14-6-38(83)84)111-71(55(103)47(62)95)120-64-32(24-128-16-8-40(87)88)112-72(56(104)48(64)96)119-63-31(23-127-15-7-39(85)86)110-70(54(102)46(63)94)117-61-29(21-125-13-5-37(81)82)108-68(52(100)44(61)92)115-59-27(19-123-11-3-35(77)78)106-66(113-57)50(98)42(59)90;;;;;;;;/h25-32,41-72,89-104H,1-24H2,(H,73,74)(H,75,76)(H,77,78)(H,79,80)(H,81,82)(H,83,84)(H,85,86)(H,87,88);;;;;;;;/q;8*+1/p-8/t25-,26-,27-,28-,29-,30-,31-,32-,41-,42-,43-,44-,45-,46-,47-,48-,49-,50-,51-,52-,53-,54-,55-,56-,57-,58-,59-,60-,61-,62-,63-,64-,65-,66-,67-,68-,69-,70-,71-,72-;;;;;;;;/m1......../s1 N Key:KMGKABOMYQLLDJ-VKHHSAQNSA-F N
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]

Overview

Sugammadex (Org 25969, tradename Bridion) is an agent for reversal of neuromuscular blockade by the agent rocuronium in general anaesthesia. It is the first selective relaxant binding agent (SRBA) .

History

Sugammadex was discovered at the Newhouse research site in Scotland. These scientists who discovered Sugammadex worked for the pharmaceutical company Organon. Organon was acquired by Schering-Plough in 2007; Schering-Plough merged with Merck in 2009. Sugammadex is now owned and sold by Merck.

On January 3, 2008, Schering-Plough submitted a New Drug Application to the US Food and Drug Administration for sugammadex, but the FDA rejected the application on August 2008. It was approved for use in the European Union on July 29, 2008.

Mechanism of action

Sugammadex is a modified γ-cyclodextrin, with a lipophilic core and a hydrophilic periphery. This gamma cyclodextrin has been modified from its natural state by placing eight carboxyl thio ether groups at the sixth carbon positions. These extensions extend the cavity size allowing greater encapsulation of the rocuronium molecule. These negatively charged extensions electrostatically bind to the quaternary nitrogen of the target as well as contribute to the aqueous nature of the cyclodextrin. Sugammadex's binding encapsulation of rocuronium is one of the strongest among cyclodextrins and their guest molecules. The rocuronium molecule (a modified steroid) bound within sugammadex's lipophilic core, is rendered unavailable to bind to the acetylcholine receptor at the neuromuscular junction.

Left: Schematic of a sugammadex molecule encapsulating a rocuronium molecule.
Right: Space-filling model of a sugammadex sodium molecule in the same orientation.

The main advantage of sugammadex is reversal of neuromuscular blockade without relying on inhibition of acetylcholinesterase. Therefore it does not cause the autonomic instability produced by anticholinesterases such as neostigmine, and antimuscarinic agents such as atropine do not need to be co-administered. Its administration is therefore associated with much greater cardiovascular and autonomic stability than the traditional reversal agents.

In addition, when a fast onset and short duration of muscle relaxant is required, there has been little choice previously apart from the use of suxamethonium. However, suxamethonium is not ideal, as it has some undesirable side effects, such as anaphylaxis, increasing serum potassium levels and other cardiovascular properties. Since, in high doses, rocuronium has a reasonably rapid onset and now can be reversed with sugammadex, it can potentially be used instead.

'Recurarisation', a phenomenon of recurrence of neuromuscular block, may occur where the reversal agents wear off before a neuromuscular blocking drug is completely cleared. This is very unusual with all but the longest acting neuromuscular blocking drugs (such as gallamine, pancuronium or tubocurarine). It has been demonstrated to occur only rarely with sugammadex, and only when insufficient doses were administered. The underlying mechanism is thought to be related to redistribution of relaxant after reversal. It may occur for a limited range of sugammadex doses which are sufficient for complex formation with relaxant in the central compartment, but insufficient for additional relaxant returning to central from peripheral compartments.

Sugammadex also has some affinity for other aminosteroid neuromuscular blocking agents such as vecuronium and pancuronium. Though sugammadex's affinity for vecuronium is lower than its affinity for rocuronium, reversal of vecuronium is still effective because fewer vecuronium molecules are present in vivo for equivalent blockade. Vecuronium is approximately seven times more potent than rocuronium and overall requires fewer molecules to induce blockade. Sugammadex encapsulates with a 1:1 ratio and therefore will adequately reverse vecuronium as there are fewer molecules to bind compared to rocuronium. Shallow Pancuronium blockade has been successfully reversed by sugammadex in phase III clinical trials.

Efficacy

A study was carried out in Europe looking at its suitability in rapid sequence induction. It found that sugammadex provides a rapid and dose-dependent reversal of neuromuscular blockade induced by high-dose rocuronium.

A Cochrane systematic review on sugammadex has been recently published by Abrishami et al. This review article included 18 randomized controlled trials on the efficacy and safety of sugammadex. The trials included a total of 1321 patients. The review concluded that "sugammadex was shown to be more effective than placebo (no medication) or neostigmine in reversing muscle relaxation caused by neuromuscular blockade during surgery and is relatively safe. Serious complications occurred in less than 1% of the patients who received sugammadex. The results of this review article (especially the safety results) need to be confirmed by future trials on larger patient populations".

Tolerability

Sugammadex was generally well tolerated in clinical trials in surgical patients or healthy volunteers. In pooled analyses, the tolerability profile of sugammadex was generally similar to that of placebo or neostigmine plus glycopyrrolate.