Sugammadex

Sugammadex (designation Org 25969) is a novel agent for reversal of neuromuscular blockade by the agent rocuronium in general anaesthesia. Sugammadex is currently in Phase 3 study and has not been approved for use. It is the first selective relaxant binding agent (SRBA).

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 positively charged ammonium group as well as contribute to the aqueous nature of the cyclodextrin. Sugammadex's binding encapsulation of rocuronium has been found to be one of the strongest among cyclodextrin and their guest molecules. The rocuronium molecule (a modified steroid) bound within sugammadex's lipophilic core, is rendered unavailable to bind to the acetycholine receptor at the neuromuscular junction. Sugammadex binding to rocuronium has been found to be very strong. 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. The use of the depolarizing neuromuscular agent suxamethonium (Celucurin) is often preferred when a fast onset and short duration is needed. The short effect of suxamethonium is of advantage when there is uncertainty of a successful endotracheal intubation. Some disadvantages with suxamethonium sometimes makes it less preferable i.e. electrolyte imbalances like high potassium, other serious cardiovascular side effects also may occur. The introduction of sugammadex will make rocuronium usable in these rare situations also. Since rocuronium has reasonably short onset with high dosage and sugammadex will abolish the effects of rocuronium and in reality make it as short acting as suxamethonium if the effect needs to be reversed.

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.

γ-cyclodextrins have eight glucose units around the central ring of the molecule. Other cyclodextrins have different numbers, and correspondingly different properties.

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