Sugammadex
Encyclopedia
Sugammadex is an agent for reversal of neuromuscular blockade by the agent rocuronium
in general anaesthesia
. It is the first selective relaxant binding agent (SRBA) and 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.
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 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
.
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.
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 (specially the safety results) need to be confirmed by future trials on larger patient populations”.
Rocuronium
Rocuronium is an aminosteroid non-depolarizing neuromuscular blocker or muscle relaxant used in modern anaesthesia, to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation.Introduced in 1994, rocuronium has...
in general anaesthesia
General anaesthesia
General anaesthesia is a state of unconsciousness and loss of protective reflexes resulting from the administration of one or more general anaesthetic agents...
. It is the first selective relaxant binding agent (SRBA) and was discovered at the Newhouse research site
Newhouse Research Site
The Newhouse Research Site is a drug research facility situated east of Glasgow in central Scotland. It is located beside the M8 motorway in Newhouse, North Lanarkshire. The site is an early drug discovery research centre with a track record of generating a succession of products in the areas of...
in Scotland
Scotland
Scotland is a country that is part of the United Kingdom. Occupying the northern third of the island of Great Britain, it shares a border with England to the south and is bounded by the North Sea to the east, the Atlantic Ocean to the north and west, and the North Channel and Irish Sea to the...
. . 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
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
for sugammadex, but the FDA rejected the application on August 2008.
It was approved for use in the European Union
European Union
The European Union is an economic and political union of 27 independent member states which are located primarily in Europe. The EU traces its origins from the European Coal and Steel Community and the European Economic Community , formed by six countries in 1958...
on July 29, 2008.
Sugammadex is a modified γ-cyclodextrin
Cyclodextrin
Cyclodextrins are a family of compounds made up of sugar molecules bound together in a ring ....
, 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 is one of the strongest among cyclodextrins and their guest molecules. The rocuronium molecule (a modified steroid
Steroid
A steroid is a type of organic compound that contains a characteristic arrangement of four cycloalkane rings that are joined to each other. Examples of steroids include the dietary fat cholesterol, the sex hormones estradiol and testosterone, and the anti-inflammatory drug dexamethasone.The core...
) bound within sugammadex's lipophilic core, is rendered unavailable to bind to the acetylcholine receptor
Acetylcholine receptor
An acetylcholine receptor is an integral membrane protein that responds to the binding of acetylcholine, a neurotransmitter.-Classification:...
at the neuromuscular junction
Neuromuscular junction
A neuromuscular junction is the synapse or junction of the axon terminal of a motor neuron with the motor end plate, the highly-excitable region of muscle fiber plasma membrane responsible for initiation of action potentials across the muscle's surface, ultimately causing the muscle to contract...
.
The main advantage of sugammadex is reversal of neuromuscular blockade without relying on inhibition of acetylcholinesterase
Acetylcholinesterase
"Acetylcholinesterase, also known as AChE or acetylcholine acetylhydrolase, is an enzyme that degrades the neurotransmitter acetylcholine, producing choline and an acetate group. It is mainly found at neuromuscular junctions and cholinergic nervous system, where its activity serves to terminate...
. Therefore it does not cause the autonomic instability produced by anticholinesterases such as neostigmine
Neostigmine
Neostigmine is a parasympathomimetic that acts as a reversible acetylcholinesterase inhibitor.- Synthesis :Neostigmine was first synthesized by Aeschlimann and Reinert in 1931....
, and antimuscarinic agents such as atropine
Atropine
Atropine is a naturally occurring tropane alkaloid extracted from deadly nightshade , Jimson weed , mandrake and other plants of the family Solanaceae. It is a secondary metabolite of these plants and serves as a drug with a wide variety of effects...
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
Gallamine
Gallamine triethiodide is a non-depolarising muscle relaxant. It acts by combining with the cholinergic receptor sites in muscle and competitively blocking the transmitter action of acetylcholine. Gallamine triethiodide has a parasympatholytic effect on the cardiac vagus nerve which causes...
, pancuronium
Pancuronium
Pancuronium is a muscle relaxant with various purposes. It is the second of three drugs administered during most lethal injections in the United States.- Mode of action :...
or tubocurarine
Tubocurarine
Tubocurarine is a neuromuscular-blocking drug or skeletal muscle relaxant in the category of non-depolarizing neuromuscular-blocking drugs, used adjunctively in anesthesia to provide skeletal muscle relaxation during surgery or mechanical ventilation...
). 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
Vecuronium
Vecuronium is a muscle relaxant in the category of non-depolarizing blocking agents. Vecuronium bromide is indicated as an adjunct to general anesthesia, to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation...
and pancuronium
Pancuronium
Pancuronium is a muscle relaxant with various purposes. It is the second of three drugs administered during most lethal injections in the United States.- Mode of action :...
. 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.
A study was carried out in Europe looking at its suitability in rapid sequence induction
Rapid sequence induction
Rapid Sequence Induction is a medical procedure involving the expeditious induction of general anesthesia and subsequent intubation of the trachea. RSI is generally used in an emergency setting or for patients who have an increased risk of aspirating stomach contents into the lungs...
. It found that sugammadex provides a rapid and dose-dependent reversal of neuromuscular blockade induced by high-dose rocuronium
Rocuronium
Rocuronium is an aminosteroid non-depolarizing neuromuscular blocker or muscle relaxant used in modern anaesthesia, to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation.Introduced in 1994, rocuronium has...
.
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 (specially the safety results) need to be confirmed by future trials on larger patient populations”.