Sugammadex

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Sugammadex
Sugammadex sodium.svg
Sugammadex sodium 3D front view.png
Clinical data
Pronunciationsoo GAM ma dex
Trade names Bridion
Other namesORG-25969
AHFS/Drugs.com Monograph
License data
Pregnancy
category
  • AU:B2
Routes of
administration 		Intravenous
ATC code
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard 100.121.931 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C72H112O48S8
Molar mass 2002.12 g·mol−1
3D model (JSmol)
  • O=C(O)CCSC[C@H]1O[C@@H]2O[C@@H]3[C@@H](CSCCC(=O)O)O[C@H](O[C@@H]4[C@@H](CSCCC(=O)O)O[C@H](O[C@@H]5[C@@H](CSCCC(=O)O)O[C@H](O[C@@H]6[C@@H](CSCCC(=O)O)O[C@H](O[C@@H]7[C@@H](CSCCC(=O)O)O[C@H](O[C@@H]8[C@@H](CSCCC(=O)O)O[C@H](O[C@@H]9[C@@H](CSCCC(=O)O)O[C@H](O[C@H]1[C@H](O)[C@H]2O)[C@H](O)[C@H]9O)[C@H](O)[C@H]8O)[C@H](O)[C@H]7O)[C@H](O)[C@H]6O)[C@H](O)[C@H]5O)[C@H](O)[C@H]4O)[C@H](O)[C@H]3O
  • InChI=1S/C72H112O48S8/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)/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 X mark.svgN
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Sugammadex, sold under the brand name Bridion, is a medication for the reversal of neuromuscular blockade induced by rocuronium and vecuronium [4] in general anaesthesia. It is the first selective relaxant binding agent (SRBA). It is marketed by Merck. [7]

Contents

The most common side effects include cough, airway problems due to the anaesthesia wearing off, reduced blood pressure and other complications such as changes in heart rate. [5]

Sugammadex is available as a generic medication. [8]

Medical uses

Sugammadex is indicated for the reversal of neuromuscular blockade induced by rocuronium or vecuronium. [4] [5]

Pharmacology

Pharmacodynamics

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.

Sugammadex encaps rocuronium.jpg
Sugammadex sodium 3D three quarters view.png
Left: Schematic of a sugammadex molecule encapsulating a rocuronium molecule.
Right: Space-filling model of a sugammadex sodium molecule in the same orientation.


Sugammadex, unlike neostigmine, does not inhibit acetylcholinesterase so cholinergic effects are not produced and co-administration of an antimuscarinic agent (glycopyrronium bromide or atropine) is not needed. Sugammadex might therefore be expected to have fewer adverse effects than the traditional reversal agents.

When muscle relaxant with rapid onset and short duration of action is required, there has been little choice apart from succinylcholine but this drug has important contraindications; for example, it can trigger malignant hyperthermia in susceptible individuals, it has a prolonged duration of action in patients with pseudocholinesterase deficiency and it causes an increase in plasma potassium concentration which is dangerous in some circumstances. Rocuronium has a comparably quick onset in high dose (0.6 mg kg−1 to 1 mg kg−1) and can be rapidly reversed with sugammadex (16 mg kg−1), so this drug combination offers an alternative to suxamethonium.

'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. [9] 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. [10]

Sugammadex has been shown to have affinity for two other aminosteroid neuromuscular blocking agents, vecuronium and pancuronium. Although sugammadex has a lower affinity for vecuronium than 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. Sugammadex encapsulates with a 1:1 ratio and therefore will adequately reverse vecuronium as there are fewer molecules to bind compared to rocuronium. [11] Shallow pancuronium blockade has been successfully reversed by sugammadex in phase III clinical trials. [12]

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. [13]

A Cochrane review on sugammadex 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". [14] The 2017 Cochrane review concluded that sugammadex has a better safety profile than neostigmine with 40% fewer adverse events. [15] Specifically the risks of postoperative residual paralysis, bradycardia, nausea and vomiting are reduced if sugammadex is used as a reversal agent. The British Journal of Anaesthesia published an article in 2015 in which the incidence of residual neuromuscular blockade could be reduced to zero if sugammadex is used as the reversal agent and the correct dosage is selected with the use of neuromuscular monitoring. [16] Also when the reversal times of each agent were compared "Data indicate that sugammadex was 10.22 minutes (6.6 times) faster than neostigmine (1.96 vs 12.87 minutes) in reversing moderate induced paralysis. Sugammadex was 45.78 minutes (16.8 times) faster than neostigmine (2.9 vs 48.8 minutes) in reversing deep induced paralysis." [15] The time saved by rapid reversal and the reduction of postoperative residual paralysis may reduce the overall hospital costs and provide significant improvements in patient safety.[ citation needed ]

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. [17] Sugammadex may theoretically interfere with hormonal contraceptives due to evidence from in vitro binding studies which showed it may bind to progestogen. [4]

History

Sugammadex was discovered by the pharmaceutical company Organon at the Newhouse Research Site in Scotland. [18] Organon was acquired by Schering-Plough in 2007; Schering-Plough merged with Merck in 2009. Sugammadex is now owned and sold by Merck.

The US Food and Drug Administration (FDA) initially rejected Schering-Plough's New Drug Application for sugammadex in 2008, [19] but finally approved the medication for use in the United States in December 2015. [20] [21] Sugammadex was approved for use in the European Union in July 2008. [5] [22]

Related Research Articles

<span class="mw-page-title-main">Pancuronium bromide</span> Aminosteroid muscle relaxant

Pancuronium is an aminosteroid muscle relaxant with various medical uses. It is used in euthanasia and is used in some states as the second of three drugs administered during lethal injections in the United States.

<span class="mw-page-title-main">General anaesthesia</span> Medically induced loss of consciousness

General anaesthesia (UK) or general anesthesia (US) is a method of medically inducing loss of consciousness that renders a patient unarousable even with painful stimuli. This effect is achieved by administering either intravenous or inhalational general anaesthetic medications, which often act in combination with an analgesic and neuromuscular blocking agent. Spontaneous ventilation is often inadequate during the procedure and intervention is often necessary to protect the airway. General anaesthesia is generally performed in an operating theater to allow surgical procedures that would otherwise be intolerably painful for a patient, or in an intensive care unit or emergency department to facilitate endotracheal intubation and mechanical ventilation in critically ill patients. Depending on the procedure, general anaesthesia may be optional or required. Regardless of whether a patient may prefer to be unconscious or not, certain pain stimuli could result in involuntary responses from the patient that may make an operation extremely difficult. Thus, for many procedures, general anaesthesia is required from a practical perspective.

<span class="mw-page-title-main">Anesthetic</span> Drug that causes anesthesia

An anesthetic or anaesthetic is a drug used to induce anesthesia ⁠— ⁠in other words, to result in a temporary loss of sensation or awareness. They may be divided into two broad classes: general anesthetics, which result in a reversible loss of consciousness, and local anesthetics, which cause a reversible loss of sensation for a limited region of the body without necessarily affecting consciousness.

<span class="mw-page-title-main">Neostigmine</span> Anti-full body paralysis drug treatment

Neostigmine, sold under the brand name Bloxiverz, among others, is a medication used to treat myasthenia gravis, Ogilvie syndrome, and urinary retention without the presence of a blockage. It is also used in anaesthesia to end the effects of non-depolarising neuromuscular blocking medication. It is given by injection either into a vein, muscle, or under the skin. After injection effects are generally greatest within 30 minutes and last up to 4 hours.

<span class="mw-page-title-main">Vecuronium bromide</span> Muscle relaxant

Vecuronium bromide, sold under the brand name Norcuron among others, is a medication used as part of general anesthesia to provide skeletal muscle relaxation during surgery or mechanical ventilation. It is also used to help with endotracheal intubation; however, agents such as suxamethonium (succinylcholine) or rocuronium are generally preferred if this needs to be done quickly. It is given by injection into a vein. Effects are greatest at about 4 minutes and last for up to an hour.

In anaesthesia and advanced airway management, rapid sequence induction (RSI) – also referred to as rapid sequence intubation or as rapid sequence induction and intubation (RSII) or as crash induction – is a special process for endotracheal intubation that is used where the patient is at a high risk of pulmonary aspiration. It differs from other techniques for inducing general anesthesia in that several extra precautions are taken to minimize the time between giving the induction drugs and securing the tube, during which period the patient's airway is essentially unprotected.

<span class="mw-page-title-main">Tubocurarine chloride</span> Obsolete muscle relaxant

Tubocurarine is a toxic benzylisoquinoline alkaloid historically known for its use as an arrow poison. In the mid-1900s, it was used in conjunction with an anesthetic to provide skeletal muscle relaxation during surgery or mechanical ventilation. Safer alternatives, such as cisatracurium and rocuronium, have largely replaced it as an adjunct for clinical anesthesia and it is now rarely used.

<span class="mw-page-title-main">Neuromuscular-blocking drug</span> Type of paralyzing anesthetic including lepto- and pachycurares

Neuromuscular-blocking drugs, or Neuromuscular blocking agents (NMBAs), block transmission at the neuromuscular junction, causing paralysis of the affected skeletal muscles. This is accomplished via their action on the post-synaptic acetylcholine (Nm) receptors.

<span class="mw-page-title-main">Rocuronium bromide</span> Chemical compound

Rocuronium bromide is an aminosteroid non-depolarizing neuromuscular blocker or muscle relaxant used in modern anaesthesia to facilitate tracheal intubation by providing skeletal muscle relaxation, most commonly required for surgery or mechanical ventilation. It is used for standard endotracheal intubation, as well as for rapid sequence induction (RSI).

<span class="mw-page-title-main">Atracurium besilate</span> Chemical compound

Atracurium besilate, also known as atracurium besylate, is a medication used in addition to other medications to provide skeletal muscle relaxation during surgery or mechanical ventilation. It can also be used to help with endotracheal intubation but suxamethonium (succinylcholine) is generally preferred if this needs to be done quickly. It is given by injection into a vein. Effects are greatest at about 4 minutes and last for up to an hour.

<span class="mw-page-title-main">Cisatracurium besilate</span> Chemical compound

Cisatracurium besilate is a bisbenzyltetrahydroisoquinolinium that has effect as a neuromuscular-blocking drug non-depolarizing neuromuscular-blocking drugs, used adjunctively in anesthesia to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation. It shows intermediate duration of action. Cisatracurium is one of the ten isomers of the parent molecule, atracurium. Moreover, cisatracurium represents approximately 15% of the atracurium mixture.

<span class="mw-page-title-main">Alcuronium chloride</span> Muscle relaxant

Alcuronium chloride is a neuromuscular blocking (NMB) agent, alternatively referred to as a skeletal muscle relaxant. It is a semi-synthetic substance prepared from C-toxiferine I, a bis-quaternary alkaloid obtained from Strychnos toxifera. C-toxiferine I itself has been tested for its pharmacological action and noted to be a very long acting neuromuscular blocking agent For a formal definition of the durations of actions associated with NMB agents, see page for gantacurium. The replacement of both the N-methyl groups with N-allyl moieties yielded N,N-diallyl-bis-nortoxiferine, now recognized as alcuronium.

Selective relaxant binding agents (SRBAs) are a new class of drugs that selectively encapsulates and binds neuromuscular blocking agents (NMBAs). The first drug introduction of an SRBA is sugammadex. Sugammadex is a modified gamma cyclodextrin that specifically encapsulates and binds the aminosteroid NMBAs: rocuronium>vecuronium>>pancuronium. SRBAs exert a chelating action that effectively terminates an NMBA ability to bind to nicotinic receptors.

<span class="mw-page-title-main">Gantacurium chloride</span> Chemical compound

Gantacurium chloride is a new experimental neuromuscular blocking drug or skeletal muscle relaxant in the category of non-depolarizing neuromuscular-blocking drugs, used adjunctively in surgical anesthesia to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation. Gantacurium is not yet available for widespread clinical use: it is currently undergoing Phase III clinical development.

<span class="mw-page-title-main">Newhouse Research Site</span>

The Newhouse Research Site is a drug research facility situated 15 miles (24 km) 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 anaesthesia and psychiatry. In 2007, the Royal Society of Chemistry Malcolm Campbell Memorial Prize was awarded to researchers for its work on a new anaesthesia drug, sugammadex. It currently employs 250 scientists across a range of disciplines including medicinal chemistry, molecular biology and drug metabolism. The site is currently the largest private drug discovery centre in Scotland, and one of the biggest in the UK.

<span class="mw-page-title-main">Acceleromyograph</span> Used to measure the force produced by a muscle

An acceleromyograph is a piezoelectric myograph, used to measure the force produced by a muscle after it has undergone nerve stimulation. Acceleromyographs may be used, during anaesthesia when muscle relaxants are administered, to measure the depth of neuromuscular blockade and to assess adequacy of recovery from these agents at the end of surgery. Acceleromyography is classified as quantitative neuromuscular monitoring.

<span class="mw-page-title-main">Neuromuscular monitoring</span>

In anesthesia, neuromuscular blocking agents may be required to facilitate endotracheal intubation and provide optimal surgical conditions. When neuromuscular blocking agents are administered, neuromuscular function of the patient must be monitored. Neuromuscular function monitoring is a technique that involves the electrical stimulation of a motor nerve and monitoring the response of the muscle supplied by that nerve. It may be used from the induction of to recovery from neuromuscular blockade. Importantly, it is used to confirm adequacy of recovery after the administration of neuromuscular blocking agents. The response of the muscles to electrical stimulation of the nerves can be recorded subjectively (qualitative) or objectively (quantitatively). Quantitative techniques include electromyography, acceleromyography, kinemyography, phonomygraphy and mechanomyography. Neuromuscular monitoring is recommended when neuromuscular-blocking drugs have been part of the general anesthesia and the doctor wishes to avoid postoperative residual curarization (PORC) in the patient, that is, the residual paralysis of muscles stemming from these drugs.

<span class="mw-page-title-main">Postoperative residual curarization</span> Medical condition

Postoperative residual curarization (PORC) or residual neuromuscular blockade (RNMB) is a residual paresis after emergence from general anesthesia that may occur with the use of neuromuscular-blocking drugs. Today residual neuromuscular blockade is defined as a train of four ratio of less than 0.9 when measuring the response to ulnar nerve stimulation at the adductor pollicis muscle using mechanomyography or electromyography. A meta-analysis reported that the incidence of residual neuromuscular paralysis was 41% in patients receiving intermediate neuromuscular blocking agents during anaesthesia. It is possible that > 100,000 patients annually in the USA alone, are at risk of adverse events associated with undetected residual neuromuscular blockade. Neuromuscular function monitoring and the use of the appropriate dosage of sugammadex to reverse blockade produced by rocuronium can reduce the incidence of postoperative residual curarization. In this study, with usual care group receiving reversal with neostigmine resulted in a residual blockade rate of 43%.

<span class="mw-page-title-main">Malouetine</span> Chemical compound

Malouetine is an aminosteroid neuromuscular blocking agent and antinicotinic alkaloid isolated from Malouetia spp.

<span class="mw-page-title-main">Neuromuscular drug</span>

Neuromuscular drugs are chemical agents that are used to alter the transmission of nerve impulses to muscles, causing effects such as temporary paralysis of targeted skeletal muscles. Most neuromuscular drugs are available as quaternary ammonium compounds which are derived from acetylcholine (ACh). This allows neuromuscular drugs to act on multiple sites at neuromuscular junctions, mainly as antagonists or agonists of post-junctional nicotinic receptors. Neuromuscular drugs are classified into four main groups, depolarizing neuromuscular blockers, non-depolarizing neuromuscular blockers, acetylcholinesterase inhibitors, and butyrylcholinesterase inhibitors.

References

  1. ↑ SUGAMMADEX ACCORD (Accord Healthcare Pty Ltd) Archived 2022-10-12 at the Wayback Machine Department of Health and Aged Care. Retrieved 30 March 2023
  2. ↑ SUGAMMADEX SANDOZ (Sandoz Pty Ltd) Archived 2022-10-12 at the Wayback Machine Department of Health and Aged Care. Retrieved 30 March 2023
  3. ↑ "Bridion 100 mg/ml solution for injection - Summary of Product Characteristics (SmPC)". (emc). 18 March 2021. Archived from the original on 27 June 2021. Retrieved 27 June 2021.
  4. 1 2 3 4 "Bridion- sugammadex injection, solution". DailyMed. 14 December 2018. Archived from the original on 10 June 2020. Retrieved 10 June 2020.
  5. 1 2 3 4 "Bridion EPAR". European Medicines Agency (EMA). 17 September 2018. Archived from the original on 10 June 2020. Retrieved 10 June 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  6. ↑ "Sugammadex Adroiq". Union Register of medicinal products. 30 May 2023. Retrieved 6 June 2023.
  7. ↑ "Dosing for Bridion (sugammadex)". www.merckconnect.com. Archived from the original on 2019-01-12. Retrieved 2019-01-11.
  8. ↑ "Sugammadex Adroiq". European Medicines Agency. 16 June 2023. Retrieved 19 June 2023.
  9. ↑ Miller RD (March 2007). "Sugammadex: an opportunity to change the practice of anesthesiology?". Anesthesia and Analgesia. 104 (3): 477–478. doi: 10.1213/01.ane.0000255645.64583.e8 . PMID   17312188.
  10. ↑ Eleveld DJ, Kuizenga K, Proost JH, Wierda JM (March 2007). "A temporary decrease in twitch response during reversal of rocuronium-induced muscle relaxation with a small dose of sugammadex". Anesthesia and Analgesia. 104 (3): 582–584. doi: 10.1213/01.ane.0000250617.79166.7f . PMID   17312212. S2CID   34811540.
  11. ↑ Welliver M (October 2006). "New drug sugammadex: a selective relaxant binding agent". AANA Journal. 74 (5): 357–363. PMID   17048555.
  12. ↑ Decoopman M (2007). "Reversal of pancuronium-induced block by the selective relaxant binding agent sugammadex". Eur J Anaesthesiol. 24(Suppl 39):110-111.
  13. ↑ Pühringer FK, Rex C, Sielenkämper AW, Claudius C, Larsen PB, Prins ME, et al. (August 2008). "Reversal of profound, high-dose rocuronium-induced neuromuscular blockade by sugammadex at two different time points: an international, multicenter, randomized, dose-finding, safety assessor-blinded, phase II trial". Anesthesiology. 109 (2): 188–197. doi: 10.1097/ALN.0b013e31817f5bc7 . PMID   18648227.
  14. ↑ Abrishami A, Ho J, Wong J, Yin L, Chung F (October 2009). Abrishami A (ed.). "Sugammadex, a selective reversal medication for preventing postoperative residual neuromuscular blockade". The Cochrane Database of Systematic Reviews (4): CD007362. doi:10.1002/14651858.CD007362.pub2. PMID   19821409.
  15. 1 2 Hristovska AM, Duch P, Allingstrup M, Afshari A (August 2017). "Efficacy and safety of sugammadex versus neostigmine in reversing neuromuscular blockade in adults". The Cochrane Database of Systematic Reviews. 8 (8): CD012763. doi:10.1002/14651858.cd012763. PMC   6483345 . PMID   28806470.
  16. ↑ Brueckmann B, Sasaki N, Grobara P, Li MK, Woo T, de Bie J, et al. (November 2015). "Effects of sugammadex on incidence of postoperative residual neuromuscular blockade: a randomized, controlled study". British Journal of Anaesthesia. 115 (5): 743–751. doi: 10.1093/bja/aev104 . PMID   25935840.
  17. ↑ Yang LP, Keam SJ (2009). "Sugammadex: a review of its use in anaesthetic practice". Drugs. 69 (7): 919–942. doi:10.2165/00003495-200969070-00008. PMID   19441874. S2CID   195685307. Archived from the original on 2011-10-08. Retrieved 2010-03-29.
  18. ↑ Naguib M (March 2007). "Sugammadex: another milestone in clinical neuromuscular pharmacology". Anesthesia and Analgesia. 104 (3): 575–581. doi: 10.1213/01.ane.0000244594.63318.fc . PMID   17312211.
  19. ↑ "U.S. FDA Issues Action Letter for Sugammadex" (Press release). Schering-Plough. 2008-08-01. Archived from the original on 2008-08-10. Retrieved 2008-08-02.
  20. ↑ "Bridion (sugammadex) Injection". U.S. Food and Drug Administration (FDA). 4 February 2016. Archived from the original on 10 June 2020. Retrieved 10 June 2020.
  21. ↑ "FDA approves Bridion to reverse effects of neuromuscular blocking drugs used during surgery" (Press release). Food and Drug Administration. 2015-12-15. Archived from the original on 2015-12-15. Retrieved 2015-12-15.
  22. ↑ "Bridion (sugammadex) Injection - First and Only Selective Relaxant Binding Agent - Approved in European Union" (Press release). Schering-Plough. 2008-07-29. Archived from the original on 2008-09-24. Retrieved 2008-08-02.
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