Sugammadex: A revolutionary drug in neuromuscular pharmacology

Sugammadex (ORG 25969) is a unique neuromuscular reversal drug; a novel cyclodextrin, the first in a new class of selective relaxant binding agents, which reverse neuromuscular blockade (NMB) with the aminosteroid non-depolarizing muscle relaxants rocuronium and vecuronium. Sugammadex can reverse moderate or deep NMB. The clinical use of sugammadex promises to eliminate many of the shortcomings in current anesthetic practice with regard to antagonism of rocuronium and other aminosteroid muscle relaxants.

CHEMICAL STRUCTURE

Sugammadex [6A,6B,6C,6D,6E,6F,6G,6H-octakis-S-(2-carboxyethyl)-6A,6B,6C,6D,6E,6F,6G,6H-octathio-γ-cyclodextrin octasodium salt] is a modified γ-cyclodextrin [Figure 1]. Chemical formula is C72H104Na8O48S8. “Su” stands for sugar and “gammadex” stands for structural molecule gamma-cyclodextrin.[1] Cyclodextrins are cyclic dextrose units joined through 1-4 glycosyl bonds that are produced from starch or starch derivates using cyclodextrin glycosyltransferase. The three natural unmodified cyclodextrins are α-, β-or γ-cyclodextrin. Compared with α-and β-cyclodextrins, γ-cyclodextrin exhibits more favorable properties in terms of the size of its internal cavity, water solubility and bioavailability. To have a better fit of the larger rigid structure of the aminosteroid muscle relaxant molecule (e.g., rocuronium or vecuronium) within the cavity of γ-cyclodextrin, the latter was modified by adding eight side chains to extend the cavity. This modification allowed the four hydrophobic steroidal rings of rocuronium to be better accommodated within the hydrophobic cavity. In addition, adding negatively charged carboxyl groups at the end of the eight side chains served two purposes. First, the repellent forces of the negative charges keep propionic acid side chains from being disordered, thereby allowing the cavity to remain open and maintain structural integrity. Second, adding these negatively charged carboxyl groups enhances electrostatic binding to the positively charged quaternary nitrogen of rocuronium [Figure 1]. Three-dimensional structure resembles a hollow, truncated cone or a doughnut.[9]

Mechanism of action

Inactivates rocuronium by encapsulating (chelating) the free molecule to form a stable complex.[10] The structure has a hydrophobic cavity and a hydrophilic exterior because of the presence of polar hydroxyl groups. Hydrophobic interactions trap the drug into the cyclodextrin cavity, resulting in the formation of a water-soluble guest–host complex. Sugammadex exerts its effect by forming very tight complexes at a 1:1 ratio with aminosteroid muscle relaxants (rocuronium > vecuronium >> pancuronium).[9,10,11,12] The intermolecular (van der Waals’) forces, thermodynamic (hydrogen) bonds and hydrophobic interactions make the sugammadex–rocuronium complex very tight. The sugammadex–rocuronium complex has a very high association rate (an association constant of 107 M-1) and a very low dissociation rate. It is estimated that, for every 25 million sugammadex–rocuronium complexes, only one complex dissociates. The resulting reduction in free rocuronium plasma concentration creates a gradient between the tissue compartment (including the NMJ) and plasma; free rocuronium moves from tissue to plasma, with a reduction in nicotinic receptor occupancy at the NMJ.[10,13,14]

Metabolism and elimination

The drug does not produce any metabolites and is mostly excreted through urine in the unchanged form within 24 h. An insignificant part is excreted through feces or in expired air (0.02%). The plasma clearance of the drug ranges from 84 to 138 ml/min.[2]

The drug is available in IV formulation only; vials of 200 mg (2 ml) or 500 mg (5 ml) and is for non-refrigerated storage.[19] The drug was originally designated as Org 25,969. Trade name is Bridion. Sugammadex was discovered at the Newhouse research site in Scotland. 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 FDA for sugammadex, but was rejected on August 2008.[20,21] It was approved for use in the European Union on July 29, 2008.[17] The drug is also approved for use in Australia, Iceland, New Zealand and Norway.

Indication

Reversal of neuromuscular blockade (NMB) in the operation theater and in the intensive care unit (ICU).[17]

Drug interactions Toremifene, a chemotherapeutic drug, which is a selective estrogen receptor modulator, can delay the reversal by displacing the formation of the rocuronium-sugammadex complex. The drug can theoretically bind with contraceptive steroids. As endogenous steroids and steroidal drugs lack the quaternary nitrogen of the aminosteroid muscle relaxants, they show a much lower affinity. Rocuronium-sugammadex complex can also be displaced by fusidic acid or high doses of flucloxacillin. Drugs like magnesium, aminoglycosides potentiate muscle relaxants; to counteract these effects, a larger dose of sugammadex may be required. Among anesthetic drugs the highest affinity constant was observed with remifentanil (0.2% of the affinity constant of sugammadex with rocuronium); it has not been shown to be clinically significant. Physical incompatibility has been reported with verapamil, ondansetron and ranitidine. Further investigations are required to assess other possible drug interactions.[1,2,9]

Sugammadex does not alter laboratory tests in general, but some modification of the serum progesterone assay and of the coagulation parameters like activated partial thromboplastin time, prothrombin time, INR has been noticed.[17]

Contraindications

Hypersensitivity to sugammadex or to any excipients.[13]

Special considerations Patients with severe renal impairment: Clearance of the drug is reduced in patients with creatinine clearance below 30 ml/min. The efficacy of the drug is not reduced in these patients.[22] There are conflicting reports of its safety in these subset of patients; hence, it is recommended to avoid its use in such patients.[2]

Patients with hepatic impairment: Sugammadex-rocuronium complex is not eliminated by hepatic metabolism; therefore, hepatic impairment does not affect its excretion. However, it is advised to be cautious regarding its use in these patients.[2]

Obese patients: Use adult dose based on actual body weight.

Patients in ICU: Sugammadex has not been investigated in patients receiving rocuronium or vecuronium in the ICU.

Elderly: Use adult dose although recovery times are slower.

Pediatric patients: Pharmacokinetic profile is quite similar to that of adults. There is no clinical trial in children below 2 years of age.

Pregnancy and lactation: Caution in pregnant women. Sugammadex can be used during lactation.

Sex, race and body weight: They have no effect on the use of sugammadex.

Adverse effects

Sugammadex is a well-tolerated and relatively free of adverse effects. Some of the adverse reported in some of the trials are dysgeusia (metal or bitter taste) mainly seen after doses of 32 mg/kg or higher, recurrence of block, movement of limbs or body or coughing during anesthesia, coughing, grimacing or suckling on the endotracheal tube, procedural hypotension.[17,27,28]

Precautions

If re-administration of rocuronium or vecuronium is required a waiting time of 24 h is recommended. If NMB is required before the recommended waiting time has passed, a non-steroidal muscle relaxant should be used. Sugammadex should not be used to reverse block induced by non-steroidal blockers such as suxamethonium or benzylisoquinolinium compounds (because it cannot form inclusion complexes with these drugs) or aminosteroid muscle relaxants other than rocuronium or vecuronium.[9,16]

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