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Sunday, February 7, 2010

"SUGAMMADEX" A NOVEL REVERSAL AGENT

THE QUEST FOR AN IDEAL NEUROMUSCULAR REVERSAL AGENT IS STILL GOING ON. THE RECENT INTRODUCTION OF THIS NOVEL AGENT SUGAMMADEX  WOULD BE AN ANSWER FOR THIS? WHY THIS DRUG IS UNIQUE IN ITS CLASS IS THAT, UNLIKE THE OTHER REVERSAL AGENTS WHICH ACT BY NATURAL DEGRADATION OR COMPETITIVE ANTGONISM ,  SUGAMMADEX  USES THE ENCAPSULATION METHOD TO TERMINATE THE EFFECTS OF NEUROMUSCULAR BLOCKING AGENTS. THE COMPLETE AND RELIABLE BINDING OF NM AGENTS  IS ASSOCIATED WITH EXCELLENT CLINICAL RECOVERY AS WELL AS FEW SIDE EFFECTS.SUGAMMADEX PREVIOUSLY KNOWN AS Org 25969, WORKS WELL AGAINST TWO AMINOSTEROID NMBS, Ie. ROCURONIUM AND VECURONIUM, BOTH THESE ARE HAVING AN INTERMEDIATE DURATION OF ACTION.

MECHANISM OF ACTION: (ref 1)

Binding of the steroidal molecule of rocuronium by a cyclodextrin is a new concept for reversal of neuromuscular block. Sugammadex is a modifiedcyclodextrin.Cyclodextrins are naturally occurring rings of glucose that geometrically resemble a truncated cone. The cavity created by the ring is lipophilic while the exterior is hydrophilic. Cyclodextrins may encapsulate lipophilic drugs  like rocuronium,  yet remain soluble in water.
Sugammadex is synthesized from a gamma cyclodextrin modified with eight carboxyl thioether extensions added at the narrow rim.This modification enlarged the cavity size increasing its affinity for two specific lipophilic NMBAs, rocuronium and vecuronium. The ability of sugammadex to encapsulate and non-covalently bind rocuronium and vecuronium terminates their paralytic effects and effectively reverses their action.Once encapsulated, the NMBAs are no longer able to diffuse across tissue membranes to exert their action at the neuromuscular cleft.after iv administration,Plasma encapsulation causes a reversal of concentration gradient and extracts NMBA molecules back into plasma  from neuromuscular junction terminating  the  neuromuscular blockade and restoration of normal motor function. and the  NMBA molecules which are pulled into the plasma are quickly encapsulated with high affinity, preventing any further drug effect.With adequate doses the reversal process occurs in minutes and then  the resultant sugammadex bound NMBA (inclusion complex) is then excreted by the kidneys.

The perioperative benefits of a direct acting, complete, and reliable NMBA reversal drug had been the dream of both surgeons and anaesthetists. The improved ability to reverse NMBAs will allow the anaesthetist to administer the maximum dose of relaxant facilitating excellent operating conditions for the surgeon especially orthopedic surgeons

Sugammadex provides faster reversal of  NM blockade, but without the adverse effects like  MH,  hyperkalemia , muscle pains or prolonged apnea of succinyl choline(depolarising agents) or without residual blockade or bradycardia , as of other non depolarisers.  rocuronium  is comparable to scoline for rapid sequence intubation in trauma patients, and the effects can be easily reversed with sugammadex, in case of a failed intubation, and this reversal of blockade takes place faster than scoline metabolism,(by plasma esterases) and patient can be made awake without persisting side effects of scoline. Thus rocuronium may replace scoline for use with rapid sequence induction  in conjunction with sugammadex. Residual paralysis is not seen with sugammadex reversal.blockade,  IV administration of sugammadex creates a concentration gradient favoring the movement of rocuronium molecules from the neuromuscular junction back into the plasma, which results in a fast recovery of neuromuscular function, a unique mechanism owned by this drug.  No additional anticholinesterase or anticholinergic drugs are needed for antagonism of residual neuromuscular blockade, which means that the cardiovascular and other side effects of anticholinesterases or anticholinergics can be avoided.

study by  H. D. de Boer1,et al,  from   Radboud University Medical Centre Nijmegen Nijmegen,showed thatSugammadex caused a rapid and complete reversal of rocuronium-induced neuromuscular block but not atrcurium or mivacurium induced block, but the drug is found to be effective against vecuronium.   The drug has a  favourable pharmacological profile as it is inactive, does not bind to plasma proteins, and appears to be safe and well tolerated. Additionally, it has no effect on acetylcholinesterase or any receptor system in the body. The compound's efficacy as an antagonist does not appear to rely on renal excretion of the cyclodextrin-relaxant complex.
The effectiveness of sugammadex is dose dependant.  At a  dose of 0.6mg/kg of rocuronium at induction (T2), 1-3 mt rapid return of TOF ratio to >0.9 requires 2-4 mg of the drug iv. At deeper levels, (PTC2), 8-16 mg is required for the same  effect.
Special thanx to : Anthony M. Harris M.D. et al, department of anaesthesia and dept  of orthopedic surgery,University of Florida & Shands
  Ref: The Internet Journal of Orthopedic Surgery 2007 : Volume 7 Number 2
          British Journal of Anaesthesia 2006 96(4):473-479; doi:10.1093/bja/ael013
          Anesth Analg 2007;104:575-581
for comments;  click on comments below

4 comments:

Dr. Asif Ahmed,Pakistan said...

this drug is FDA approved but still not marketed. just completed phase three trial and under evaluation, thanks for this short but descriptive information

Waqar said...

I need to know about the time line in which this drug will be available in the market.

Anonymous said...

Sugammadex is not FDA approved

Anonymous said...

I want that this drug be soon approved by the FDA and be made availabe in India . When will we be getting to use in India.