Calabadions: New Broad Spectrum Agent to Reverse Neuromuscular Blockade.

Calabadions: New Broad Spectrum Agent to Reverse Neuromuscular Blockade.





The introduction of neuromuscular blockers (NMBs) revolutionized the practiceanesthesia. It allowed adjusting the degree

of muscle relaxation independently of hypnosisor analgesia favoring orotracheal intubation and mechanical ventilation; avoided the needto maintain too deep anesthetic planes that contributed to increasing the morbimortalityof the patients and facilitated the realization of certain surgical techniques.The use of D-tubocurarine increased the mortality rate six times due to residual relaxationof the respiratory muscles in the postoperative period, but mechanical ventilation and

reversal of the neuromuscular block with anticholinesterases significantly reduced thecomplication.The introduction of new NMBs has allowed the rational use of these drugs according tothe surgical needs and the indications of the patient. However, they continue to havelimitations to approach the ideal drug that acts quickly does not accumulate over time, is

independent of renal or hepatic function, easily reversible and free of side effects.Today we have two groups of muscle relaxants: depolarizers such as succinylcholine andnondepolarizing. Among the latter are esters (rocuronium, vecuronium, pancuronium ...)and benzylisoquinolones (atracurium, cisatracurium ...). An effect of these drugs is thepossibility of presenting a residual neuromuscular blockade that increases the risk ofbroncho aspiration and of weakness or even inability to speak, swallow or breathe.



Neuromuscular monitoring


Neuromuscular monitoring is of great utility in maintaining adequate neuromuscular blockor diagnosing residual paralysis,

although the drug administered is a non-depolarizingneuromuscular blocker of intermediate duration. Only monitoring by an objective methodcan eliminate or reduce this complication that occurs with a non-negligible incidence.A peripheral nerve stimulator, also known as a train-of- four monitors (TOF), is used toassess neuromuscular transmission when neuromuscular blocking agents (NMBAs) aregiven to block musculoskeletal activity.


Valuest; 0.9 suggest a possibility of low residual blockade and sufficient neuromuscularrecovery to deal with extubation and immediate postoperative period. However, there aresituations in which we can not expect to have adequate TOF values for decision making.We need pharmacological reversers.



Neuromuscular Relaxant Reverser


Inhibitor of the enzyme colinesterasaIn 1939, the FDA approved the use of neostigmine, one of the first drugs along withphysostigmine that allowed the reversal of neuromuscular blockade. It is an indirectan agonist that inhibits the enzyme acetylcholinesterase (Ach) by increasing the amount ofacetylcholine available in the neuromuscular junction, which generates a competitiveagonism between Ach and the relaxant.


Inhibition of Ach occurs not only in the neuromuscular junction but also in the rest ofmuscarinic receptors leading to effects such as miosis, hypersalivation, bronchospasm,nausea and vomiting, increased incidence of atelectasis or pulmonary edema amongothers. For the administration of neostigmine, a TOF greater than 2 is required, as lowervalues could lead to depolarizing muscle blockade.



Encapsulating or wrapping agents.


The first advance in these drugs was made by Merck with the appearance of Sugammadex(Bridion®), a cyclodextrin gamma that inactivates ester-type NMR by encapsulation in a 1:1 ratio; that is, each molecule of Sugammadex captures a molecule of rocuronium orvecuronium. The effect of uptake occurs by a diffusion gradient that is generated betweenthe Sugammadex present in the vessels and the relaxant in the neuromuscular plaque.It reduces recovery of NMRs by 975% faster than neostigmine (for TOF> 0.9) without thepresence of undesirable cholinergic effects. It use has spread more widely in Europe thanin the US because of FDA restrictions, given the hypersensitivity reactions and a possibledose dependent anticoagulant action (APTT and elongated PT although it has not beenshown to increase the risk of bleeding).


Nevertheless, and despite the great advance that has been the Sugammadex, there is noreverser for the NMR type benzylisoquinolones and hence the good expectations beforethe appearance of the cucurbitiles.Cucurbitiles are synthesized by an acidic condensation reaction between glycoluril andformaldehyde. There are cyclic and acyclic cucurbitiles, including calabashes, which aremore flexible and allow molecules to be wrapped more easily. They present astoichiometry between drug and reverser of 1: 1.


The first generation of the calabadions (Calabadion-1) facilitates the reversion of bothesters and benzylisoquinolones NMR, without hemodynamic affectation, nor of pH, nor ofgases according to studies in vivo in rats. The affinity for rocuronium appears to be slightlylower compared to Sugammadex.According to in vivo studies in rats, the second generation (Calabadion-2) with respect tothe half-dose Calabadion-1, is able to produce a reversal of the NMR (TOF > 0.9) 98%faster (87s vs 14s). For cisatracurium, Calabadion-2 is 5 times more related thancalabadion-1. The affinity of the Calabadion-2 for the rocuronium is high and 89 timesgreater than that of the Sugammadex due to the ion-dipole junctions that are generatedin the hydrophobic chamber.Calabadion-2 has a selectivity 18,900 times greater for rocuronium than for anacetylcholine molecule, reducing the risk of binding to other molecules.



Pharmacological interactions


The ability of 27 drugs to displace NMRs of the Calabadion-NMR complex has beenstudied. With the use of rocuronium or vecuronium, most of the molecules tested showno change in the Calabadion-NMR binding, except for ranitidine, which should be studiedin trials In vivo more thoroughly.During the use of cisatracurium, ranitidine has a slightly lower binding strength to theCalabadion than the NMR. This may be due to the fact that the affinity for thebenzylisoquinolones is slightly lower (about 700 times less than for rocuronium at thesame dose).


Regardless of the use of NMR, the calabadion shows an important affinity for the cocainemolecule. Their use could be studied in the case of cocaine toxicity. It is also effective for thereversal of ketamine and etomidate.The elimination of the Calabadion-2 is eminently renal. In vivo, it has been shown that atdoses of 40 to 80 mg within the first hour after administration, 49 ± 37% would have beeneliminated; While at doses of 5 to 10 mg, 62 ± 17% would be eliminated.Preliminary in vivo molecular affinity data suggest that succinylcholine could be safely andeffectively used after reversing NMB with Calabadion-2. Similarly, Sugammadex also doesnot affect the onset of action of Succinylcholine.




Dr. Oscar Uribe

OCC Health Care



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