Calabadions: New Broad Spectrum Agent to Reverse Neuromuscular Blockade.
Anesthesia The introduction of neuromuscular blockers (NMBs) revolutionized the practice anesthesia. It allowed adjusting the degree of muscle relaxation independently of hypnosis or analgesia favoring orotracheal intubation and mechanical ventilation; avoided the need to maintain too deep anesthetic planes that contributed to increasing the morbimortality of the patients and facilitated the realization of certain surgical techniques.The use of D-tubocurarine increased the mortality rate six times due to residual relaxation of the respiratory muscles in the postoperative period, but mechanical ventilation andreversal of the neuromuscular block with anticholinesterases significantly reduced the complication.The introduction of new NMBs has allowed the rational use of these drugs according to the surgical needs and the indications of the patient. However, they continue to have limitations to approach the ideal drug that acts quickly does not accumulate over time, isindependent of renal or hepatic function, easily reversible and free of side effects.Today we have two groups of muscle relaxants: depolarizers such as succinylcholine and nondepolarizing. Among the latter are esters (rocuronium, vecuronium, pancuronium …) and benzylisoquinolones (atracurium, cisatracurium …). An effect of these drugs is the possibility of presenting a residual neuromuscular blockade that increases the risk of broncho aspiration and of weakness or even inability to speak, swallow or breathe.
Neuromuscular monitoring Neuromuscular monitoring is of great utility in maintaining adequate neuromuscular block or diagnosing residual paralysis, although the drug administered is a non-depolarizing neuromuscular blocker of intermediate duration. Only monitoring by an objective method can 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 to assess neuromuscular transmission when neuromuscular blocking agents (NMBAs) are given to block musculoskeletal activity.
Valuest; 0.9 suggest a possibility of low residual blockade and sufficient neuromuscular recovery to deal with extubation and immediate postoperative period. However, there are situations 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 colinesterasa In 1939, the FDA approved the use of neostigmine, one of the first drugs along with physostigmine that allowed the reversal of neuromuscular blockade. It is an indirect an agonist that inhibits the enzyme acetylcholinesterase (Ach) by increasing the amount of acetylcholine available in the neuromuscular junction, which generates a competitive agonism between Ach and the relaxant.
Inhibition of Ach occurs not only in the neuromuscular junction but also in the rest of muscarinic receptors leading to effects such as miosis, hypersalivation, bronchospasm, nausea and vomiting, increased incidence of atelectasis or pulmonary edema among others. For the administration of neostigmine, a TOF greater than 2 is required, as lower values 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 or vecuronium. The effect of uptake occurs by a diffusion gradient that is generated between the 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 the presence of undesirable cholinergic effects. It use has spread more widely in Europe than in the US because of FDA restrictions, given the hypersensitivity reactions and a possible dose dependent anticoagulant action (APTT and elongated PT although it has not been shown to increase the risk of bleeding).
Nevertheless, and despite the great advance that has been the Sugammadex, there is no reverser for the NMR type benzylisoquinolones and hence the good expectations before the appearance of the cucurbitiles. Cucurbitiles are synthesized by an acidic condensation reaction between glycoluril and formaldehyde. There are cyclic and acyclic cucurbitiles, including calabashes, which are more flexible and allow molecules to be wrapped more easily. They present a stoichiometry between drug and reverser of 1: 1.
The first generation of the calabadions (Calabadion-1) facilitates the reversion of both esters and benzylisoquinolones NMR, without hemodynamic affectation, nor of pH, nor of gases according to studies in vivo in rats. The affinity for rocuronium appears to be slightly lower compared to Sugammadex. According to in vivo studies in rats, the second generation (Calabadion-2) with respect to the 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 than calabadion-1. The affinity of the Calabadion-2 for the rocuronium is high and 89 times greater than that of the Sugammadex due to the ion-dipole junctions that are generated in 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.
The ability of 27 drugs to displace NMRs of the Calabadion-NMR complex has been studied. With the use of rocuronium or vecuronium, most of the molecules tested show no 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 the Calabadion than the NMR. This may be due to the fact that the affinity for the benzylisoquinolones is slightly lower (about 700 times less than for rocuronium at the same dose).
Regardless of the use of NMR, the calabadion shows an important affinity for the cocaine molecule. Their use could be studied in the case of cocaine toxicity. It is also effective for the reversal of ketamine and etomidate.The elimination of the Calabadion-2 is eminently renal. In vivo, it has been shown that at doses of 40 to 80 mg within the first hour after administration, 49 ± 37% would have been eliminated; 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 and effectively used after reversing NMB with Calabadion-2. Similarly, Sugammadex also does not affect the onset of action of Succinylcholine.
Dr. Oscar Uribe
OCC Health Care