Novel Methods To Terminate Neuromuscular Blockade.
University Hospital Antwerp.
Residual post-anesthetic neuromuscular block is still a major and underestimated issue. A TOF value of 0.9 is now considered to be the minimum value to discharge the patients safely from the recovery room. Debaene (1) reported the incidence of residual paralysis after a single intubating dose of intermediate acting nondepolarizing relaxants. 526 patients received an intubating dose of vecuronium, rocuronium or atracurium. He found more than 30% of the patients not reaching the safety limit of TOF 0.9, even after 120 minutes.
How can we increase patient safety in the view of an almost general underuse of neuromuscular transmission monitoring? Theoretically, one can do four things to shorten the clinical effect of neuromuscular blockers:
1. Increase the amount of acetylcholine in the neuromuscular junction.
2. Slow down the metabolisation of acetylcholine.
3. Look for ultra-short acting neuromuscular blockers.
4. Remove the neuromuscular blocking agent from the neuromuscular junction.
1. The amount of acetylcholine in the neuromuscular junction can be increased by potassium channel blockers eg. 4-aminopyridine or tetraethyl-ammonium. These compounds prolong nerve action potential which causes an increase of neurotransmitter in all tissues. These agents are not suitable for clinical use since they cross the blood brain barrier and cause CNS excitation .
2. We all routinely use acetylcholinesterase inhibitors to slow down the metabolisation of acetylcholine. This causes an increase of ACh in all cholinergic synapses, including muscarinic and nicotinic receptors. The combination with muscarinic receptor antagonists, atropine or glycopyrrolate, reduces the mainly cardiac side-effects, but can on the other hand cause tachycardia. It is important to know that acetylcholinesterase inhibitors can not antagonise a deep neuromuscular block.
3. The search for ultra-short acting neuromuscular blocking agents is going on since more than 15 years. New ultra-short acting neuromuscular blocking agents that were under investigation in the last five years are: GW280430, G-1-64, TAAC3, SZ1677.
GW280430A is an ultrashort-acting NMBA intended to facilitate endotracheal intubation. It has a structural similarity to mivacurium and is degraded rapidly in vitro, most likely by ester hydrolysis. In a volunteer study doses ranging from 0.18 mg/kg to 4.0 mg/kg were given. At reappearence T1, edrophonium was given and a recovery index was measured (MMG). T1 25% to TOF 90% was 3.0 minutes. This index did not change between doses. These data are only reported in an abstract in Anesthesiology in 1999 (2).
G-1-64 is a bis-quaternary tropine diester (3). Next to the benzylisoquinolines and the aminosteroid series, it may be the prototype of a new series of NMBA.The interonium distance of 14.74 Angstrom and the large substitution on the Nitrogen atoms gives this compound its nondepolarising NMB properties. It has been investigated in different animal species. It shows a rapid onset (0.9 to 2.1 minutes) and a short duration of action ( 5 to 12 minutes). Cardiovascular side-effects, ganglion block or histamine release were absent. Termination of the effect is probably by organ independent hydrolysis. No information is available on possible metabolisation. No further data on early phase human investigation are available until now.
TAAC3 is another compound of the tropinyl-diester derivatives (4). The neuromuscular blocking properties and the autonomic side effects have been studied in comparison with rocuronium. TAAC3 has a faster onset (0.8-1.0 min), a shorter recovery index (0.6-1.1 min) and a shorter duration of action (1.8-3.5 min). A similar degree of cardiac vagal block as with rocuronium was documented in the cat and in pigs without other autonomic side effects. As for G-1-64 only animal data are available at the moment.
Finally, SZ1677 is another new non depolarizing NMBA that has been studied in animals and in human tissue experiments (5). A relatively short duration of action (8 min from administration to maximal recovery), no accumulation and no side effects have been reported.
All these compounds are in preclinical investigation, except for GW280430A on which a study in volunteers has been reported in 1999 in abstract form. There are reasons to conclude that the clinical availability of one of these compounds, if ever, will take years from now.
4. Remove the neuromuscular blocking agent from the neuromuscular junction.
An interesting alternative is the development of Org 25969 (6), a γ-cyclodextrin that is designed to remove rocuronium from the neuromuscular junction.
Cyclodextrins are a family of cyclic oligosacharides with three major groups α, β and γ cyclodextrins. This is based on the number of glucose units that constitute the molecule: 6, 7 or 8. The diameter of the “donut” shaped molecule depends on the number of glucose units. Cyclodextrins are used in pharmacology and in medicine in a number of situations:
- to enhance the physical and chemical stability of drugs
- to enhance the solubility of drugs (typically steroidal compounds)
- to avoid the side effects of organic solvents used to make a solution of otherwise poorly soluble compounds (e.g. propofol, ethomidate)
- to accelerate the desintegration of tablets.
The idea to use cyclodextrins as a NMB “remover” started as follows: During in vitro experiments, rocuronium was to be solububilised at high concentrations. Cyclodextrins are used to solubilise steroidal compounds. Commercial cyclodextrins reverse neuromuscular block at very high concentrations. This started the idea of a rocuronium-specific cyclodextrin that can accept a rocuronium molecule and that can hold this molecule. The complex should be water soluble.
The diameter for the cyclodextrins are as follows: α: 5.7, β: 7.8 and γ: 9.5 Angstrom. A γ cyclodextrin has to be used since the dimensions of rocuronium are 7.5 – 8.3 Angstrom.
Org 25969 has been tailored to rocuronium. (7) This was done by:
- using the γ-cyclodextrin molecule with a diameter of 9.5 Angstrom.
- inreasing the depth of the cavity to fully encapsulate the hydrophobic steroidal ring in the lipophylic cavity.
- attaching anionic functional groups at the rim of the cavity. These interact electrostatically with the + charged ammonium groups of rocuronium. At the same time, these groups maintain the high water solubility of the complex.
Results of laboratory-, preclinical- and early clinical (phase 2A) investigations will be presented.
Conclusion: Existing reversal agents (neostigmine) act to increase the acetylcholine level in the neuromuscular junction. They are used in combination with atropine or glycopyrrolate. This results in important cardiovascular side-effects. Further, these agents can not reverse a “deep” neuromuscular block. Org 25969 has the possibility to reverse a profound neuromuscular block. Until now, it seems to be a safe reversal agent with minimal side effects.
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