Allosteric inhibition of muscle-type nicotinic acetylcholine receptors by a neuromuscular blocking agent pancuronium.

Muscle relaxants are indispensable for surgical anesthesia. Early studies suggested that a classical non-depolarizing muscle relaxant pancuronium competitively binds to the ligand binding site to block nicotinic acetylcholine receptors (nAChR). Our group recently showed that nAChR which has two distinct subunit combinations are expressed in zebrafish muscles, αßδε and αßδ, for which potencies of pancuronium are different. Taking advantage of the distinct potencies, we generated chimeras between two types of nAChRs and found that the extracellular ACh binding site is not associated with the pancuronium sensitivity. Furthermore, application of either 2 µM or 100 µM ACh in native αßδε or αßδ subunits yielded similar IC50 of pancuronium. These data suggest that pancuronium allosterically inhibits the activity of zebrafish nAChRs.

Allosteric interaction of the neuromuscular blockers vecuronium and pancuronium with recombinant human muscarinic M2 receptors.

Neuromuscular blocking drugs produce muscle weakness by interaction with nicotinic-acetylcholine receptors. Cardiovascular side effects have been reported. In this study the neuromuscular blocking drug vecuronium and the controls gallamine and pancuronium slowed the rate of atropine induced [(3)H]N-methylscopolamine dissociation from Chinese hamster ovary cells expressing recombinant human muscarinic M2 receptors K(off) values min(-1); vecuronium (125 nM), atropine 0.45+/-0.07+blocker 0.04+/-0.02; gallamine (21 nM), atropine 0.42+/-0.05+blocker 0.15+/-0.04; pancuronium(21 nM), atropine 0.36+/-0.03+blocker 0.03+/-0.01). These data indicate that vecuronium, gallamine and pancuronium interact with an allosteric site on the muscarinic M2 receptor (located on the heart) and this may explain some of their cardiac side effects.

Vecuronium kinetics and dynamics in anesthetized infants and children.

Vecuronium kinetics and dynamics were determined in five infants (3 to 11 months old) and five children (1 to 5 years old) during anesthesia with 70% nitrous oxide and 0.9 MAC halothane. Vecuronium was infused intravenously at a rate of 2.5 micrograms/kg/min while twitch tension of the adductor pollicis muscle was recorded and venous blood samples were drawn for determination of vecuronium concentrations by mass spectrometry. The elimination t1/2 was determined by linear regression of the log postdistribution concentration-time data; these values and noncompartmental techniques were used to calculate total plasma clearance (Cl), volume of distribution at steady state (Vdss), and mean residence time. The steady-state plasma concentration resulting in 50% depression of twitch tension (Cpss50) was determined by an effect compartment and a sigmoid concentration vs. paralysis model. Vdss was larger in infants (357 +/- 70 ml/kg; mean +/- SD) than in children (204 +/- 116 ml/kg), and Cl was of the same order for infants and children (5.6 +/- 1.0 and 5.9 +/- 2.4 ml/kg/min). Mean residence time was longer in infants (66.3 +/- 22.9 minutes) than in children (34.3 +/- 8.0 minutes). Cpss50 was lower in infants (57 +/- 18 ng/ml) than in children (110 +/- 28 ng/ml). The quantity of vecuronium in the body at steady state at 50% depression of twitch tension (Vdss X Cpss50) was similar in infants and children (21.2 +/- 9.9 and 19.0 +/- 3.3 micrograms/kg). During comparable nitrous oxide-halothane anesthesia, age-related changes in Vdss, Cl, and Cpss50 were much like those found for d-tubocurarine.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical pharmacokinetics of the non-depolarising muscle relaxants.

Muscle relaxants are of great benefit to the anaesthetist as adjuncts to anaesthesia. These drugs are used to facilitate endotracheal intubation and to reduce muscle tone during surgery, and may also find application in assisting ventilator care in the intensive care situation. The pharmacological effect of the relaxants may be readily assessed by the anaesthetist by means of a variety of techniques to quantify muscular activity in response to electrical stimulation. A number of factors may modify the effects of the muscle relaxants including anaesthetic agents, hypothermia, patient age and disease status and a variety of drugs. The disposition kinetics of the muscle relaxants have been well characterised although information on protein binding and placental transfer is somewhat scanty. A common characteristic of their pharmacokinetics is multicompartmental behaviour. Clearance of the relaxants ranges from total elimination by the kidneys (gallamine) to substantial hepatic clearance (fazadinium), and thus their clearance may be adversely affected by renal or hepatic disease. Dosage regimens have been designed using knowledge of the disposition kinetics of the relaxants to provide for continuous adequate relaxation during prolonged surgical procedures. With the use of sophisticated pharmacokinetic and pharmacodynamic models good relationships have been demonstrated between plasma concentrations of the relaxants throughout the entire range of relaxant response.

A new method for studying the relationship between hepatic uptake of drugs and their pharmacodynamic effects in anaesthetized cats.

1 A new in vivo experimental method is described whereby the liver can be temporarily excluded from the general circulation by means of a portocaval shunt operation. The influence of this manoeuvre upon the effects of pancuronium and Org 6368 was investigated using the tibialis muscle preparation of anaesthetized cats. 2 The procedure also allowed intraportal injections of the drugs to be made so that the effect of first-passage uptake by the liver could be compared with hapatic exclusion in the same animal. 3 Hepatic exclusion greatly increased the duration of action of both drugs. Whereas intraportal injection did not significantly alter the effect of pancuronium on the tibialis muscle, the effect of Org 6368 was greatly diminished when given by this route. 4 The liver appears to tolerate short periods of hepatic exclusion and it is concluded that this technique may become a useful tool for studying the handling of drugs by this organ.

Inhibition of ionotropic neurotransmitter receptors by antagonists: strategy to estimate the association and the dissociation rate constant of antagonists with very strong affinity to the receptors.

Since binding of an agonist to an ionotropic neurotransmitter receptor causes not only channel opening, but also desensitization of the receptor, inhibition of the receptor by the antagonist sometimes becomes very complicated. The transient state kinetics of ligand association and dissociation, and desensitization of the receptor were considered on the basis of the minimal model proposed by Hess' group, and the following possibilities were proposed. 1) When an agonist is simultaneously applied to the receptor with an antagonist whose affinity to the receptor is extremely strong and different from that of the agonist, it is usually impossible to estimate the real inhibition constant exactly from the responses because desensitization of the receptor proceeds before the equilibrium of the ligand binding. Simultaneous addition of the antagonist with strong affinity to the receptor may apparently accelerate inactivation (desensitization) of the receptor. The association rate constant of the antagonist can be estimated by analyses of the rate of the inactivation in the presence and the absence of the antagonist. 2) A preincubated antagonist with a slow dissociation rate constant, i.e., a very effective inhibitor, may cause apparent noncompetitive inhibition of the receptor, since the receptor is desensitized by an agonist as soon as the antagonist dissociates from the receptor and the dissociation of the antagonist from the receptor becomes the rate-determining step. A nicotinic acetylcholine receptor (nAChR) was expressed in Xenopus oocytes by injecting mRNA prepared from Electrophorus electricus electroplax and used for the experiments on inhibition by an antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)

Vecuronium: a new nondepolarizing neuromuscular-blocking agent. Clinical pharmacology, pharmacokinetics, cardiovascular effects and use in special clinical situations.

Vecuronium provides additional flexibility to the clinician using neuromuscular-blocking drugs. Its shorter duration of action, lack of significant cardiovascular effects and lack of dependence on the kidney for elimination provide clinical advantages over, or alternatives to, currently available, nondepolarizing neuromuscular-blocking drugs.

Anesthesia related muscle paralysis in renal failure.

We present 3 patients with chronic renal failure who had postoperative paralysis due to the administration muscle relaxants. One of them received gallamine, a non-depolarizing blocking agent that is mainly excreted by the kidney (70--90%). Two of them received pancuronium bromide, also a non-depolarizing blocking agent which is partially excreted by the kidneys (37--44%). All of them received succinylcholine. Succinylcholine is hydrolyzed by the serum cholinesterase into succinylmonocholine and choline. These active metabolites are excreted by the kidney. These patients serve as examples of the importance of considering the route of excretion of drugs and their metabolites in clinical situations involving the renal failure patient. The pharmacology of drugs administered relative to surgical procedures is reviewed.

Paradoxical antagonism of neuromuscular block by vecuronium metabolites.

Vecuronium is hydrolyzed in the body to 3-deacetyl (ORG 7268), 17-deacetyl (ORG NC58), and 3, 17-bis-deacetyl (ORG 7402) derivatives. Interactions of vecuronium and these metabolites were studied in phrenic nerve-hemidiaphragm preparations of rats. As already reported, ORG 7268 had a potent neuromuscular blocking action, and ORG NC58 and ORG 7402 had a weak neuromuscular blocking action. As expected, ORG 7268 increased the degree of neuromuscular block by vecuronium. However, a low concentration (10 microM) of ORG NC58 and ORG 7402 reversed the block by vecuronium. At a high concentration (50 microM), ORG NC58 and ORG 7402 increased the degree of block by vecuronium. Although we do not have enough data to explain these paradoxical reversal of neuromuscular block at this moment, we postulate that these results reflect the interaction between "slow" and "fast" competitive antagonists. Regardless of the mechanism, it should be emphasized that the concentrations of ORG NC58 and ORG 7402 which are necessary to reverse the block are much lower than those which facilitate the block. It is conceivable that this paradoxical reversal of the block occurs in experimental and clinical situations. Therefore, in determining the neuromuscular blocking action of a compound, the "antagonistic" effect of its metabolites should also be considered.

Pharmacodynamics of vecuronium and pancuronium in cats with and without ligated renal pedicles.

The pharmacodynamic behaviour upon continuous infusion and bolus administration of pancuronium and vecuronium was studied in cats with and without ligated renal pedicles. In all circumstances vecuronium had a shorter time course of action than pancuronium. Ligation of the renal pedicles, i.e. acute renal failure, did not significantly influence the time course of the respective neuromuscular blockades. It is suggested that uptake by aspecific binding sites of the compounds is the main determining factor in termination of the blockade. A difference between acute and chronic renal failure is expected to exist.

[Role of vecuronium in comparison with curariform drugs used in man]. / Place du vécuronium par rapport aux curares utilisés en clinique humaine.

Vecuronium, a new non-depolarizing muscle relaxant, was more powerful than d-tubocurarine, gallamine and alcuronium. Its muscle blocking effect was similar to that of pancuronium. It had a smaller distribution volume and a quicker elimination half-life than the other non-depolarizing muscle blocking drugs. The time of onset and duration of action, as well as the time for recovery were also shorter, being 3-5 min, 17-22 min and 25 min respectively. The accumulation of vecuronium in the body was low; increasing the dose increases the duration of action, but not the recovery time. No adverse effect has been reported as yet. Compared with suxamethonium, a depolarizing muscle relaxant, it had a longer time of onset and duration of action. Vecuronium cannot therefore replace suxamethonium for endotracheal intubation.

[Determinations of steroidal muscle relaxants and their metabolites].

Pancuronium, vecuronium and pipecuronium are quaternary ammonium steroidal neuromuscular blocking agents. These drugs are typical nondepolarizing muscle relaxants. The steroidal compounds and/or their metabolites have been determined using mass spectrometry or gas chromatography. In this review, these analytical methods and application of the methods to pharmacokinetics are introduced.

[Pharmacokinetics and pharmacodynamics of vecuronium in children]. / Pharmacocinétique et pharmacodynamique du vécuronium chez l'enfant.

Pharmacodynamics of vecuronium have been studied in children 1 to 10 years old. Doses from 0.015 to 0.1 mg/kg were given and the effects measured mechanically and by electromyography. For 0.1 mg/kg the pharmacokinetics were established. A smaller distribution volume and higher plasma clearance in children as compared to adults have been found, while the dose-effect ratio is the same. The action of vecuronium is shorter in children than in adults.