The New Non-Depolarizing Muscle Relaxant ORG NC 45 in Clincal Anaesthesia: Preliminary Results

The neuromuscular and cardiac vagus blocking actions of pancuronium, vecuronium (Org NC45) and their respective potential hydroxy metabolites have been studied in the chloralose-anaesthetized cat. Pancuronium was three times more potent as a neuromuscular blocker than its 3-hydroxy derivative, 20 times more potent than the 17-hydroxy derivative and 45 times more potent than the 3,17-dihydroxy derivative. The vagal:neuromuscular block ratios measured at 50% inhibition for these compounds were pancuronium 3.0, 3-hydroxy derivative 6.4, 17-hydroxy derivative 1.1 and 3,17-dihydroxy derivative 0.36 (a value greater than unity indicated greater potency at the neuromuscular junction). Vecuronium was 1.4 times more potent than its 3-hydroxy derivative, 24 times more potent than the 17-hydroxy derivative and 72 times more potent than the 3,17-dihydroxy derivative as a neuromuscular blocker. The vagal:neuromuscular block ratios were vecuronium 79.8, 3-hydroxy derivative 40.4, 17-hydroxy derivative 0.85 and 3,17-dihydroxy derivative 0.15. The 3-hydroxy derivative of vecuronium, the most likely first metabolite of vecuronium, thus possessed only slightly less neuromuscular blocking potency than vecuronium, coupled with a high safety margin between neuromuscular and vagal blocking doses. In addition, the time-course of its action was not different from that of vecuronium. Thus, it is concluded that this potential metabolite is unlikely to give rise to tachycardia in man. It is unlikely that the 17-hydroxy and 3,17-dihydroxy derivatives of vecuronium would be produced in sufficiently great quantities by metabolism from vecuronium to result in either tachycardia or residual neuromuscular blockade.

Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 96%

Neuromuscular and Vagal Blocking Actions of Pancuronium Bromide, Its Metabolites, and Vecuronium Bromide (Org Nc 45)and Its Potential Metabolites in the Anaesthetized Cat

Marshall

Gibb

Durant

1983

“…Carrier-mediated transport processes are possibly involved in the uptake and excretion of this group of drugs by the liver. The large concentrations of vecuronium appearing in the bile 20 min after the injection of vecuronium, together with the apparently large amounts expected to be found in the liver at about 30 min after injection, coincide with the rapid recovery from the neuromuscular blockade produced by an intubating dose (100 ng kg" 1 ) of vecuronium (Agoston et al, 1980;Buzello et al, 1980;Fahey et al, 1981;Fragen et al, 1982;Gramstad Lilleaasen and Minsaas, 1983;Rupp, Miller and Gencarelli, 1984). If vecuronium is taken up rapidly and to such a large extent by the liver as is suggested by this study, it is plausible that its short duration of action is chiefly attributable to its rapid hepatic uptake.…”

Section: Discussionmentioning

confidence: 93%

Hepatobiliary Disposition of Vecuronium Bromide in Man

Bencini

Scaf

Sohn

et al. 1986

The plasma and bile concentrations, the biliary excretion and the neuromuscular blocking effect of vecuronium bromide were studied during surgery in 13 patients who had received 150 micrograms kg-1 i.v. The amount of vecuronium in liver biopsies taken after i.v injection was measured in a separate group of six patients. Vecuronium appeared early in the bile, in concentrations that were 30-50 times greater than those in the plasma. On the basis of the measured amount of vecuronium excreted in the bile, together with the accepted average daily bile flow, it was estimated that more than 40% of vecuronium was excreted in the bile in 24 h. Liver biopsies indicated that the liver may contain more than 50% of the i.v. dose 30 min after injection. The large distribution of vecuronium into the liver may account for the initial rapid decline in vecuronium plasma concentration and its relatively short duration of action. In this study, neuromuscular blockade was prolonged, possibly as a result of interference, by surgical manipulation, with the rapid hepatic uptake of vecuronium.

“…However, any change in the patient's ability to redistribute or eliminate the drug should be reflected in a change in the duration of action and thus the derived rate of infusion. Cumulation, when giving repeated doses, does not occur, or occurs to a very small extent [6][7][8][9].…”

Section: Discussionmentioning

confidence: 99%

Prediction of Infusion Rates: Validation of a Computer Simulation Using Vecuronium

Harrison

1990

In Phase 1 of the study a loading dose of vecuronium was given to 24 patients, followed by a sequence of infusions and boluses. The relationship between the duration of a bolus dose and the infusion rate necessary to maintain the required degree of neuromuscular block was demonstrated. In Phase 2 the data acquired from Phase 1 were used in an attempt to produce a predetermined degree of neuromuscular block. The aim was a block of neuromuscular function so that the height of the first twitch of a train-of-four was 15% of control. In the 10 patients studied the average height was 14.7% (SD 4.95%). It was concluded that it is possible to predict accurately the infusion dose of vecuronium required to achieve a predetermined degree of neuromuscular block, according to the duration of action of one or two test doses.