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At least 19 recordsLinked to original sources
PubMed1979

The neuromuscular and autonomic blocking activities of pancuronium, Org NC 45, and other pancuronium analogues, in the cat.

Twenty-six mono- or bis-quaternary salts of 3,17-dioxy-2 beta, 16 beta-dipiperidino-5 alpha-androstanes (including pancuronium) and one 17-desoxy congener were tested for neuromuscular blocking and autonomic blocking activities in the chloralose-anaesthetized cat. The 17 beta-acetoxy series, all the members of which contain an acetylcholine-like fragment in the steroidal D-ring, was most selective for effecting neuromuscular blockade. The salient member of this series is 3 alpha, 17 beta-diacetoxy-2 beta, 16 beta-dipiperidino-5 alpha-androstane 16 beta-N-monomethobromide (Org NC 45) which is highly selective in blocking neuromuscular transmission in that a dose approximately sixty times greater than the neuromuscular blocking dose was required to block responses to vagal stimulation. In contrast, in doses sufficient to produce neuromuscular block, pancuronium simultaneously blocked responses to vagal stimulation. Moreover, pancuronium and Org NC 45 exhibited the same order of neuromuscular blocking activity and therefore the latter potentially represents a useful addition to the armamentarium of neuromuscular blocking agents currently in clinical use.

Androstanes↗
PubMed1978

The comparative potency and pharmacokinetics of pancuronium and its metabolites in anesthetized man.

To determine the potency of pancuronium and its metabolites, 3-OH-, 17-OH- and 3,17-OH-pancuronium, cumulative dose-response curves were determined in five anesthetized patients with each drug. Pancuronium (ED50 = 0.041 mg/kg) was 2 times more potent than 3-OH-pancuronium (ED50 = 0.082 mg/kg), 50 times more potent than 17-OH-pancuronium (ED50 = 2.0 mg/kg) and 54 times more potent than 3,17-OH--pancuronium (ED50 = 2.15 mg/kg). In 21 other patients, one equipotent dose of either pancuronium or one of its metabolites was given as an i.v. bolus. Onset time and duration of neuromuscular blockade from 3-OH- and 3,17-OH-pancuronium did not differ significantly from that of pancuronium; 17-OH-pancuronium had a shorter duration of action than did pancuronium. Although pancuronium tended to have a slightly longer elimination half-life, the pharmacokinetics of the four drugs did not differ significantly. The elimination half-lifes were 110, 68, 73 and 71 min for pancuronium and its 3-OH, 17-OH and 3,17-OH derivatives, respectively. We conclude that although pancuronium is more potent than its 3-OH, 17-OH and 3,17-OH metabolites, the pharmacokinetics of these three metabolites do not differ from each other and from that of pancuronium.

Dose-Response Relationship, Drug↗
PubMed1975

The effect of pancuronium on myocardial contraction and catecholamine metabolism.

The effects of pancuronium bromide infusion on the uptake and release of [14C] noradrenaline (14C-NA) by the isolated, perfused rat heart and on the chronotropic and inotropic activity of the isolated heart were evaluated. Hearts were removed from animals under light ether anaesthesia, transferred to a modified Langendorff perfusing apparatus and perfused with Krebs-Ringer bicarbonate solution at a rate of 5 ml min-1. The effect of pancuronium on the uptake of noradrenaline was determined by perfusing hearts for 5 min with perfusate containing various concentrations of pancuronium and 200 ng ml-1 of 14C-NA. After 5 min pancuronium-treated hearts contained less 14C-NA. The degree of reduced uptake increased with increasing concentrations of pancuronium. In addition, the combination of pancuronium perfusion and electrical stimulation (15 mA for 10 ms at 4 Hz) blocked the 50 min uptake of 14C-NA by the heart to a greater degree than either factor separately. The release of noradrenaline was determined after perfusing hearts with 14C-NA followed by perfusion with solution containing pancuronium but no 14C-NA for 1 h. Pancuronium infusion did not significantly alter the release of 14C-NA from the heart after 1 h of perfusion. The infusion of pancuronium caused a reduction in both the rate and strength of myocardial contraction of the isolated heart which was reversed by perfusion with perfusate free of pancuronium. Following perfusion with pancurnium the rate and strength of contraction of the heart was seen to "rebound" above pre-pancuronium values for a short period. The rebound of myocardial rate and contraction may have been due to the presence of myocardial noradrenaline previously blocked from reuptake by pancuronium since hearts removed from reserpinized animals did not demonstrate "rebound."

Animals↗
PubMed1978

Sympathomimetic effects of pancuronium bromide on the cardiovascular system of the pithed rat: a comparison with the effects of drugs blocking the neuronal uptake of noradrenaline.

1. The effects of pancuronium bromide on the cardiovascular system of the pithed rat were examined. Pancuronium had two effects, a short-lasting cardiovascular stimulation following injection and a longer-lasting potentiation of responses to sympathetic nerve stimulation. 2 The initial effect of pancuronium was compared with that of tyramine. The cardioaccelerator but not the pressor responses to both pancuronium and tyramine were significantly reduced following sympathectomy with 6-hydroxydopamine (6-OHDA). 3 The action of pancuronium in potentiating sympathetic nerve responses was compared with that of known blockers of the neuronal uptake of noradrenaline (NA). Pancuronium (1 mg/kg) and cocaine (0.5 mg/kg) potentiated cardioaccelerator and pressor responses to sympathetic stimulation. These effects of pancuronium could be obtained following adrenalectomy and during neuromuscular blockade with gallamine. Pancuronium and uptake blockers potentiated the cardioaccelerator response to NA, reduced the response to tyramine, but did not affect the response to isoprenaline. Pancuronium and uptake blockers potentiated the pressor response to NA, but did not affect the response to tyramine or clonidine. 4 Following sympathectomy with 6-OHDA, pancuronium failed to potentiate cardioaccelerator and pressor responses to NA. 5 These results are discussed in relation to two main cardiovascular effects of pancuronium; an indirect sympathomimetic action and blockade of the neuronal uptake of NA.

Adrenalectomy↗
PubMed1977

Kinetic analysis of pancuronium interaction with sodium channels in squid axon membranes.

The interaction of pancuronium with sodium channels was investigated in squid axons. Sodium current turns on normally but turns off more quickly than the control with pancuronium 0.1-1mM present internally; The sodium tail current associated with repolarization exhibits an initial hook and then decays more slowly than the control. Pancuronium induces inactivation after the sodium inactivation has been removed by internal perfusion of pronase. Such pancuronium-induced sodium inactivation follows a single exponential time course, suggesting first order kinetics which represents the interaction of the pancuronium molecule with the open sodium channel. The rate constant of association k with the binding site is independent of the membrane potential ranging from 0 to 80 mV, but increases with increasing internal concentration of pancuronium. However, the rate constant of dissociation l is independent of internal concentration of pancuronium but decreases with increasing the membrane potential. The voltage dependence of l is not affected by changine external sodium concentration, suggesting a current-independent conductance block, The steady-state block depends on the membrane potential, being more pronounced with increasing depolarization, and is accounted for in terms of the voltage dependence of l. A kinetic model, based on the experimental observations and the assumption on binding kinetics of pancuronium with the open sodium channel, successfully simulates many features of sodium current in the presence of pancuronium.

Action Potentials↗
PubMed1975

[The metabolism of pancuronium in man].

The metabolic disposition of pancuronium was investigated in man under clinical condition. Pancuronium and its desacetylated derivatives were determined in body fluids using the previously described bromophenol blue method (3). The metabolites were isolated by thin layer chromatography. One minute after the intravenous injection of a mg of pancuronium the drug reaches a serum concentration of 2,2 plus or minus 0,2mug/ml. As an exponential function the concentration curve then falls to half of the initial value during the first 30 to 60 min. The end of the neuromuscular block conincides with a concentration of 0,1 to 0,3 mug/ml serum which is reached about 2 hours after the injection. After 3 to 4 hours no more pancuronium can be detected in the serum. The renal elimination of pancuronium can be folowed up for 12 hours. On average half of the injected dose is recovered in the urine. 80% of this proportion is unchanged pancuronium and 20% desacetylated metabolites. The monodesacetylated derivatives of pancuronium are still pharmacologically active. The biliary excretion 24 hours after the administration of pancuronium accounts for 5 to 10% of the injected dose...

Bile↗
PubMed1977

Bradycardia during antagonism of pancuronium-induced neuromuscular block.

Heart rate was compared in matched patients during antagonism of neuromuscular block induced by tubocurarine, pancuronium or alcuronium with neostigmine 0.03 mg kg-1 preceded by atropine 0.015 mg kg-1. The frequency of bradycardia was greater during antagonism of pancuronium compared with alcuronium. Although there was a difference between the group receiving pancuronium and that receiving tubocurarine, it was not statistically significant. The decrease in heart rate was more rapid and profound in the pancuronium group; seven of the 15 patients who received pancuronium required an additional dose of atropine as compared with only one patient who received tubocurarine. However, the difference in heart rate between those who received pancuronium and those receiving tubocurarine was short-lasting, whereas the heart rate of those who received alcuronium was higher than that in the other groups during the entire 60-min period of observation. The findings with pancuronium may be a result of its inhibitory effect on serum cholinesterase.

Adult↗
PubMed1978

Pancuronium pharmacokinetics in patients with liver cirrhosis.

The serum and urinary concentrations of pancuronium were measured in 14 surgical patients with cirrhosis and 12 patients free from liver disease undergoing abdominal surgery. A two-compartment open model was used in the pharmacokinetic analysis of the data. A two-fold increase in both the distribution half-life (T 1/2 alpha) from 11 min to 24 min and in the elimination half-life (T 1/2 beta) from 114 min to 208 min was observed in patients with cirrhosis. In these individuals, the total apparent volume of distribution of pancuronium was increased by 50%. Plasma clearance of pancuronium was decreased by 22%. No significant difference was found in the urinary excretion and biotransformation pattern of pancuronium. These results suggest that there is a risk of prolonged duration of action of pancuronium in patients with cirrhosis. In these patients, the initial dose to achieve adequate muscle relaxation is high and simultaneously there is slow disappearance of pancuronium from plasma. These alterations are mainly a consequence of the increase in the distribution volume of pancuronium in patients with cirrhosis.

Abdomen↗
PubMed1979

Pre- and postsynaptic effects of pancuronium at the neuromuscular junction of the mouse.

The dose-effectiveness of pancuronium as it relates to membrane potentials, action potentials, electrical membrane constants, miniature endplate potentials, endplate potentials, and quantal release was studied in murine phrenic nerve-diaphragm preparations in vitro. Emphasis was placed on comparison of presynaptic with postsynaptic effects of pancuronium under similar experimental conditions. At low concentrations of pancuronium (5 X 10(-8) g/ml or less), no presynaptic effect was found. At high concentration (5 X 10(-7) g/ml), pancuronium depressed quantal release to 26 per cent of control in cut-fiber preparations and 40 per cent of control in high-magnesium preparations. Postsynaptic effects as measured by the amplitude of miniature endplate potentials and relative depolarization induced by 20 microns carbachol, revealed depression to 16 and 22 per cent of control, respectively, at a pancuronium concentration of 5 X 10(-7) g/ml. Pancuronium had no effect on directly elicited action potentials and electrical membrane constants. The authors conclude that presynaptic as well as postsynaptic effects of pancuronium in paralytic doses are essential in contributing to the total efficacy of neuromuscular depression.

Action Potentials↗
PubMed1979

On the mechanism of pancuronium-induced supersensitivity to noradrenaline in rat smooth muscle.

1. Pancuronium bromide (5 x 10(-5) M) caused supersensitivity to noradrenaline in the rat isolated vas deferens and hepatic portal vein. This supersensitivity was manifest as a parallel leftward shift of the dose-response curve for noradrenaline with no alteration of the maximum response to the agonist. 2. Pancuronium did not potentiate the response of the vas and portal vein to St 91, an alpha-adrenoceptor agonist which is not a substrate for Uptake1. 3. Pancuronium did not potentiate the response of the vas to CaCl2. 4. In vasa deferentia made supersensitive to noradrenaline by treatment with cocaine (1 x 10(-5) M) pancuronium induced no further potentiation of the response to noradrenaline. However, the supersensitivity to noradrenaline induced by pancuronium alone was augmented by the addition of cocaine. 5. Histofluorescence studies showed that pancuronium inhibited neuronal uptake of alpha-methyl noradrenaline in various noradrenergically-innervated tissues from reserpine-treated rats. 6. This study, with support from the literature, suggests that pancuronium induces noradrenaline supersensitivity by blockade of Uptake1.

Animals↗
PubMed1992

Effects of pancuronium bromide on cerebral blood flow changes during seizures in newborn pigs.

We investigated the effects of pancuronium bromide pretreatment on cerebral blood flow (CBF) during bicuculline-induced seizures in anesthetized piglets. Arterial blood pressure, gases, pH, cerebral electrocortical activity, and CBF (radioactive microsphere) were monitored at baseline, 10 min after administration of pancuronium (0.3 mg/kg i.v.; n = 9) or vehicle (normal saline; n = 8), and again at 5, 15, and 60 min after bicuculline (3 mg/kg i.v.). No change in CBF from baseline was observed at 10 min after either saline or pancuronium treatment, before induction of seizures. In the saline group, CBF was 36 +/- 3 mL.min-1.100 g-1 before bicuculline and increased to 166 +/- 24 and 205 +/- 35 mL.min-1.100 g-1 at 5 and 15 min, respectively, after bicuculline, returning toward baseline by 60 min. In the pancuronium group at 5 min after bicuculline, CBF increased from 45 +/- 7 to 169 +/- 26 mL.min-1.100 g-1, but fell to 88 +/- 17 mL.min-1.100 g-1 at 15 min in contrast to saline-treated piglets. Also, at 15 min of seizures, differences between groups were observed in arterial blood pressure, gases, and pH. Although these variables were in the normal range with pancuronium treatment, the saline-treated animals had increased arterial blood pressure (81 +/- 6 mm Hg) and PCO2 (6 +/- 0.4 kPa) and decreased PO2 (7 +/- 0.5 kPa) and pH (6.91 +/- 0.06). Electrocortical activity was abnormal during seizures in both groups. At 60 min, reversal to normal activity was observed in six of nine pancuronium-treated animals versus two of eight saline-treated animals. These data suggest that pancuronium limits cerebral hyperemia during prolonged seizures by attenuating increases in blood pressure as a result of elimination of skeletal muscle activity. This leads to minimal alteration of arterial PCO2, PO2, and pH during seizures.

Animals↗
PubMed1991

[Nitroglycerin reduces requirement of pancuronium in surgical patients].

We performed a study on 34 adult surgical patients between 15 and 56 years of age, to evaluate whether synergism between nitroglycerin and pancuronium exists or not. Neuromuscular (NM) transmission was measured by electromyography of the thenar muscle using transcutaneous electrodes. Anesthesia was induced by droperidol 0.2 mg.kg-1, fentanyl 50 micrograms, thiamylal 150-250 mg, and succinylcholine 1 mg.kg-1, and maintained with nitrous oxide and O2 (67:33) supplemented with repeated i.v. doses of fentanyl (within 15 micrograms.kg-1). Pancuronium 4 mg was given at the 20% recovery from succinylcholine induced NM block. Sequential i.v. doses of pancuronium 1 mg were injected repeatedly at the every 20% recovery until the end of operation. To control blood pressure, nitroglycerin, ranging from 0 to 5 micrograms.kg-1.min-1, was given intravenously. The linear multiple regression analysis was performed between the dose of pancuronium (micrograms.kg-1.hr-1) and the dose of nitroglycerin (micrograms.kg-1.min-1), the age, sex, or body weight of the patients. The results show that the dose of pancuronium decreases with increasing dose of nitroglycerin. No relationship was found between the dose of pancuronium and the age, sex, or body weight of the patients. In conclusion, nitroglycerin reduces requirement of pancuronium in surgical patients.

Adolescent↗
PubMed1978

Hypothermia and the pharmacokinetics and pharmacodynamics of pancuronium in the cat.

We tested the effect of hypothermia on the pharmacokinetics and pharmacodynamics of pancuronium in the cat. In 14 cats given pancuronium, 120 microgram/kg i.v., we found that neuromuscular block lasted between 2.5 and 3.0 times longer at 29 degrees C (N = 5) than at 34 degrees C (N = 5) or 39 degrees C (N = 4). The apparent plasma elimination half-life was 46 +/- 7 min (S.E.) at 29 degrees C as compared to 21 +/- 2 and 25 +/- 6 min at 34 and 39 degrees C, respectively. The volume of distribution of the central compartment and total volume of distribution at steady state were less at 29 and 34 dgrees C than at 39 degrees C. Total plasma clearance was 4.3 +/- 0.4 ml/kg/min at 29 degrees C and 10.7 +/- 0.9 and 10.9 +/- 1.5 ml/kg/min at 34 and 39 degrees C, respectively. The reduced plasma clearance resulted at least in part from a markedly reduced biliary and urinary excretion of pancuronium at 29 degrees C as compared to 34 and 39 degrees C. In four other cats, the plasma concentration of pancuronium was correlated with depression of twitch tension under steady-state conditions. The ED50 of pancuronium (plasma concentration required for a 50% depression of twitch tension) was 0.035 and 0.073 microgram/ml at 29 and 38 degrees C, respectively. We conclude that a pancuronium neuromuscular block is prolonged at 29 degrees C because of an increased sensitivity of the neuromuscular junction to pancuronium and delayed biliary and urinary excretion.

Animals↗
PubMed1975

The inhibition of cholinesterases by pancuronium.

Pancuronium causes a powerful and highly selective inhibition of human serum cholinesterase in vitro. The inhibition was studied in serum from 14 individuals of both sexes (5-60 years of age) with normal reactions to suxamethonium. Pancuronium, in a concentration of 2.3 x 10(-7) M, caused a 50% inhibition of the enzymatic hydrolysis of acetylcholine, when this substrate was present in a concentration of 10 x 10(-3) M. The same I50 value was also found for a commercial preparation of human serum cholinesterase. The inhibition was reversible and competitive in type. Pancuronium inhibition of the acetylcholinesterase in human red blood cells and from the electric eel was more than one thousand times weaker. Thus pancuronium is one of the most selective inhibitors of serum cholinesterase described so far. The in vivo activity of the serum cholinesterase in four patients receiving pancuronium 0.1 mg/kg decreased, during the first 3 min, by 60-80%, from the pre-induction value. After this a slow recovery occurred with 40% depression remaining at 45 min after the injection. The tachycardia produced by pancuronium may be related to this selective inhibition of serum cholinesterase. It is suggested that relaxants which selectively inhibit serum cholinesterase also selectively block the cardiac muscarinic receptors.

Acetylcholine↗
PubMed1979

Prolongation of pancuronium-induced neuromuscular blockade by intravenous infusion of nitroglycerin.

Based upon clinical observation of undue prolongation of pancuronium-induced blockade in the presence of intravenous infusion of nitroglycerin, neuromuscular blockades produced by pancuronium, succinylcholine and d-tubocurarine were studied in 51 cats using the sciatic-gastrocnemius nerve-muscle preparation. Pancuronium-induced blockade was found to be significantly prolonged (P less than 0.1) in the presence of a nitroglycerin infusion of 1 microgram/kg/min (65 vs. 127 min). Less, but still significant, prolongation occurred when nitroglycerin, 0.5 microgram/kg/min, was infused. The intravenous infusion of nitroglycerin must be started prior to the pancuronium injection for the block to be prolonged. Neuromuscular blocks produced by succinylcholine and d-tubocurarine were not altered by nitroglycerin. In experiments using the isolated rat diaphragm preparation, the depth of pancuronium-induced block was found not to be changed by nitroglycerin, suggesting an effect of nitroglycerin on the process of recovery from blockade. These findings indicate a selective pancuronium-nitroglycerin interaction.

Animals↗
PubMed1979

Dose-response and plasma concentration-response relationships of pancuronium in man.

The dose-response and plasma concentration-response relationships for pancuronium in man were studied during its intravenous administration to eight patients at a rate of 1.62 microgram/kg/min. The (log) dose-response relationships resulted in a sigmoid curve that was linear in its central range. At 20, 50 and 80 per cent paralysis the cumulative dosages (mean +/- SEM) were 0.04 (+/- 0.01), 0.06 (+/- 0.01), and 0.08 (+/- 0.02) mg/kg, respectively. Administration of pancuronium, 56 microgram/kg, to another 12 patients at a more rapid rate resulted in a maximum intensity of blockade of more than 50 per cent. The (log) plasma concentration-response curve was not parallel to the dose-response curve, with mean (+/- SEM) concentrations at 20, 50 and 80 per cent paralysis of 0.21 (+/- 0.04), 0.25 (+/- 0.04), and 0.30 (+/- 0.04) microgram/ml, respectively during the onset of paralysis. Following cessation of the infusion, plasma concentrations of pancuronium were usually lower for the same intensity of paralysis. Using data for the entire response range during recovery from paralysis, the mean effective plasma concentration of pancuronium for a 50 per cent response was 0.20 microgram/ml. Recovery from blockade to 95 per cent paralysis (5 per cent of control twitch height) was associated with a plasma concentration of 0.25 microgram/ml, a value in agreement with plasma concentrations obtained following a single bolus administration of pancuronium, 6 mg, to 30 patients. For 27 patients the rate of decline of paralysis from 80 to 20 per cent showed a highly statistically significant relationship to the apparent rate of decline in the plasma concentrations of pancuronium.

Adult↗