L.H.D.J. Booij

Intradermal Histamine Release by 3 Muscle Relaxants

The induration and redness caused by intradermal injections of equipotent doses of atracurium, vecuronium and d‐tubocurarine were measured in six healthy, male volunteers. Atracurium and d‐tubocurarine were almost indistinguishable in their reactions. Vecuronium caused a significantly smaller response than both atracurium and d‐tubocurarine. We therefore suggest that of these three drugs, vecuronium may cause the least histamine release and is, perhaps, the drug of choice in patients with a history of asthma or allergy.

Relative Potency of Org NC45, Pancuronium, Alcuronium and Tubocurarine in Anaesthetized Man

The relative potency, time-course of action and cardiovascular effects of Org NC 45, a new non-depolarizing neuromuscular blocking agent, have been compared with those of pancuronium, alcuronium and tubocurarine in 64 anaesthetized patients. The relative potency (ED50) to Org NC 45 was 1.74, 3.69 and 8.57 respectively. In doses which caused useful surgical relaxation, duration of action of Org NC 45 was 34%, 39% and 26% that of pancuronium, alcuroniuym and tubocurarine. After administration of repeated doses no cumulation was seen for Org NC 45. The new drug was free from any effect on arterial pressure and heart rate.

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.

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.