P. Duvaldestin

Pharmacokinetics and pharmacodynamics of vecuronium (ORG NC 45) in patients with cirrhosis.

To evaluate the effect of liver cirrhosis on the pharmacokinetics and the pharmacodynamics of vecuronium, 12 patients with cirrhosis, aged (mean ± SD) 52 ± 12 yr, and 14 control patients, 42 ± 15 yr, undergoing elective surgery under general anesthesia were studied. The simultaneous time courses of the plasma concentration of vecuronium and of the neuromuscular blockade were studied after the administration of a bolus dose of 0.2 mg · kg−1. Vecuronium plasma concentration declined biexponentially in both groups. Vecuronium plasma clearance was reduced significantly (P < 0.01) from 4.26 ± 1.38 ml · min−1 · kg−1 in the controls to 2.73 ± 1.19 ml · min−1 · kg−1 in the patients with cirrhosis. The elimination half-life was 58 ± 19 min in the controls and was prolonged significantly to 84 ± 23 min (P < 0.01) in the patients with cirrhosis. The total apparent volume of distribution was unchanged in patients with cirrhosis (0.253 ± 0.086 1 · kg−1 vs. 0.246 ± 0.092 1 · kg−1 in the controls). Cirrhosis caused a prolongation of the neuromuscular blockade induced by vecuronium: the duration of effect from injection to 50% recovery of the twitch height was prolonged by 100% (P < 0.01) from 62 ± 16 min in the controls to 130 ± 52 min in patients with cirrhosis. The recovery rate (TH 25–75) also was prolonged (P < 0.05) from 21 ± 7 min in the controls to 44 ± 18 min in patients with cirrhosis. Vecuronium plasma concentration measured during recovery from paralysis indicates that cirrhosis did not alter the sensitivity to the relaxant, the plasma concentration corresponding to 50% of recovery (Cp 50) being unchanged between the two groups: 247 ± 60 ng · ml−1 in the controls versus 281 ± 129 ng · ml−1 in the cirrhotic patients. Thus, vecuronium seems to exert a prolonged neuromuscular blockade in patients with cirrhosis, and this change is mediated through its delayed elimination.

Pharmacokinetics and pharmacodynamics of rocuronium in patients with cirrhosis.

BackgroundRocuronium, like other steroidal nondepolarizing muscle relaxants, may in part be eliminated by the liver. To determine the influence of liver disease on its neuromus-cular blocking effect, we studied the pharmacokinetics and pharmacodynamics of rocuronium in patients with cirrhosis. MethodsEighteen patients undergoing elective surgery, 10 with cirrhosis and 8 with normal liver function, were studied. Anesthesia was induced with Intravenous thiopental 5–7 mg. kg−1 and maintained with 60% nitrous oxide in oxygen and repeated doses of fentanyl 2 μg. kg−1. The force of thumb adduction in response to supramaximal ulnar nerve stimulation was monitored and recorded. An intravenous bolus of rocuronium 0.6 mg. kg−1 was administered and venous blood sampled at frequent intervals for 6 h. Plasma concentrations of rocuronium was measured by high-pressure liquid chromatography. Data were fitted to both a pharmacokinetic and a pharmacodynamic model by using a two-compartment open model and an effect compartment model. Data were analyzed by least-squares regression. ResultsThe onset of neuromuscular blockade was longer (P >< 0.01) in patients with cirrhosis (158 ± 56 s) than in normal patients (108 ± 33 s). Recovery of the thumb twitch to 75 and 90% of its control value was 77 ± 25 and 88 ± 29 min in cirrhotic patients versus 57 ± 11 and 64 ± 13 mln, respectively, in normal patients (P < 0.05). The central volume of distribution of rocuronium was 104 ± 21 in cirrhotic patients and 78 ± 24 ml. kg−1 in normal patients (P < 0.05). No significant difference in elimination kinetics was observed between the two groups. The elimination half-life was 87.5 ± 17.5 mln in normal patients and 96.0 ± 36.8 min in cirrhotic patients (difference not significant). This increased onset time was linearly correlated to the increased central volume of distribution of rocuronium in cirrhosis. ConclusionRocuronium onset time is longer in cirrhotic patients than in those with normal liver function; this can be explained by an increase in the volume in which rocuronium initially distributes. Although elimination kinetics are unchanged in patients with cirrhosis, rocuronium recovery time is prolonged in cirrhotic patients.

Sufentanil pharmacokinetics in patients with cirrhosis.

The effects of cirrhosis on the elimination kinetics and plasma protein binding of sufentanil were evaluated in 12 anesthetized patients with uncomplicated cirrhosis and these findings were compared with data from age-matdied control anesthetized patients with normal hepatic and renal function. Sufentanil 3 μg/kg was Xiuen intravenously as a bolus injection and venous plasnza concentrations were measured at intervals up to 10 hrs. The average (±SD) elimination half life was 3.5 ± 0.9 lirs in controls and did not differ in cirrhotics: 4.1 ± 0.6 hrs. The plasma clearance did not differ between the two groups: 11.3 ± 2.5 ml·min−1·kg−1 in controls and 10.8 ± 4.6 ml·min−1·kg−1 in cirrhotic patients. The sufentanil free fraction was also similar in controls (8.3 ± 1.590) and in cirrhotic patients (9.6 ± 1.8%). These data suggest that sufentanil in a single dose should hazle a similar duration of action in patients with uncomplicated cirrhosis and in normal patients.

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.