THE PHARMACOKINETICS AND PHARMACODYNAMICS OF ROCURONIUM IN PATIENTS WITH HEPATIC CIRRHOSIS

Aims To determine the effects of hepatic cirrhosis on the pharmacodyna mics and pharmacokinetics of rocuronium bromide. Methods We studied 21 healthy patients and 17 patients with mild or moderate cirrhosis (Chi ld-Pugh Class A and B). Patients were premedicated with diazepam orall y; anaesthesia was induced with fentanyl and thiopentone, and maintain ed with isoflurane 0.6% (end-tidal) and nitrous oxide 66% in oxygen. T he compound action potential of the adductor pollicis muscle in respon se to supramaximal stimulation of the ulnar nerve was recorded using t he train-of-four (TOF) twitch technique. A bolus dose of rocuronium 0. 6 mg kg(-1) was then given. Venous blood samples were taken for up to 8 h, and plasma rocuronium concentrations determined by h.p.l.c. Resul ts The time to onset of neuromuscular block and maximal block achieved did not differ between the two groups. The mean (s.d.) recovery times were prolonged in the cirrhotic compared with the healthy group: 25% recovery T-1:T-0, 53.7 (18.1) vs 42.3 (14.2) min; 50% recovery T-1:T-0 , 73.9 (33.9) vs 52.6 (19.8) min; 75% recovery T-1:T-0, 84.2 (24.5) vs 66.8 (27.2) min (all P < 0.05); recovery of T-4:T-1 to 70%, 114.9 (31 .7) vs 76.1 (28.8) min (P < 0.01). A pharmacokinetic and pharmacodynam ic model was fitted to the data for each patient. Three compartments w ere used to model the pharmacokinetic data; an effect compartment was added to model the pharmacodynamic data. Plasma clearance was signific antly reduced in the cirrhotic group (2.66 (0.60) vs 3.70 (1.03) ml kg (-1) min; P < 0.005). The central (V-1) and steady state volumes of di stribution (V-ss) did not differ significantly between the groups. The slow redistribution (t(1/2 lambda 1)) and elimination (t(1/2,z)) half -lives were both significantly prolonged in cirrhosis (28.3 (12.1) vs 16.8 (4.6) min, P < 0.005; and 143 (80) vs 92 (40) min, P < 0.05 respe ctively). The exit rate constant for the effect compartment k(eo) was significantly increased in the cirrhotic group (0.25 (0.18) vs 0.16 (0 .06) min(-1); P < 0.05), but cirrhosis had no significant effect on th e parameters of the concentration-effect relationship C-P50(ss) and ga mma. Conclusions Hepatic elimination is an important pathway in the cl earance of rocuronium, and delayed disposition causes the effect to be prolonged.