The pharmacodynamics of mivacurium in the rabbit with carbon tetrachloride-induced liver disease

Abstract

Neuromuscular blocking effects according to the severity of liver dysfunction have not been evaluated. We assessed the neuromuscular effects of mivacurium in carbon tetrachloride (CCl4)-treated rabbits with toxic hepatitis in vivo. We compared the dose-response relationships and the neuromuscular blocking effects of mivacurium in 66 rabbits randomly treated with 0.3 mL kg(-1) of corn oil, 0.3 mL kg(-1) of CCl4 or 0.6 mL kg(-1) of CCl4 for 11 weeks, respectively. Train-of-four stimuli were applied every 10 s to the common peroneal nerve and the force of contraction of the tibialis anterior muscle was measured. Severe hepatitis was associated with a rightward shift of the mivacurium dose-response curves, but mild hepatitis had no effect. The calculated ED50 values for the control, mild and severe hepatitis were 17.1+/-2.6, 18.2+/-2.7 and 31.8+/-3.2 microg kg(-1), respectively. Rabbits with severe hepatitis had a significantly prolonged recovery time from neuromuscular blockade compared with other rabbits. Cholinesterase activity had a negative correlation with recovery indices of mivacurium even in severe hepatic injury. Severe hepatitis induced a prolongation of action duration of repeated doses, but maintained the constant intervals. The dose-response and the time course of neuromuscular blockade of mivacurium differ in mild hepatitis compared with severe hepatitis, but required no adjustments of different doses for repeated injection after the desired depth of neuromuscular block, and had a negative correlation with the activity of plasma cholinesterase in both hepatic injuries.