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Dose-dependent effect of metoclopramide on cholinesterases and suxamethonium metabolism
Y J Kao1, J Tellez, D R Turner
1Department of Anesthesiology, Texas Tech University Health Sciences Center, School of Medicine, Lubbock 79430.
In obstetric patients undergoing postpartum tubal ligation, we found that metoclopramide produced dose-dependent prolongation of suxamethonium-induced neuromuscular block. Mean block times after suxamethonium 1 mg kg-1 were 8.0 min, 9.83 min and 12.45 min for control and metoclopramide 10 mg and metoclopramide 20 mg groups, respectively. A laboratory study was therefore conducted on the inhibition of human plasma cholinesterase (PCHE) and erythrocyte acetylcholinesterase (ACHE) activity by varying concentrations of metoclopramide using acetylthiocholine as substrate. PCHE showed a greater sensitivity to inhibition by metoclopramide; the concentration of metoclopramide producing 50% inhibition of activity (I50) was 3.16 x 10(-7) mol litre-1, which is within the therapeutic range. ACHE was less sensitive to inhibition by metoclopramide (I50 2.24 x 10(-5) mol litre-1). Analysis of enzyme kinetics at varying substrate concentrations revealed that metoclopramide produced a potent non-competitive, dose-dependent inhibition of both ACHE and PCHE. The inhibition constant, Ki, was 1.88 x 10(-7) mol litre-1 for PCHE and 9.5 x 10(-8) mol litre-1 for ACHE. As metoclopramide is a potent inhibitor of PCHE, interactions might be expected to occur between metoclopramide and drugs that require PCHE for biotransformation, such as suxamethonium and ester local anaesthetics.
In obstetric patients undergoing postpartum tubal ligation, we found that metoclopramide produced dose-dependent prolongation of suxamethonium-induced neuromuscular block. Mean block times after suxamethonium 1 mg kg-1 were 8.0 min, 9.83 min and 12.45 min for control and metoclopramide 10 mg and metoclopramide 20 mg groups, respectively. A laboratory study was therefore conducted on the inhibition of human plasma cholinesterase (PCHE) and erythrocyte acetylcholinesterase (ACHE) activity by varying concentrations of metoclopramide using acetylthiocholine as substrate. PCHE showed a greater sensitivity to inhibition by metoclopramide; the concentration of metoclopramide producing 50% inhibition of activity (I50) was 3.16 x 10(-7) mol litre-1, which is within the therapeutic range. ACHE was less sensitive to inhibition by metoclopramide (I50 2.24 x 10(-5) mol litre-1). Analysis of enzyme kinetics at varying substrate concentrations revealed that metoclopramide produced a potent non-competitive, dose-dependent inhibition of both ACHE and PCHE. The inhibition constant, Ki, was 1.88 x 10(-7) mol litre-1 for PCHE and 9.5 x 10(-8) mol litre-1 for ACHE. As metoclopramide is a potent inhibitor of PCHE, interactions might be expected to occur between metoclopramide and drugs that require PCHE for biotransformation, such as suxamethonium and ester local anaesthetics.