Ropivacaine and its active metabolite

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Ropivacaine is homologous to Bupivacaine . If local anaesthetics are administered into the vein or artery it results to very high systemic levels possibly causing CNS and CV toxicity due to rapid penetration into these regions. Both bupivacaine and ropivacaine are amide linked esters. They are extensively bound in the plasma. Amides extensively bind to the alpha-1 acid glycoprotein (AAG) with ~94% ropivacaine bound to it; it has a higher affinity even though albumin binds to greater amount due to its relative abundance in the human plasma. AAG concentration increases after operative surgery. Ropivacaine is metabolised by the cytochrome P450 isoenzymes CYP1A2 and CYP3A4 to four metabolites, 3-OH-2’6’-pipecoloxylidide, 4-OH-ropivacaine, 3-OH-ropivacaine, and N-dealkylated PPX. Reduced protein binding means that there is higher fraction of the unbound drug circulating in the plasma. Furthermore, amides are hepatically metabolised by amidases. Amidase metabolism is much slower than plasma hydrolysis in which ester linked local anaesthetics undergo. This means that amides are prone to accumulation when administered by continuous infusion. Drug accumulation is also influenced by reduced hepatic perfusion and hepatic dysfunction. It has been reported that high concentrations of unbound bupivacaine are linked with higher rates of early symptoms of CNS toxicity.
Various paediatric studies have been carried out to assess the efficacy and effectiveness of ropivacaine as the choice of local anaesthesia in children. Bosenberg et al evaluated the PK and efficacy of ropivacaine for continuous epidural infusion in neonates and infants under the age of one. The results showed that there were higher concentrations of unbound ropivacaine in neona...

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...clearance and volume of distribution of unbound drug increased after post menstrual age with an increase of 41% and 25% of mature values respectively. The terminal half life decreased with an increase in age. This could be accounted for by differences in body weight and increase in metabolising enzymes as the subjects mature. Ropivacaine metabolism occurs by 1st order kinetics to PPX. the fraction metabolised utilised PPX urinary amounts. Post menstrual age and body weight were required in the expression of clearance, only body weight was required for the expression of volume. Clearance of unbound PPX achieved half of its mature value at 46.5 weeks post menstrual age. There was an increase of fraction metabolised in coloured and mixed race groups aged less than 1 year. The effects of increased volume and clearance are minimal as the metabolite in excreted anyway.

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