Clinical Pharmacokinetics of Local Anaesthetics1

Abstract

The introduction of the new long acting local anaesthetics, bupivacaine and etidocaine, has stimulated an expansion of interest in regional anaesthesia, particularly for obstetrical applications and pain therapy. System toxicity following injection of local anesthetics occurs albeit infrequently, and tentative correlations have been made between the onset of CNS and cardiovascular effects and circulating drug concentrations in both adults and neonates. Amongst other factors, interpretation of these relationships depends upon blood distribution and plasma binding of the agents, sampling sites and acid-base balance. The disposition kinetics and placental transfer of the amide type agents have been well characterised. In adults their clearance is almost entirely hepatic but in neonates an increase in the renal component is, in part, a reflection of the immaturity of some of the enzymes responsible for their metabolism. Ester type agents are rapidly hydrolysed by plasma pseudocholinesterase and this has led to a preference for chloroprocaine in some obstetric procedures. Major determinants of the systemic absorption of the agents after perineural administration include their physicochemical and vasoactive properties, perfusion and tissue binding at the site of injection and whether or not adrenaline has been added. In respect of blood drug concentrations achieved after various regional anaesthetic procedures, the margin of systemic safety appears to favour bupivacaine and etidocaine compared to shorter acting analogues such as lignocaine and mepivacaine. The time course of local anaesthetic remaining at the site of injection has been calculated following intravenous regional anaesthesia and peridural block. This has allowed prediction of the local and systemic accumulation of the drugs following contined dosage. Blood concentrations of local anaesthetics after perineural injection are not closely related to age, weight or pregnancy but may be influenced by diseases associated with haemodynamic changes and by other drugs given at or around the time of regional blockade.

Relative Nerve Blocking Properties of Bupivacaine and Ropivacaine in Dogs Undergoing Brachial Plexus Block Using a Nerve Stimulator

“…In the present study, there were no significant changes in heart and respiratory rates, and adverse effects indicating central nervous system toxicity, such as excitement, tremor and convulsion, were not observed in any groups. In addition, Tucker et al [20] reported that the order of absorption speeds for identical local anesthetics is intercostal > sacroepidural > lumber epidural > brachial plexus > subarachnoid > infiltration anesthesia > subcutaneous. Considering that the absorption speed of local anesthetics administrated to the brachial plexus is slow, 0.75% ropivacaine at 0.4 ml/ kg with BPB is sufficiently safe, at least in dogs with the body weight range used in this study.…”

Effect of lignocaine in myocardial contusion: an experiment on rabbit isolated heart

“…These doses corresponded to concentrations of 15 and 30 gM (4 and 8 jig ml-l) in buffer respectively. The first concentration was considered as the upper limit of therapeutic concentration and the second concentration was considered to reflect a mild toxic concentration (Tucker and Mather, 1979); almost all the molecules are free in buffer since the concentration of albumin is very low and no binding occurs on hydroxy-ethyl-starch (unpublished data).…”

The impairment of lignocaine clearance by propranolol‐major contribution from enzyme inhibition.

“…These calculations were based upon the 'well-stirred' model and the 'parallel-tube model' (Shand, 1978) (Tucker etal., 1977;Tucker & Mather, 1979). It has been shown that propranolol does not alter the plasma binding of lignocaine when the drugs are present together in clinically relevant concentrations (McNamara et al, 1981).…”