Developments in local anaesthetic drugs.

Most of the recent developments in local anaesthetics have been a direct consequence of the recognition, 20 yr ago, of the acute, life-threatening cardiotoxicity of bupivacaine. All local anaesthetics produce a dose dependent delay in the transmission of impulses through the cardiac conduction system by their action on the cardiac sodium and potassium channels. However, overt cardiotoxicity usually only becomes apparent as the last feature of a reasonably predictable sequence of changes. One of the speci®c features of bupivacaine is that clinical evidence of accumulation of the drug in plasma may be diminished until a fairly late stage because of its high af®nity for plasma protein binding sites. The `free' concentration of drug in plasma remains low until all the protein binding sites are fully occupied after which it increases rapidly, and toxicity can occur without patients exhibiting signs of CNS toxicity before cardiovascular collapse. 110 In addition to, and probably more important than, this pharmacokinetic component to its toxicity, bupivacaine has been shown to have selective cardiac effects related to the slow rate at which it dissociates from the sodium channel. An important aspect of this toxicity is that it involves a signi®cant degree of stereo-speci®city, with the `S' isomer showing signi®cantly less cardio-depressant effect than the `R'. These ®ndings generated two parallel areas of research, one clinical and the other laboratory; the outcome of both has affected clinical practice. The clinical programme was aimed at avoidance of the rapid accidental intravascular injection of a large dose of bupivacaine, the common factor in all serious reactions. Much study of `test' doses has shown that no such test is completely reliable at identifying accidental intravascular placement. Thus, it is still essential that the main dose of local anaesthetic is injected incrementally (4±5 ml at a time) with suf®cient pause between each bolus to allow identi®cation of any systemic consequences. The laboratory research programme was aimed at identifying a local anaesthetic with a similar clinical pro®le, but with less cardiotoxicity than bupivacaine. Given that a more cautious approach to clinical use seems to have prevented any further deaths, it may be argued that the expense of a new agent is unnecessary. However, it is an agent with a relatively low therapeutic index, and as little as 50 mg has caused primary ventricular ®brillation on accidental i.v. administration in a susceptible patient. Less risk of toxicity may be justi®cation alone for new drugs when very large doses are required as in brachial plexus block. However, perhaps a new drug should offer additional advantages when used in other ways if the expense is to be justi®ed. The search for alternatives to bupivacaine has concentrated on amide-linked agents, which in current practice have largely superseded the ester type drugs. Investigation of the possible aetiological mechanisms of local anaesthetic induced cardiotoxicity, along with advances in stereoselective synthesis, have demonstrated the potential clinical advantages of agents comprised of a single enantiomer. 97 99 Of the commonly used, older amide drugs, only lidocaine is not `chiral'; for example, it exists as a single structural entity at molecular level. Prilocaine, mepivacaine, and bupivacaine all have an `asymmetric' carbon atom which means that traditional manufacturing methods result in the production of equal amounts of `S' and `R' isomers, something which is re ̄ected in the clinically available preparations. Ropivacaine and levobupivacaine are two relatively new amide local anaesthetic agents that have been produced in order to address the issue of bupivacaine cardiotoxicity. Each is produced as a pure `S' isomer. Levobupivacaine is the `S' isomer of bupivacaine. Ropivacaine is the propyl analogue of, bupivacaine having a butyl group in the same position. Current developments are not exclusively restricted to variations on the traditional amide drug theme as a response to rare toxic reactions. Other work is looking to identify British Journal of Anaesthesia 87 (1): 27±35 (2001)