Local anaesthetic agents in infancy

In clinical practice new drugs are enthusiastically utilized until side effects are later discovered. News of the benefits of cocaine crossed the Atlantic in four weeks, from its first report in 1884 (de Jong 1994) but no fewer than 13 fatalities were reported in the first seven years following its introduction (Petersen 1977). This stimulated the search for safer and more suitable agents, culminating in the synthesis of lignocaine by Lofgren in 1943. In spite of its low therapeutic index, common to all local anaesthetic agents, and short duration of action, lignocaine is the standard by which new agents are judged. However, a recent report suggests that one of the lignocaine metabolites in humans, 2,6 dimethylaniline (2,6 DMA) is carcinogenic in experimental animals (Beardsley 1994). The history of bupivacaine is more erratic. Bupivacaine, because of its high fat solubility and high protein binding, became the first clinically useful long acting anaesthetic agent, but like the other long acting agents, tetracaine and nupercaine is also significantly more toxic than lignocaine. In 1977, Moore railed at the FDA 'it is high time that we stopped trying to comment on drug performance without data of sufficient quality to justify professional regulatory assessment and decisions.' (Moore et al. 1977). The response to this liberal demand was prompt. Albright, in an editorial drew attention to the particular cardiotoxicity of the newer more potent long acting agents, bupivacaine and etidocaine, and suggested animal studies to investigate a dose response differential between the central nervous system and cardiac toxicity as well