Prilocaine hydrolysis

The local anesthetics can be broadly categorized on the basis of the chemical nature of the linkage contained within the intermediate alkyl chain group. The amide local anesthetics include lidocaine (7.5), mepivacaine (7.6), bupivacaine (7.7), etidocaine (7.8), prilocaine (7.9), and ropivacaine (7.10) the ester local anesthetics include cocaine (7.11), procaine (7.12), benzocaine (7.13), and tetracaine (7.14). Since the pharmacodynamic interaction of both amide and ester local anesthetics with the same Na" channel receptor is essentially idenhcal, the amide and ester functional groups are bioisosterically equivalent. However, amide and ester local anesthetics are not equal from a pharmacokinetic perspective. Since ester links are more susceptible to hydrolysis than amide links. 

These are generally metabolised in the hepatic endoplasmic reticulum, the initial reaction being N-dealkylation, with subsequent hydrolysis. An exception to this is prilocaine, where the initial step is hydrolysis, forming o-toluidine. This is further metabolised to 4- and 6-hydro toluidine. The latter is believed to be responsible for the methaemoglobinaemia which may follow high doses. The amidelinked local anaesthetics are extensively protein-bound (between 55% and 95%) particularly to ol-acid glycoprotein. 

Prilocaine (No. 10) represents an interesting situation in that the presence of only one o-methyl group has two consequences. A predictably shorter duration of action because of more facile amide hydrolysis, as compared with lidocaine, and a significant likelihood of methemoglobinemia at higher doses being produced by o-toluidine that results from this amide hydrolysis. The much lower levels of 2,6-xylidine produced from lidocaine (Fig. 13-8) do not produce this hematological toxicity. However, because of more rapid metabolism and the resultant shorter duration of action, overall toxicity of prilocaine is about 40% less than lidocaine. 

Prilocaine was synthesised in 1960 and was found to be very similar to lidocaine. It has a wider safety margin which is probably because it has a lower partition coefficient (Table 15.1) than lidocaine and also the amide bond is more readily enzymatically hydrolysed than that in lidocaine. It does have an additional problem in that the 2-methyl aniline hydrolysis product of metabolism (Fig. 15.10) can cause methaemoglobinaemia, a condition where the oxygen-carrying capacity of blood cells is reduced due to oxidation of iron (II) in haemoglobin to iron (III). Prilocaine has a chiral centre but it is administered as racemate. However, it is only one of the enantiomers which are rapidly hydrolysed in the liver causing toxicity this provides an example of how chirality can influence therapeutic activity. 

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