Lidocaine analog

The local anesthetic activities of lidocaine analogs (39, eq. 171) have been eompared with their acute toxidties (eq. 172) [776]. Possible reasons for the differences between both equations were discussed, but no structural proposals were derived for local anesthetics with lower toxicity. 

The structure of HIDA is shown in Figure 2. This compound was originally synthesized by Loberg(7 ) as a lidocaine analog capable of complexing Tc. When the ""Tc-complex of HIDA was prepared and its biodistribution determined in mice, it was found to rapidly leave the circulation and accumulate in the liver. 

Historically, local anesthetics have been known for many years. Cocaine, the first such agent, was isolated in 1860 and introduced for clinical application in 1884. Procaine was developed as a synthetic analog of cocaine in 1905 and lidocaine was synthesized in 1943. The development of new chemical entities as putative local anesthetics remains an ongoing activity in medicinal chemistry. 

The second type of oxidative biotransformation comprises dealkylations. In the case of primary or secondary amines, dealkylation of an alkyl group starts at the carbon adjacent to the nitrogen in the case of tertiary amines, with hydroxylation of the nitrogen (e.g., lidocaine). The intermediary products are labile and break up into the dealkylated amine and aldehyde of the alkyl group removed. O-dealkylation and S-dear-ylation proceed via an analogous mechanism (e.g., phenacetin and azathioprine, respectively). 

FIGURE 18.6 Graded concentration-effect curve for intravenous lidocaine in patients with neuropathic pain. Pain was scored from 0 to 10 with an analog pain scale. The median pretreatment pain score was 7 and a score of 0 meant no pain. Blood levels of lidocaine were measured every 10 minutes and pain was scored at the same time points. The graph relates the blood level of lidocaine to the severity of pain. (Adapted from data published by Ferrante FM, Paggioli J, Cherukuri S, Arthur GR. Anesth Analg 1996 82 91-7.)... 

A recent study has employed deuterium labeling to show that the mechanism for the oxidative N-demethylation of nicotine may involve two modes of breakdown for a proposed carbinolamine intermediate, dealkylation with formaldehyde formation and dehydration to an iminium ion.72 The formation of such an sp2-hybrid intermediate may help to explain why both a primary and substantial / -secondary deuterium isotope effect were observed for the N-deethylation of the antiarrhythmic agent, lidocaine.73 In contrast, only a primary isotope effect was observed on the rate of oxidative O-deethylation of deuterated analogs of the analgesic, phenacetin. 77 These results indicate differences in the mechanism of oxidative 0- and N-dealkylation. A final example of the use of secondary deuterium isotope effects in studying enzymes involved in drug metabolism revealed an SN-2-like transition state for the transfer of a methyl group catalyzed by catechol-O-methyl transferase.73... 

Subsequent studies have supported the above results. For instance, ibuprofen terpene eutectic systems vs. a saturated aqueous solution of ibuprofen applied to untreated and to terpene pretreated skin were reported to cause a significant flux enhancement [59]. A system composed of ibuprofen thymol 40 60 (% w/w) produced a flux 5.9 and 12.7 times higher than the flux values from a saturated aqueous solution with thymol pretreated skin and from a saturated aqueous solution across nonpretreated skin, respectively. Analogous data were achieved in permeation experiments through snake skin with lidocaine menthol eutectic mixtures [60]. 

Furthermore, addition of hydrophobic ibuprofen resulted in a collapse of all of the gels. The latter is analogous to the findings by Scherlund et al. on the temperature-induced gelation of PEO-PPO-PEO block copolymers on addition of lidocaine and prilocaine in their base forms (see Figure 1.14), as well as to the findings by Carlsson et al. on pH-dependent reductions of the cloud points of poly(A -isopropyl acrylamide) solutions on addition of either lidocaine or prilocaine (215). 

While lidocaine and procaine amide are effective antiarrhythmics, lack of oral activity s and toxicity has led to the development of newer analogs. The following have been reported to possess local anesthetic and anti arrhythmic activities in a number of experimentally-induced cardiac arrhythmias S u ... 

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