Ch3

Bupivacaine

Bupivacaine

Levobupivacaine S (-)

Bupivacaine was synthesized simultaneously with mepiva-caine in 1957 but was at first overlooked because of the increased toxicity compared with mepivacaine. When the methyl on the cyclic amine of mepivacaine is exchanged for a butyl group the lipophilicity, potency and the duration of action all increase. Literature reports of cardiovascular toxi-city, including severe hypotension and bradycardia, are abundant in the literature.91 Bupivacaine is highly bound to plasma proteins (95%), and thus the free concentration may remain low until all of the protein binding sites are occupied. After that point, the plasma levels of bupivacaine rise rapidly and patients may progress to overt cardiac toxicity without ever showing signs of CNS toxicity.92 The cardiotoxicity of bupivacaine is a result of its affinity to cardiac tissues and its ability to depress electrical conduction and predispose the heart to reentry types of arrhythmias. The cardiotoxicity of bupivacaine was found to be significantly more prominent with the "R" isomer, or the racemic mixture, thus the "S" stereoisomer is now on the market as levobupivacaine.93

Levobupivacaine is the pure "S" enantiomer of bupiva-caine and in vivo and in vitro studies confirm that it does not undergo metabolic inversion to R(+) bupivacaine. The pKa of the tertiary nitrogen is 8.09, the same as bupivacaine's pKa. Levobupivacaine is available in solution for epidural administration, peripheral nerve block administration, and infiltration anesthesia. Clinical trials have shown that levobupivacaine and bupivacaine have similar anesthetic effects.94 Levobupivacaine has lower CNS and cardiotoxic-ity than bupivacaine although unintended intravenous injection when performing nerve blocks may result in toxicity. Racemic bupivacaine is metabolized extensively with no unchanged drug found in the urine or feces. Liver enzymes including the CYP3A4 and CYP1A2 isoforms are responsible for N-dealkylation and 3-hydroxylation of levobupivacaine followed by glucuronidation or sulfation.95

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