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Metabolism of Amide Local Anesthetics. Amide local anesthetics undergo varying rates of metabolism by microsomal enzymes located primarily in the liver. Prilocaine undergoes the most rapid metabolism; lidocaine and mepivacaine are intermediate; and etidocaine, bupivacaine, and ropivacaine undergo the slowest metabolism among the amide local anesthetics. Compared with that of ester local anesthetics, the metabolism of amide local anesthetics is more complex and slower. This slower metabolism means that sustained increases of the plasma concentrations of amide local anesthetics, and thus systemic toxicity, are more likely than with ester local anesthetics. Furthermore, cumulative drug effects of amide local anesthetics are more likely than with ester local anesthetics.

  1. Lidocaine

    1. The principal metabolic pathway of lidocaine is oxidative dealkylation in the liver to monoethylglycinexylidide (approximately 80% of the activity of lidocaine for protecting against cardiac dysrhythmias) followed by hydrolysis of this metabolite to xylidide.

    2. Xylidide has only approximately 10% of the cardiac antidysrhythmic activity of lidocaine.

  2. Prilocaine is an amide local anesthetic that is metabolized to orthotoluidine (an oxidizing compound capable of converting hemoglobin to its oxidized form, methemoglobin, resulting in a potentially life-threatening complication, methemoglobinemia).

    1. Methemoglobinemia is readily reversed by the administration of methylene blue, 1 to 2 mg/kg intravenously (IV), over 5 minutes (total dose should not exceed 7 to 8 mg/kg).

    2. Prilocaine causes less vasodilation than other local anesthetics and thus can be utilized without epinephrine added to the local anesthetic solution.

  3. Mepivacaine

    1. Mepivacaine has pharmacologic properties similar to those of lidocaine, although the duration of action of mepivacaine is somewhat longer.

    2. In contrast to lidocaine, mepivacaine lacks vasodilator activity (an alternate selection when addition of epinephrine to the local anesthetic solution is not recommended).

  4. Bupivacaine

    1. Possible pathways for metabolism of bupivacaine include aromatic hydroxylation, N-dealkylation, amide hydrolysis, and conjugation.

    2. 1-Acid glycoprotein is the most important plasma protein binding site of bupivacaine, and its concentration is increased in many clinical situations, including postoperative trauma.

  5. Ropivacaine is metabolized to 2,6-pipecoloxylidide and 3-hydroxyropivacaine by hepatic cytochrome P-450 enzymes (both metabolites have significantly less local anesthetic potency than ropivacaine).

    1. Because only a very small fraction of ropivacaine is excreted unchanged in the urine (about 1%) when the liver is functioning normally, dosage adjustments based on renal function do not seem necessary.

    2. Overall, clearance of ropivacaine is higher than that determined for bupivacaine (may offer an advantage over bupivacaine in terms of systemic toxicity).

    3. Ropivacaine is highly bound to 1-acid glycoprotein.

  6. Dibucaine is an amide local anesthetic known for its ability to inhibit the activity of normal butyrylcholinesterase (plasma cholinesterase) by more than 70%, compared with only approximately 20% inhibition of the activity of atypical enzyme. Laboratory evaluation of patients suspected of having atypical pseudocholinesterase is facilitated by measurement of the degree of enzyme suppression by dibucaine, a test termed the dibucaine number.