Meperidine (Demerol) (Fig. 24.9) was discovered in 1939 during a serendipitous screening of compounds being studied for antispasmodic activity. Mice given meperidine were noted to carry their tails in an erect position (the Straub tail reaction), which was indicative of narcotic analgesia. This led to the study of meperidine and derivatives as analgesic agents. Meperidine was found to have low potency at the receptor compared with morphine (0.2%) but much higher penetration into the brain resulting in a compound with about 10% of the potency of morphine.41 Meperidine is an agonist at the /-receptor and a 300-mg oral or 75-mg IV dose is reported to be equianalgesic with morphine 30-mg oral or 10-mg IV dose.
The 4-ethyl ester was found to be the optimal length for analgesic potency. Increasing or decreasing the chain length decreased activity.41 Structural changes that increase the potency of meperidine include the introduction of an m-hydroxyl on the phenyl ring, substituting the methyl on the N for a phenylethyl or a p-aminophenylethyl.41 Replacing the N-methyl with an N-allyl or N-cyclopropylmethyl group does not generate an antagonist, unlike the similar substitution of the morphine congeners. Meperidine quickly penetrates the blood-brain barrier and thus has a quick onset of activity and a high abuse potential. Meperidine is metabolized to normeperidine (Fig. 24.10) by the liver enzymes CYP3A4 and CYP2C18 and in the brain by CYP2B6. Meperidine and normeperidine are also metabolized by liver carboxylesterases.78,79 The metabolism to normeperidine has clinical consequences. The duration of analgesia of meperidine may be shorter than the 3- to 4-hour half-life of the drug. This may necessitate frequent dosing to relieve pain, and thus the excessive formation of normeperidine. Normeperidine has been shown to cause central nervous system (CNS) excitation that presents clinically as tremors, twitches, "shaky feelings," and multifocal myoclonus potentially followed by grand mal seizures.80 Patients at the greatest risk of developing normeperidine toxicity are those that are on high doses, long durations (greater than 3 days), have
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