Opioid Analgesics: Meperidine and Related Phenylpiperidine Derivatives

Meperidine and Related Phenylpiperidine Derivatives

Clinical Uses and Adverse Effects

Meperidine (Demerol) is a phenylpiperidine derivative of morphine that was developed in the late 1930s as a potential anticholinergic agent. It has some anticholin-ergic side effects that lead to tachycardia, blurred vi-sion, and dry mouth. Meperidine is approximately one-fifth as potent as morphine and is absorbed only half as well when administered orally as parenterally. It has a rapid onset and short duration of action (2 hours), that is, approximately one-fourth that of morphine.

Like morphine, meperidine has an active metabo-lite, normeperidine, formed by N-demethylation of meperidine. Normeperidine is not analgesic but is a proconvulsant and a hallucinogenic agent. For this rea-son, meperidine use in patients with renal or liver insuf-ficiency is contraindicated because of the decreased clearance of the drug and its metabolite. Convulsant ac-tivity has been documented in elderly patients given meperidine and in patients using PCA who have de-creased renal function.

Meperidine differs from morphine in that it has far less antitussive effect and little constipative effect. The drug is particularly useful in cancer patients and in pul-monary patients, in whom the cough reflex must remain intact. However, it does have more seizure-inducing ac-tivity than morphine. Although meperidine produces spasms of the biliary tract and colon, such spasms are of shorter duration than those produced by morphine.

Meperidine readily passes the placenta into the fe-tus. However, respiratory depression in the newborn has not been observed, and meperidine clearance in the newborn is rapid in that it does not rely upon conjuga-tion to glucuronides. Meperidine, unlike morphine, has not been associated with prolongation of labor; con-versely, it increases uterine contractions.

Symptoms of overdose with meperidine are qualita-tively different from those of morphine in that seizures rather than sedation are common. Respiratory depres-sion and miosis are present. While naloxone reverses overdose-associated toxicity, its use in patients who have received large, frequent doses of meperidine may precipitate seizures.

Diphenoxylate (Lomotil) is a meperidine derivative used as an antidiarrheal. It exhibits no morphinelike ef-fects at low doses, but it produces mild opioid effects, such as sedation, euphoria, and dependence, at higher doses. Its salts are highly insoluble in water, which re-duces recreational use. Preparations often include at-ropine.

Difenoxin is a metabolite of diphenoxylate with an-tidiarrheal effects similar to the parent drug. Loperamide (Imodium) is a piperidine derivative of diphenoxylate, which acts both at the level of the gut and also in the CNS to reduce GI motility. Its use as an antidiar-rheal and its potency are similar to those of diphenoxy-late.

Contraindications

Contraindications are similar to those of morphine. In addition, because normeperidine accumulates in renal dysfunction and meperidine accumulates in hepatic dys-function, meperidine is contraindicated in such patients because of convulsant effects. Similarly, the use of meperidine is contraindicated in patients who have a history of seizures or who are taking medication to pre-vent seizures. Phenytoin administered for seizures may reduce the effectiveness of meperidine by increasing the metabolism of the drug in the liver. Meperidine is not generally used in patients with cardiac dysfunction, since its anticholinergic effects can increase both heart rate and ectopic beats.