Norpethidine Explained

Norpethidine (normeperidine, pethidine intermediate B) is a 4-phenylpiperidine derivative that is both a precursor to, and the toxic metabolite of, pethidine (meperidine). It is scheduled by UN Single Convention on Narcotic Drugs. It is a Schedule II Narcotic controlled substance in the United States and has an ACSCN of 9233. The 2014 annual manufacturing quota was .^[1]

Norpethidine is a controlled drug because of its potential uses in manufacturing both pethidine itself and a range of N-substituted derivatives, but it has little opioid activity in its own right. Instead, norpethidine acts as a stimulant and causes convulsions.^{[2] [3]} Bioaccumulation of norpethidine is a major complication when pethidine is used in medicine as an analgesic, as when pethidine is used in high doses^[4] or administered by intravenous infusion,^[5] norpethidine can accumulate in the body at a faster rate than it is being excreted, particularly in elderly patients^[6] or those with compromised liver or kidney function,^[7] resulting in a range of toxic effects, mainly convulsions, but also myoclonus^[8] and hyponatremia.^[9] These complications can be serious and have sometimes resulted in death.^[10]

Metabolism of pethidine to norpethidine is carried out mainly by the CYP enzymes, CYP2B6, CYP2C19 and CYP3A4, in the liver, and since the activity of these enzymes can vary between individuals and can be influenced by concurrent use of other drugs, the rate and extent of norpethidine production can be difficult to predict.^{[11] [12]}

Norpethidine can be used as a precursor in synthesis of other drugs, including etoxeridine,^[13] benzethidine,^[14] furethidine,^[15] morpheridine, anileridine, phenoperidine, piminodine and oxpheneridine.

See also

• Nortilidine
• O-Desmethyltramadol
• Moramide intermediate
• Methadone intermediate
• Pethidine intermediate A
• Pethidine intermediate C (pethidinic acid)

Notes and References

1. Web site: Conversion Factors for Controlled Substances . Diversion Control Division . Drug Enforcement Administration (DEA), U.S. Department of Justice .
2. Umans JG, Inturrisi CE . Antinociceptive activity and toxicity of meperidine and normeperidine in mice . The Journal of Pharmacology and Experimental Therapeutics . 223 . 1 . 203–6 . October 1982 . 7120119 .
3. Plummer JL, Gourlay GK, Cmielewski PL, Odontiadis J, Harvey I . Behavioural effects of norpethidine, a metabolite of pethidine, in rats . Toxicology . 95 . 1–3 . 37–44 . January 1995 . 7825188 . 10.1016/0300-483x(94)02871-q .
4. Simopoulos TT, Smith HS, Peeters-Asdourian C, Stevens DS . Use of meperidine in patient-controlled analgesia and the development of a normeperidine toxic reaction . Archives of Surgery . Chicago, Ill. . 137 . 1 . 84–8 . January 2002 . 11772223 . 10.1001/archsurg.137.1.84 . free .
5. Stone PA, Macintyre PE, Jarvis DA . Norpethidine toxicity and patient controlled analgesia . British Journal of Anaesthesia . 71 . 5 . 738–40 . November 1993 . 8251291 . 10.1093/bja/71.5.738 . free .
6. Holmberg L, Odar-Cederlof I, Boreus LO, Heyner L, Ehrnebo M. Comparative disposition of pethidine and norpethidine in old and young patients. European Journal of Clinical Pharmacology. 1982;22(2):175-9.
7. Pond SM, Tong T, Benowitz NL, Jacob P, Rigod J . Presystemic metabolism of meperidine to normeperidine in normal and cirrhotic subjects . Clinical Pharmacology and Therapeutics . 30 . 2 . 183–8 . August 1981 . 7249503 . 10.1038/clpt.1981.146 . 10117158 .
8. Reutens DC, Stewart-Wynne EG . Norpethidine induced myoclonus in a patient with renal failure . Journal of Neurology, Neurosurgery, and Psychiatry . 52 . 12 . 1450–1 . December 1989 . 2614458 . 1031622 . 10.1136/jnnp.52.12.1450 .
9. Appel WC . Possible roles of normeperidine and hyponatremia in a postoperative death . Canadian Medical Association Journal . 137 . 10 . 912–3 . November 1987 . 3676934 . 1267380 .
10. Jiraki K . Lethal effects of normeperidine . The American Journal of Forensic Medicine and Pathology . 13 . 1 . 42–3 . March 1992 . 1585886 . 10.1097/00000433-199203000-00009 . 32005631 .
11. Ramírez J, Innocenti F, Schuetz EG, Flockhart DA, Relling MV, Santucci R, Ratain MJ . CYP2B6, CYP3A4, and CYP2C19 are responsible for the in vitro N-demethylation of meperidine in human liver microsomes . Drug Metabolism and Disposition: The Biological Fate of Chemicals . 32 . 9 . 930–6 . September 2004 . 15319333 .
12. McHugh GJ . Norpethidine accumulation and generalized seizure during pethidine patient-controlled analgesia . Anaesthesia and Intensive Care . 27 . 3 . 289–91 . June 1999 . 10389564 .
13. US . 2858316 . New piperidine derivatives . granted . Henri M . UCB SA . 28 October 1958 .
14. Frearson PM, Stern ES . 622. Some new analogues of pethidine. Part III. 1-Aryloxy-alkylnorpethidines, and close analogues. . Journal of the Chemical Society (Resumed) . 1958 . 3065–7 . 10.1039/JR9580003065 .
15. Frearson PM, Hardy DG, Stern ES . 426. Some new analogues of pethidine. Part IV. Substituents at the 1-position incorporating cyclic ether groups. . Journal of the Chemical Society (Resumed) . 1960 . 2103–7 . 10.1039/JR9600002103 .