Norpethidine

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 11 grams (0.39 oz).^[2]

Norpethidine

Clinical data
ATC code	none
Legal status
Legal status	AU: Unscheduled BR: Class A1 (Narcotic drugs)[1] CA: Schedule I DE: Anlage II (Authorized trade only, not prescriptible) US: Schedule II UN: Narcotic Schedule I
Identifiers
IUPAC name Ethyl 4-phenylpiperidine-4-carboxylate
CAS Number	77-17-8 Y
PubChem CID	32414
ChemSpider	30039 Y
UNII	JG096PMW2N
KEGG	C22685
ChEMBL	ChEMBL1052 Y
CompTox Dashboard (EPA)	DTXSID50227806
ECHA InfoCard	100.000.918
Chemical and physical data
Formula	C14H19NO2
Molar mass	233.311 g·mol−1
3D model (JSmol)	Interactive image
SMILES O=C(OCC)C2(c1ccccc1)CCNCC2
InChI InChI=1S/C14H19NO2/c1-2-17-13(16)14(8-10-15-11-9-14)12-6-4-3-5-7-12/h3-7,15H,2,8-11H2,1H3 Y Key:QKHMFBKXTNQCTM-UHFFFAOYSA-N Y
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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.^[3][4]

Bioaccumulation of norpethidine is a major complication when pethidine is used in medicine as an analgesic, as when pethidine is used in high doses^[5] or administered by intravenous infusion,^[6] norpethidine can accumulate in the body at a faster rate than it is being excreted, particularly in elderly patients^[7] or those with compromised liver or kidney function,^[8] resulting in a range of toxic effects, mainly convulsions, but also myoclonus^[9] and hyponatremia.^[10] These complications can be serious and have sometimes resulted in death.^[11]

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.^[12][13]

Norpethidine can be used as a precursor in synthesis of other drugs, including etoxeridine,^[14] benzethidine,^[15] furethidine,^[16] morpheridine, anileridine, phenoperidine, piminodine and oxpheneridine.

See also

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

References

1. Anvisa (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-16.
2. "Conversion Factors for Controlled Substances". Diversion Control Division. Drug Enforcement Administration (DEA), U.S. Department of Justice.
3. Umans JG, Inturrisi CE (October 1982). "Antinociceptive activity and toxicity of meperidine and normeperidine in mice". The Journal of Pharmacology and Experimental Therapeutics. 223 (1): 203–6. PMID 7120119.
4. Plummer JL, Gourlay GK, Cmielewski PL, Odontiadis J, Harvey I (January 1995). "Behavioural effects of norpethidine, a metabolite of pethidine, in rats". Toxicology. 95 (1–3): 37–44. doi:10.1016/0300-483x(94)02871-q. PMID 7825188.
5. Simopoulos TT, Smith HS, Peeters-Asdourian C, Stevens DS (January 2002). "Use of meperidine in patient-controlled analgesia and the development of a normeperidine toxic reaction". Archives of Surgery. 137 (1). Chicago, Ill.: 84–8. doi:10.1001/archsurg.137.1.84. PMID 11772223.
6. Stone PA, Macintyre PE, Jarvis DA (November 1993). "Norpethidine toxicity and patient controlled analgesia". British Journal of Anaesthesia. 71 (5): 738–40. doi:10.1093/bja/71.5.738. PMID 8251291.
7. 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.
8. Pond SM, Tong T, Benowitz NL, Jacob P, Rigod J (August 1981). "Presystemic metabolism of meperidine to normeperidine in normal and cirrhotic subjects". Clinical Pharmacology and Therapeutics. 30 (2): 183–8. doi:10.1038/clpt.1981.146. PMID 7249503. S2CID 10117158.
9. Reutens DC, Stewart-Wynne EG (December 1989). "Norpethidine induced myoclonus in a patient with renal failure". Journal of Neurology, Neurosurgery, and Psychiatry. 52 (12): 1450–1. doi:10.1136/jnnp.52.12.1450. PMC 1031622. PMID 2614458.
10. Appel WC (November 1987). "Possible roles of normeperidine and hyponatremia in a postoperative death". Canadian Medical Association Journal. 137 (10): 912–3. PMC 1267380. PMID 3676934.
11. Jiraki K (March 1992). "Lethal effects of normeperidine". The American Journal of Forensic Medicine and Pathology. 13 (1): 42–3. doi:10.1097/00000433-199203000-00009. PMID 1585886. S2CID 32005631.
12. Ramírez J, Innocenti F, Schuetz EG, Flockhart DA, Relling MV, Santucci R, Ratain MJ (September 2004). "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. PMID 15319333.
13. McHugh GJ (June 1999). "Norpethidine accumulation and generalized seizure during pethidine patient-controlled analgesia". Anaesthesia and Intensive Care. 27 (3): 289–91. PMID 10389564.
14. US granted 2858316, Henri M, "New piperidine derivatives", published 28 October 1958, assigned to UCB SA
15. Frearson PM, Stern ES (1958). "622. Some new analogues of pethidine. Part III. 1-Aryloxy-alkylnorpethidines, and close analogues". Journal of the Chemical Society (Resumed): 3065–7. doi:10.1039/JR9580003065.
16. Frearson PM, Hardy DG, Stern ES (1960). "426. Some new analogues of pethidine. Part IV. Substituents at the 1-position incorporating cyclic ether groups". Journal of the Chemical Society (Resumed): 2103–7. doi:10.1039/JR9600002103.