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Pethidine

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This article is about drug also called "dolantin". For dilantin, see phenytoin.
Pethidine
Clinical data
Trade namesDemerol
Pregnancy
category
  • AU: C
Dependence
liability		High
Routes of
administration		oral, intravenous, intramuscular, subcutaneous
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability50–60% (Oral), 80-90% (Oral, in cases of hepatic impairment)
Protein binding65-75%
MetabolismLiver
Elimination half-life2.5-4 hours, 7-11 hours (liver disease)
ExcretionRenal
Identifiers
  • Ethyl 1-methyl-4-phenylpiperidine-4-carboxylate
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.000.299 Edit this at Wikidata
Chemical and physical data
FormulaC15H21NO2
Molar mass247.33g/mol g·mol−1
3D model (JSmol)
  • O=C(C1(CCN(CC1)C)C2=CC=CC=C2)OCC
  • InChI=1S/C15H21NO2/c1-3-18-14(17)15(9-11-16(2)12-10-15)13-7-5-4-6-8-13/h4-8H,3,9-12H2,1-2H3 checkY=
  • Key:XADCESSVHJOZHK-UHFFFAOYSA-N checkY=
  (verify)

Pethidine, also known as meperidine and Demerol, is a synthetic opioid pain medication of the phenylpiperidine class.[1][2][3][4][5][6] Synthesized in 1939 as a potential anticholinergic agent by the German chemist Otto Eisleb, its analgesic properties were first recognized by Otto Schaumann while working for IG Farben, Germany.[7] Pethidine was the first wholly synthetic opioid developed [8] and is the prototype of a large family of analgesics including the pethidine 4-phenylpiperidines (pethidine, piminodine, anileridine and others) the prodines (alphaprodine, MPPP, etc.), bemidones (ketobemidone, etc.), and others more distant including diphenoxylate and analogues.[8]

Pethidine is indicated for the treatment of moderate to severe pain, and is delivered as a hydrochloride salt in tablets, as a syrup, or by intramuscular, subcutaneous, or intravenous injection. For much of the 20th century, pethidine was the opioid of choice for many physicians; in 1975, 60% of doctors prescribed it for acute pain and 22% for chronic severe pain.[9]

Compared with morphine, pethidine was thought to be safer, carry a lower risk of addiction, and to be superior in treating the pain associated with biliary spasm or renal colic due to its putative anticholinergic effects.[3] These were later discovered to be all myths, as it carries an equal risk of addiction, possesses no advantageous effects on biliary spasm or renal colic compared to other opioids, and due to its toxic metabolite norpethidine is more toxic than other opioids - especially during long-term use.[3] The norpethidine metabolite was found to have serotonergic effects, so pethidine could, unlike most opioids, contribute to serotonin syndrome.[3][4]

Synthesis

Pethidine synthesis

Pethidine can be produced in a two-step synthesis. The first step is starting from benzyl cyanide and bis (chloroethyl) methylamine in the presence of sodium amide cyclization to piperidine. After the formation of the ester of the nitrile function.[10]

Control

Pethidine is in Schedule II of the Controlled Substances Act 1970 of the United States as a Narcotic with ACSCN 9230 with a 6250 kilo aggregate manufacturing quota as of 2014. The free base conversion ratio for salts includes 0.87 for the hydrochloride and 0.84 for the hydrobromide. The A, B, and C intermediates in production of pethidine are also controlled, with ACSCN being 9232 for A (with a 6 gramme quota) and 9233 being B (quota of 11 grammes) and 9234 being C (6 gramme quota).[11] It is listed under the Single Convention for the Control of Narcotic Substances 1961 and is controlled in most countries in the same fashion as is morphine.

Medical uses

Pethidine is the most widely used opioid in labour and delivery[12] but has fallen out of favour in some countries such as the United States in favour of other opioids, due to its potential drug interactions (especially with serotonergics) and its neurotoxic metabolite, norpethidine.[6] It is still commonly used in the United Kingdom and New Zealand,[13] and is the preferred opioid in the United Kingdom for use during labour.[14] Pethidine is the preferred painkiller for diverticulitis, because it decreases intestinal intraluminal pressure.[15]

Adverse effects

The adverse effects of pethidine administration are primarily those of the opioids as a class: nausea, vomiting, sedation, dizziness, diaphoresis, urinary retention, and constipation. Unlike other opioids, it does not cause miosis because of its anticholinergic properties. Overdose can cause muscle flaccidity, respiratory depression, obtundation, cold and clammy skin, hypotension, and coma. A narcotic antagonist such as naloxone is indicated to reverse respiratory depression and other effects of pethidine. Serotonin syndrome has occurred in patients receiving concurrent antidepressant therapy with selective serotonin reuptake inhibitors or monoamine oxidase inhibitors. Convulsive seizures sometimes observed in patients receiving parenteral pethidine on a chronic basis have been attributed to accumumulation in plasma of the metabolite norpethidine (normeperidine). Fatalities have occurred following either oral or intravenous pethidine overdose.[16][17]

Interactions

Pethidine has serious interactions that can be dangerous with monoamine oxidase inhibitors (e.g., furazolidone, isocarboxazid, moclobemide, phenelzine, procarbazine, selegiline, tranylcypromine). Such patients may suffer agitation, delirium, headache, convulsions, and/or hyperthermia. Fatal interactions have been reported including the death of Libby Zion.[18] It is thought to be caused by an increase in cerebral serotonin concentrations. It is probable that pethidine can also interact with a number of other medications, including muscle relaxants, some antidepressants, benzodiazepines, and ethanol.

Mechanism of action

Main article: Opioid

Like morphine, pethidine exerts its analgesic effects by acting as an agonist at the μ-opioid receptor.[19]

Pethidine is often employed in the treatment of postanesthetic shivering. The pharmacologic mechanism of this antishivering effect is not fully understood,[20] but it may involve the stimulation of κ-opioid receptors.[21]

Pethidine has structural similarities to atropine and other tropane alkaloids and may have some of their effects and side effects.[22] In addition to these opioidergic and anticholinergic effects, it has local anesthetic activity related to its interactions with sodium ion channels.

Pethidine's apparent in vitro efficacy as an antispasmodic agent is due to its local anesthetic effects. It does not have antispasmodic effects in vivo.[23] Pethidine also has stimulant effects mediated by its inhibition of the dopamine transporter (DAT) and norepinephrine transporter (NET). Because of its DAT inhibitory action, pethidine will substitute for cocaine in animals trained to discriminate cocaine from saline.[24]

Several analogs of pethidine such as 4-fluoropethidine have been synthesized that are potent inhibitors of the reuptake of the monoamine neurotransmitters dopamine and norepinephrine via DAT and NET.[25][26] It has also been associated with cases of serotonin syndrome, suggesting some interaction with serotonergic neurons, but the relationship has not been definitively demonstrated.[24][26][27][28]

It is more lipid-soluble than morphine, resulting in a faster onset of action. Its duration of clinical effect is 120–150 minutes, although it is typically administered at 4– to 6-hour intervals. Pethidine has been shown to be less effective than morphine, diamorphine, or hydromorphone at easing severe pain, or pain associated with movement or coughing.[24][26][28]

Like other opioid drugs, pethidine has the potential to cause physical dependence or addiction. It may be more likely to be abused than other prescription opioids, perhaps because of its rapid onset of action.[29] When compared with oxycodone, hydromorphone, and placebo, pethidine was consistently associated with more euphoria, difficulty concentrating, confusion, and impaired psychomotor and cognitive performance when administered to healthy volunteers.[30] The especially severe side effects unique to pethidine among opioids—serotonin syndrome, seizures, delirium, dysphoria, tremor—are primarily or entirely due to the action of its metabolite, norpethidine.[26][28]

Pharmacokinetics

Pethidine is quickly hydrolysed in the liver to pethidinic acid and is also demethylated to norpethidine, which has half the analgesic activity of pethidine but a longer elimination half-life (8–12 hours);[31] accumulating with regular administration, or in renal failure. Norpethidine is toxic and has convulsant and hallucinogenic effects. The toxic effects mediated by the metabolites cannot be countered with opioid receptor antagonists such as naloxone or naltrexone, and are probably primarily due to norpethidine's anticholinergic activity probably due to its structural similarity to atropine, though its pharmacology has not been thoroughly explored. The neurotoxicity of pethidine's metabolites is a unique feature of pethidine compared to other opioids. Pethidine's metabolites are further conjugated with glucuronic acid and excreted into the urine.

Recreational use

In data from the U.S. Drug Abuse Warning Network, mentions of hazardous or harmful use of pethidine declined between 1997 and 2002, in contrast to increases for fentanyl, hydromorphone, morphine, and oxycodone.[32] The number of dosage units of pethidine reported lost or stolen in the U.S. increased 16.2% between 2000 and 2003, from 32,447 to 37,687.[33]

This article uses the terms "hazardous use", "harmful use", and "dependence" in accordance with Lexicon of alcohol and drug terms published by the World Health Organization (WHO) in 1994.[34] In WHO usage, the first two terms replace the term "abuse" and the third term replaces the term "addiction".[34][35]

The first QSAR focused on exploring how changing the nature of the aromatic substituents alters monoamine reuptake inhibitor affinities.[36][37]

File:Meperidine.gif
Pethidine
Nitrile Precursors → Pethidine/Analogs Ki & IC50, μM
Ar [3H]Pax [3H]CFT [3H]Dop
Ph ? → 0.413 ? → 17.8 ? → 12.6
p-F 10.1 → 0.308 45% → 10.7 8% → 47%
p-Cl 5.11 → 0.277 22.0 → 4.10 36% → 26.9
p-I 0.430 → 0.0211 8.34 → 3.25 36.7 → 11.1
p-Me 13.7 → 1.61 41.8 → 12.4 22% → 76.2
m,p-Cl2 0.805 → 0.0187 2.67 → 0.125 11.1 → 1.40
β-Naph 0.125 → 0.0072 2.36 → 1.14 21.8 → 11.6
Mean ± SEM of 3 experiments in triplicate. % inhibition @ 100μM

Particular emphasis needs to be placed on the ↑ D/S of the p-iodo and β-Naph analogs.

  • p-I, D/S = 155
  • BN, D/S = 158

In behavioral activity studies, none of the compounds would substitute for cocaine in mice, and they were also inactive as LMA stimulants.

This is in direct contrast to the methylphenidate analogs which more convincingly displayed cocaine-like traits.

The aryl moiety can be modified depending on whether DAT affinity is actually desirable or SERT affinity is wanted.[38]

Meperidine was initially found to be selective for the SERT over the DAT.

All the further analogs in the second QSAR study are based around the m,p-Cl2 phenyl substitution pattern.

m,p-Cl2 Meperidine esters
R CFT nM Para nM Ratio
Et 125 18.7 6.7
Me 383 15.4 25
n-Pr 449 16.4 27
i-Pr 271 43.3 6.3
n-Bu 864 16.0 54
n-Pen 283 44.3 6.4

The N-demethyl metabolite of meperidine is toxic and accumulates upon repeat dosing.

Also, the ester in meperidine is readily hydrolyzed.

The above picture is of "UCB" a SRI/NK1 antagonist currently under development by Astra Zeneca.[39]

A fourth paper on 3,4-dichlorophenylmeperidine analogs was also afforded (2010).[40]

See also

References

  1. ^ "Demerol, Pethidine (meperidine) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 9 April 2014.
  2. ^ Shipton, E (March 2006). "Should New Zealand continue signing up to the Pethidine Protocol?" (PDF). The New Zealand Medical Journal. 119 (1230): U1875. PMID 16532042.
  3. ^ a b c d Latta, KS; Ginsberg, B; Barkin, RL (January–February 2002). "Meperidine: a critical review". American Journal of Therapeutics. 9 (1): 53–68. doi:10.1097/00045391-200201000-00010. PMID 11782820.
  4. ^ a b MacPherson RD, Duguid MD (2008). "Strategy to Eliminate Pethidine Use in Hospitals" (PDF). Journal of Pharmacy Practice and Research. 38 (2): 88–89.
  5. ^ Mather, LE; Meffin, PJ (September–October 1978). "Clinical pharmacokinetics of pethidine". Clinical Pharmacokinetics. 3 (5): 352–68. doi:10.2165/00003088-197803050-00002. PMID 359212.
  6. ^ a b Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3.
  7. ^ Michaelis, Martin; Schölkens, Bernward; Rudolphi, Karl (April 2007). "An anthology from Naunyn-Schmiedeberg's archives of pharmacology". Naunyn-Schmiedeberg's Archives of Pharmacology. 375 (2). Springer Berlin: 81–84. doi:10.1007/s00210-007-0136-z. PMID 17310263.
  8. ^ a b Morphine and Allied Drugs, AK Reynolds & LO Randall, U of Toronto Press, Toronto 1957, and Oxford University Press (London) No ISBN given in book; pp 273-319
  9. ^ Kaiko, Robert F.; Kathleen M. Foley; Patricia Y. Grabinski; George Heidrich; Ada G. Rogers; Charles E. Inturrisi; Marcus M. Reidenberg (February 1983). "Central Nervous System Excitatory Effects of Meperidine in Cancer Patients". Annals of Neurology. 13 (2). Wiley Interscience: 180–185. doi:10.1002/ana.410130213. PMID 6187275.
  10. ^ Patent Appl. DE 679 281 IG Farben 1937.
  11. ^ http://www.deadiversion.usdoj.gov/fed_regs/quotas/2014/fr0825.htm
  12. ^ "Parenteral opioids for labor pain relief: A systematic review - American Journal of Obstetrics & Gynecology". www.ajog.org. Retrieved 2015-07-11.
  13. ^ "WHO | Parenteral opioids for maternal pain relief in labour". apps.who.int. Retrieved 2015-06-20.
  14. ^ "Pain relief in labour - Pregnancy and baby guide - NHS Choices". www.nhs.uk. Retrieved 2015-06-20.
  15. ^ Blueprints - Family Medicine (3rd edition)
  16. ^ Baselt, R. (2008). Disposition of Toxic Drugs and Chemicals in Man (8 ed.). Foster City, CA: Biomedical Publications. pp. 911-914.
  17. ^ Package insert for meperidine hydrochloride, Boehringer Ingelheim, Ridgefield, CT, 2005.
  18. ^ Brody, Jane (February 27, 2007). "A Mix of Medicines That Can Be Lethal". New York Times. Retrieved 2009-02-13. The death of Libby Zion, an 18-year-old college student, in a New York hospital on March 5, 1984, led to a highly publicized court battle and created a cause célèbre over the lack of supervision of inexperienced and overworked young doctors. But only much later did experts zero in on the preventable disorder that apparently led to Ms. Zion's death: a form of drug poisoning called serotonin syndrome.
  19. ^ Bronwen Bryant; Kathleen Knights (2010). Pharmacology for Health Professionals, 3rd Edition. Chatswood: Mosby Australia. ISBN 978-0-7295-3929-6. {{cite book}}: Unknown parameter |lastauthoramp= ignored (|name-list-style= suggested) (help)
  20. ^ Koczmara, C; Perri, D; Hyland, S; Rousseaux, L (2005). "Meperidine (Demerol®) safety issues" (PDF). Official Journal of the Canadian Association of Critical Care Nurses. 16 (1): 8–12. ISSN 1201-2580. Retrieved 2014-01-11.
  21. ^ Laurence, Brunton (2010). Goodman & Gilman's pharmacological basis of therapeutics (12th ed.). McGraw-Hill. p. 549. ISBN 0071624422.
  22. ^ http://www.fass.se/LIF/produktfakta/artikel_produkt.jsp?NplID=19741206000040&DocTypeID=3&UserTypeID=0
  23. ^ Wagner, Larry E., II; Michael Eaton; Salas S. Sabnis; Kevin J. Gingrich (November 1999). "Meperidine and Lidocaine Block of Recombinant Voltage-Dependent Na+ Channels: Evidence that Meperidine is a Local Anesthetic". Anesthesiology. 91 (5). Lippincott Williams & Wilkins: 1481–1490. doi:10.1097/00000542-199911000-00042. PMID 10551601.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  24. ^ a b c Izenwasser, Sari; Amy Hauck Newman; Brian M. Cox; Jonathan L. Katz (January–February 1996). "The cocaine-like behavioral effects of meperidine are mediated by activity at the dopamine transporter". European Journal of Pharmacology. 297 (1–2). Elsevier: 9–17. doi:10.1016/0014-2999(95)00696-6. PMID 8851160.
  25. ^ Lomenzo, Stacey A.; Jill B. Rhoden; Sari Izzenwasser; Dean Wade; Theresa Kopajtic; Jonathan L. Katz; Mark L. Trudell (2005-03-05). "Synthesis and Biological Evaluation of Meperdine Analogs at Monoamine Transporters". Journal of Medicinal Chemistry. 48 (5). American Chemical Society: 1336–1343. doi:10.1021/jm0401614. PMID 15743177.
  26. ^ a b c d "Demerol: Is It the Best Analgesic?" (PDF), Pennsylvania Patient Safety Reporting Service Patient Safety Advisory, 3 (2), Pennsylvania Patient Safety Authority, June 2006, retrieved 2013-04-15
  27. ^ Davis, Sharon (August 2004). "Use of pethidine for pain management in the emergency department: a position statement of the NSW Therapeutic Advisory Group" (PDF). New South Wales Therapeutic Advisory Group. Retrieved 2007-01-17.
  28. ^ a b c Latta, Kenneth S.; Brian Ginsberg; Robert L. Barkin (January–February 2002). "Meperidine: A Critical Review". American Journal of Therapeutics. 9 (1). Lippincott Williams & Wilkins: 53–68. doi:10.1097/00045391-200201000-00010. PMID 11782820.
  29. ^ "In Brief" (PDF). NPS Radar. National Prescribing Service. December 2005. Retrieved 2009-12-22.
  30. ^ Walker, Diana J.; James P. Zacny (June 1999). "Subjective, Psychomotor, and Physiological Effects of Cumulative Doses of Opioid µ Agonists in Healthy Volunteers". The Journal of Pharmacology and Experimental Therapeutics. 289 (3). American Society for Pharmacology and Experimental Therapeutics: 1454–1464. PMID 10336539.
  31. ^ Molloy, A (2002). "Does pethidine still have a place in therapy?" (PDF). Australian Prescriber. 25 (1). NPS MedicineWise: 12–13.
  32. ^ Gilson AM, Ryan KM, Joranson DE, Dahl JL (2004). "A reassessment of trends in the medical use and abuse of opioid analgesics and implications for diversion control: 1997-2002" (PDF). J Pain Symptom Manage. 28 (2): 176–188. doi:10.1016/j.jpainsymman.2004.01.003. PMID 15276196.
  33. ^ Joranson DE, Gilson AM (2005). "Drug crime is a source of abused pain medications in the United States" (PDF). J Pain Symptom Manage. 30 (4): 299–301. doi:10.1016/j.jpainsymman.2005.09.001. PMID 16256890.
  34. ^ a b Babor T, Campbell R, Room R, Saunders J, eds. (1994). Lexicon of alcohol and drug terms (PDF). Geneva: World Health Organization. ISBN 92-4-154468-6.
  35. ^ http://pubs.acs.org/doi/suppl/10.1021/jm0401614/suppl_file/jm0401614_s.pdf
  36. ^ Lomenzo, S.; Rhoden, J.; Izenwasser, S.; Wade, D.; Kopajtic, T.; Katz, J.; Trudell, M. (2005). "Synthesis and biological evaluation of meperidine analogues at monoamine transporters". Journal of Medicinal Chemistry. 48 (5): 1336–1343. doi:10.1021/jm0401614. PMID 15743177.
  37. ^ Lomenzo, S.; Izenwasser, S.; Gerdes, R. M.; Katz, J. L.; Kopajtic, T.; Trudell, M. L. (1999). "Synthesis, dopamine and serotonin transporter binding affinities of novel analogues of meperidine". Bioorganic & Medicinal Chemistry Letters. 9 (23): 3273–3276. doi:10.1016/S0960-894X(99)00606-X.
  38. ^ Rhoden, J. B.; Bouvet, M.; Izenwasser, S.; Wade, D.; Lomenzo, S. A.; Trudell, M. L. (2005). "Structure-activity studies of 3'-4'-dichloro-meperidine analogues at dopamine and serotonin transporters". Bioorganic & Medicinal Chemistry. 13 (19): 5623–5634. doi:10.1016/j.bmc.2005.05.025. PMID 15993612.
  39. ^ Millan, M. (2009). "Dual- and triple-acting agents for treating core and co-morbid symptoms of major depression: novel concepts, new drugs". Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics. 6 (1): 53–77. doi:10.1016/j.nurt.2008.10.039. PMID 19110199.
  40. ^ Gu, X.; Izenwasser, S.; Wade, D.; Housman, A.; Gulasey, G.; Rhoden, J. B.; Savoie, C. D.; Mobley, D. L.; Lomenzo, S. A.; Trudell, M. L. (2010). "Synthesis and structure–activity studies of benzyl ester meperidine and normeperidine derivatives as selective serotonin transporter ligands". Bioorganic & Medicinal Chemistry. 18 (23): 8356. doi:10.1016/j.bmc.2010.09.060.
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