Wikipedia

Pethidine

(Redirected fromDemerol)
This article is about the analgesic drug also sold under the trade name Dolantin. For the anticonvulsant sold under the trade name Dilantin, seephenytoin.

Pethidine,also known asmeperidineand sold under the brand nameDemerolamong others, is a fully syntheticopioidpain medicationof thephenylpiperidineclass.[5][6][7][8][9][10]Synthesized in 1938[11]as a potentialanticholinergicagent by the German chemist Otto Eisleb, its analgesic properties were first recognized by Otto Schaumann while working forIG Farben,in Germany.[12]Pethidine is the prototype of a large family of analgesics including the pethidine 4-phenylpiperidines (e.g.,piminodine,anileridine), the prodines (e.g.,alphaprodine,MPPP), bemidones (e.g.,ketobemidone), and others more distant, includingdiphenoxylateand analogues.[13]

Pethidine
Clinical data
Trade namesDemerol, others
Other namesMeperidine (USANUS)
Pregnancy
category
  • AU:C
Dependence
liability		High
Addiction
liability		High[1]
Routes of
administration		By mouth,intravenous,intramuscular,intrathecal,[2]subcutaneous,epidural[3]
Drug classOpioid
ATC code
Legal status
Legal status
Pharmacokineticdata
Bioavailability50–60% (Oral), 80–90% (Oral, in cases of hepatic impairment)
Protein binding65–75%
MetabolismLiver:CYP2B6,CYP3A4,CYP2C19,Carboxylesterase 1
Metabolites•Norpethidine
•Pethidinic Acid
• others
Eliminationhalf-life2.5–4 hours, 7–11 hours (liver disease)
ExcretionRenal
Identifiers
  • Ethyl 1-methyl-4-phenylpiperidine-4-carboxylate
CAS Number
PubChemCID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard(EPA)
ECHA InfoCard100.000.299Edit this at Wikidata
Chemical and physical data
FormulaC15H21NO2
Molar mass247.338g·mol−1
3D model (JSmol)
  • CCOC(=O)C1(c2ccccc2)CCN(C)CC1
  • 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,3,9-12H2,1-2H3checkY
  • Key:XADCESSVHJOZHK-UHFFFAOYSA-NcheckY
(verify)

Pethidine is indicated for the treatment of moderate to severe pain, and is delivered as ahydrochloridesalt in tablets, as a syrup, or byintramuscular,subcutaneous,orintravenous 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.[14]

It was patented in 1937 and approved for medical use in 1943.[15]Compared withmorphine,pethidine was considered to be safer, carry a lower risk of addiction, and to be superior in treating the pain associated withbiliary spasmorrenal colicdue to its assumedanticholinergiceffects.[7]These were later discovered to be inaccurate assumptions, as it carries an equal risk of addiction, possesses no advantageous effects on biliary spasm or renal colic compared to other opioids. Due to theneurotoxicityof its metabolite,norpethidine,it is more toxic than other opioids—especially during long-term use.[7]The norpethidine metabolite was found to haveserotonergiceffects, so pethidine could, unlike most opioids, increase the risk of triggeringserotonin syndrome.[7][8]

Medical uses

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Pethidine is the most widely used opioid in labour and delivery.[16]It 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.[10]It is still commonly used in the United Kingdom and New Zealand,[17]and was the preferred opioid in the United Kingdom for use during labour, but has been superseded somewhat by other strong semi-synthetic opioids (e.g.hydromorphone) to avoid serotonin interactions since the mid-2000s.[18]

Pethidine is the preferred painkiller fordiverticulitis,because it decreases intestinal intraluminal pressure.[19]Pethidine is the preferred drug for the management of shivering duringtherapeutic hypothermia,as it provides the greatest reduction in the shivering threshold.[20]

Before 2003, it was on theWorld Health Organization's List of Essential Medicines,the most effective and safe medicines needed in a health system.[21][22]

Adverse effects

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The adverse effects of pethidine administration are primarily those of the opioids as a class: nausea, vomiting, dizziness, diaphoresis, urinary retention, and constipation. Due to moderate stimulant effects mediated by pethidine's dopamine and norepinephrine reuptake inhibition, sedation is less likely compared to other opioids. Unlike other opioids, it does not causemiosisbecause of its anticholinergic properties. Overdose can cause muscle flaccidity, respiratory depression,obtundation,psychosis,cold and clammy skin, hypotension, and coma.[23][24]

A narcotic antagonist such asnaloxoneis indicated to reverse respiratory depression and other effects of pethidine.Serotonin syndromehas occurred in patients receiving concurrent antidepressant therapy withselective serotonin reuptake inhibitors(SSRIs) ormonoamine oxidase inhibitors,or other medication types (see Interactions below). Convulsive seizures sometimes observed in patients receiving parenteral pethidine on a chronic basis have been attributed to accumulation in plasma of the metabolite norpethidine (normeperidine). Fatalities have occurred following either oral or intravenous pethidine overdose.[25][26]

Interactions

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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/orhyperthermia.Fatal interactions have been reported including the death ofLibby Zion.[27]

Seizures may develop whentramadolis given intravenously following, or with, pethidine.[28]It can interact as well withSSRIsand otherantidepressants,antiparkinson agents, migraine therapy,stimulantsand other agents causingserotonin syndrome.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,benzodiazepines,andethanol.

Mechanism of action

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Main article:Opioid

Likemorphine,pethidine exerts its analgesic effects by acting as anagonistat theμ-opioid receptor.[29]

Pethidine is often employed in the treatment of postanesthetic shivering. The pharmacologic mechanism of this antishivering effect is not fully understood,[30]but it may involve the stimulation ofκ-opioid receptors.[31]

Pethidine has structural similarities toatropineand othertropane alkaloidsand may have some of their effects and side effects.[32]In addition to these opioidergic and anticholinergic effects, it haslocal anestheticactivity related to its interactions withsodium ion channels.

Pethidine's apparentin vitroefficacy as an antispasmodic agent is due to its local anesthetic effects. It does not have antispasmodic effectsin vivo.[33]Pethidine also has stimulant effects mediated by its inhibition of thedopamine transporter(DAT) andnorepinephrine transporter(NET). Because of its DAT inhibitory action, pethidine will substitute for cocaine in animals trained to discriminate cocaine from saline.[34]

Severalanalogsof pethidine such as4-fluoropethidinehave been synthesized that are potent inhibitors of the reuptake of themonoamine neurotransmittersdopamine andnorepinephrinevia DAT and NET.[35][36]It has also been associated with cases ofserotonin syndrome,suggesting some interaction withserotonergic neurons,but the relationship has not been definitively demonstrated.[34][36][37][38]

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,orhydromorphoneat easing severe pain, or pain associated with movement or coughing.[34][36][38]

Like other opioid drugs, pethidine has the potential to causephysical dependenceoraddiction.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.[36][38]

Pharmacokinetics

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Pethidine is quickly hydrolysed in the liver topethidinic acidand is also demethylated to norpethidine, which has half the analgesic activity of pethidine but a longer elimination half-life (8–12 hours);[39]accumulating with regular administration, or inkidney 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 withglucuronic acidand excreted into the urine.

Recreational use

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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 forfentanyl,hydromorphone, morphine, and oxycodone.[40]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.[41]

This article uses the terms "hazardous use", "harmful use", and "dependence" in accordance withLexicon of alcohol and drug[42]terms, published by theWorld Health Organization(WHO) in 1994.[43]In WHO usage, the first two terms replace the term "abuse" and the third term replaces the term "addiction".[43][34]

Synthesis

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Pethidine can be produced in a two-step synthesis. The first step is reaction ofbenzyl cyanideandchlormethinein the presence ofsodium amideto form apiperidinering. Thenitrileis then converted to anester.[44]

Pethidine synthesis

Control

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Pethidine is inSchedule II of the Controlled Substances Act 1970of 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 Cintermediatesin production of pethidine are also controlled, with ACSCN being9232for A (with a 6 gram quota) and9233being B (quota of 11 grams) and9234being C (6 gram quota).[45]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.

Society and culture

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In John D. MacDonalds 's book "Dress Her in Indigo" (1969) one of the protagonists speaks of thinking of killing an immobilized enemy of hers by injecting him with meperedine which was left over from a husband who used it while terminally ill.

InRaymond Chandler's novelThe Long Goodbye(1953), in response to "How is Mrs. Wade?", police Lieutenant Bernie Ohls answers, "Too relaxed. She must have grabbed some pills. There's a dozen kinds up there -- even demerol. That's bad stuff."

Harold Shipmanwas addicted to pethidine at one stage, convicted of forging prescriptions to obtain it, fined £500 and briefly attended a drug rehabilitation clinic.[46][47]

Danish writerTove Ditlevsensuffered a lifelong addiction to pethidine after her husband, a doctor, had injected her with Demerol as a painkiller for an illegal abortion in 1944.[48]

Pethidine is referenced by its brand name Demerol in the song "Morphine" by singerMichael Jacksonon his 1997 albumBlood on the Dance Floor: HIStory in the Mix.[49]Pethidine was one of several prescription drugs which Michael Jackson was addicted to at the time and the singer describes this in the lyrics of the song with phrases such as "Relax/This won't hurt you" and "Yesterday you had his trust/Today he's taking twice as much".[50]

Pethidine is referenced in the television showBroadchurch,season 2, episode 3, as it was given to the character Beth after she has her baby.

In the 1987Malayalammovie,Amrutham Gamaya,Mohanlal's character, Dr. P.K. Haridas injects pethidine in himself and gets addicted to it.

A doctor in the TV showCall the Midwifebecomes addicted to pethidine.[51]

InWilliam Gibson's bookNeuromancer,one of the characters say ' "A mixture of cocaine and meperidine, yes." The Armenian went back to the conversation he was having with the Sanyo. "Demerol, they used to call that," said the Finn.'[52]

South Carolina-based modern rock groupCrossfadementions Demerol in the lyrics of their 2004 song, "Dead Skin".

In Korean dramaPunch (TV series),main character Park Jung-hwan is illegally given Demerol by his doctor in exchange for legal counseling.

In the episode "The Fight"of the TV showParks and Recreation,some characters become intoxicated on a mixed drink called Snake Juice. The character Ann (Rashida Jones), who is a nurse, asks, "What the hell is in Snake Juice? Demerol?"

InDavid Foster Wallace's bookInfinite Jest,one of the main characters, Don Gately, is a Demerol addict in recovery.

See also

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References

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