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| {{Drugbox|
| | #REDIRECT [[Meperidine]] |
| | IUPAC_name = Ethyl-1-methyl-4-phenylpiperidine-4-carboxylate
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| | image = Pethidine-2D-skeletal.png
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| | width = 200px
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| | CAS_number = 57-42-1
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| | ATC_prefix = N02
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| | ATC_suffix = AB02
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| | PubChem = 4058
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| | DrugBank = APRD00074
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| | C=15 | H=21 | N=1 | O=2
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| | molecular_weight = 247.33
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| | bioavailability = 50-60%
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| | protein_bound = 65-75%
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| | metabolism = [[Liver]]
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| | elimination_half-life = 3-5 hours
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| | excretion = [[Renal]]
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| | pregnancy_AU = C
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| | pregnancy_US = C
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| | legal_AU = S8
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| | legal_UK = Class A
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| | legal_US = Schedule II
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| | legal_status =
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| | Dependence liability = High
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| | routes_of_administration = oral, [[intravenous|IV]], [[intramuscular|IM]]
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| }}
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| '''Pethidine''' ([[International Nonproprietary Name|INN]]) or '''meperidine''' ([[United States Adopted Name|USAN]]) (also referred to as: isonipecaine; lidol; pethanol; piridosal; Algil<sup>®</sup>; Alodan<sup>®</sup>; Centralgin<sup>®</sup>; Demerol<sup>®</sup>; Dispadol<sup>®</sup>; Dolantin<sup>®</sup>; Petidin<sup>®</sup> Dolargan<sup>®</sup> (in [[Poland]]);<ref name="dolarganpl">
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| {{cite web | title = Lekopedia - Dolargan | publisher =jestemchory.pl | url=http://www.jestemchory.pl/lek.via?id=99824&str=19&l=d&r=h&VSID=4c69dc1b3a23b828e497dea2157f0263 |accessdate=2006-08-01}}</ref>
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| Dolestine<sup>®</sup>; Dolosal<sup>®</sup>; Dolsin<sup>®</sup>; Mefedina<sup>®</sup>) is a fast-acting [[opioid]] [[analgesic]] drug. In the United States and Canada, it is more commonly known as meperidine or by its brand name Demerol.<ref>[http://www.rxlist.com/drugs/search.aspx?query=DEMEROL Demerol] RxList. Retrieved 19 Jun. 2006.</ref>
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| Pethidine is indicated for the treatment of moderate to severe [[Pain and nociception|pain]], and is delivered as its [[hydrochloride]] salt in tablets, as a syrup, or by [[intramuscular]] or [[intravenous injection]]. For much of the 20<sup>th</sup> century, pethidine was the opioid of choice for many physicians; in 1983 60% of doctors prescribed it for acute pain and 22% for chronic severe pain.<ref name="Kaiko">{{cite journal | last = Kaiko | first = Robert F. | coauthors = Kathleen M. Foley, Patricia Y. Grabinski, George Heidrich, Ada G. Rogers, Charles E. Inturrisi, Marcus M. Reidenberg | title = Central Nervous System Excitatory Effects of Meperidine in Cancer Patients | journal = Annals of Neurology | volume = 13 | issue = 2 | pages = 180-185 | publisher = Wiley Interscience | date = February 1983 | id = ISSN: 0364-5134}}</ref> Compared to morphine, pethidine was supposed to be safer and carry less risk of addiction, and to be superior in treating the pain associated with [[Gallstone|biliary spasm]] or [[renal colic]] due to its putative antispasmodic effects. In fact, pethidine is no more effective than morphine at treating biliary or renal pain, and its low potency, short duration of action, and unique toxicity (i.e. seizures, delirium, other neuropsychological effects) relative to other available opioid analgesics have seen it fall out of favor in recent years, for all but a very few, very specific indications.<ref name="Wong">{{Cite web|url=http://www.mosbysdrugconsult.com/WOW/op024.html|title=Notes on Meperidine|accessdate=2007-04-13|publisher=Elsevier|year=2002-03-15|author=Donna Wong|work=Wong on Web Papers}}</ref> Several countries, including [[Australia]], have put severe limits on its use or curtailed it outright.<ref name="nsw">{{cite web|url=www.clininfo.health.nsw.gov.au/nswtag/publications/posstats/Pethidinefinal.pdf |title=Use of pethidine for pain management in the emergency department: a position statement of the NSW Therapeutic Advisory Group |accessdate=2007-01-17 |last=Davis |first=Sharon |date=August 2004 |format=PDF |publisher=New South Wales Therapeutic Advisory Group }}</ref> Nevertheless, some physicians continue to use it as a first-line strong opioid.
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| ==Pharmacodynamics/Mechanism of Action==
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| {{main|Opioid}}
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| Pethidine's efficacy as an analgesic was discovered almost accidentally; it was synthesized in 1939 as an [[anticholinergic|antimuscarinic]] agent.<ref name = "Latta">{{cite journal | last = Latta | first = Kenneth S. | coauthors = Brian Ginsberg, Robert L. Barkin | title = Meperidine: A Critical Review | journal = American Journal of Therapeutics | volume = 9 | issue = 1 | pages = 53-68 | publisher = Lippincott Williams & Wilkins | date = January/February 2002 | id = ISSN: 1075-2765
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| }}</ref> Pethidine also has structural similarities to [[atropine]] and other tropane [[alkaloids]] and may have some of their effects and side effects.[http://www.fass.se/LIF/produktfakta/artikel_produkt.jsp?NplID=19741206000040&DocTypeID=3&UserTypeID=0] Pethidine exerts its analgesic effects by the same mechanism as [[morphine]], by acting as an [[agonist]] at the [[Opioid receptor|μ-opioid receptor]]. In addition to its strong opiodergic and anticholinergic effects, it has [[local anesthetic]] activity related to its interactions with [[sodium ion channel]]s. Pethidine's apparent ''[[in vitro]]'' efficacy as an "[[antispasmodic]]" is due to its local anesthetic effects. It does not, contrary to popular belief, have antispasmodic effects ''[[in vivo]]''.<ref>{{cite journal | last = Wagner | first = Larry E., II | coauthors = Michael Eaton, Salas S. Sabnis, Kevin J. Gingrich | title = Meperidine and Lidocaine Block of Recombinant Voltage-Dependent Na<sup>+</sup> Channels: Evidence that Meperidine is a Local Anesthetic | journal = Anesthesiology | volume = 91 | issue = 5 | pages = 1481-1490 | publisher = Lippincott Williams & Wilkins | date = November 1999 | id = ISSN: 0003-3022}}</ref> Pethidine also has stimulant effects mediated by its inhibition of the [[dopamine]] [[Dopamine transporter|transporter (DAT)]] and [[norepinephrine]] [[Norepinephrine transporter|transporter (NAT)]]. Because of its DAT inhibitory action, pethidine will substitute for cocaine in animals trained to discriminate cocaine from saline.<ref name="izenwasser">{{cite journal | last = Izenwasser | first = Sari | coauthors = Amy Hauck Newman, Brian M. Cox, Jonathan L. Katz | title = The cocaine-like behavioral effects of meperidine are mediated by activity at the dopamine transporter | journal = European Journal of Pharmacology | volume = 297 | issue = 1-2 | pages = 9-17 | publisher = Elsevier | date = January/February 1996 | doi = 10.1016/0014-2999(95)00696-6 | id = ISSN: 0014-2999}}</ref> Several analogues of pethidine have been synthesized that are potent inhibitors of the reuptake of the [[monoamine neurotransmitter]]s dopamine and [[norepinephrine]] via DAT and NAT.<ref>{{cite journal | last = Lomenzo | first = Stacey A. | coauthors = Jill B. Rhoden, Sari Izzenwasser, Dean Wade, Theresa Kopajtic, Jonathan L. Katz, Mark L. Trudell | title = Synthesis and Biological Evaluation of Meperdine Analogs at Monoamine Transporters | journal = Journal of Medicinal Chemistry | volume = 48 | issue = 5 | pages = 1336-1343 | publisher = American Chemical Society | date = [[2005-03-05]] | id = ISSN: 0022-2623}}</ref><ref name="psrs">{{cite journal | title = Demerol: Is It the Best Analgesic? | journal = Pennsylvania Patient Safety Reporting Service Patient Safety Advisory | volume = 3 | issue = 2 | publisher = Pennsylvania Patient Safety Authority | date = June 2006 | url = http://www.psa.state.pa.us/psa/lib/psa/advisories/v3n2june2006/junevol_3_no_2_article_g_demerol.pdf | accessdate = 2007-01-16}}</ref> It has also been associated with cases of [[serotonin syndrome]], suggesting some interaction with [[Serotonin|serotonergic neurons]], but the relationship has not been definitively demonstrated.<ref name="nsw"/><ref name="Latta"/><ref name="izenwasser"/><ref name="psrs"/> It is more lipid-soluble than morphine, resulting in a faster onset of action. Its duration of clinical effect is 120-150 minutes. Despite producing analgesia for 2-3 hours at most, pethidine is typically administered at 4-6 hour intervals, so that the patient spends at least an hour (and up to four hours) between doses without any analgesia, resulting in much unnecessary pain and suffering. In addition, pethidine has been shown to be less effective than morphine or [[hydromorphone]] at easing severe pain, or pain associated with movement or coughing.<ref name="Latta"/><ref name="izenwasser"/><ref name="psrs"/> Like other opioid drugs, pethidine has the potential to cause [[physical dependence]] or [[addiction]]. In fact, pethidine may be more addictive than other opioids because of its exceptionally rapid onset of action and associated "rush", and additional activity as a monoamine transporter inhibitor, which results in cocaine-like stimulant effects in addition to its typical opioid effects.<ref>{{cite web|url=http://www.npsradar.org.au/site.php?page=1&content=/npsradar/content/latestnews.html |title=In Brief |accessdate=2007-01-17 |coauthors= |date=December 2005 |work=NPS Radar |publisher=National Prescribing Service }}</ref> 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.<ref>{{cite journal | last = Walker | first = Diana J. | coauthors = James P. Zacny | title = Subjective, Psychomotor, and Physiological Effects of Cumulative Doses of Opioid µ Agonists in Healthy Volunteers | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 289 | issue = 3 | pages = 1454-1464 | publisher = American Society for Pharmacology and Experimental Therapeutics | date = June 1999}}</ref> 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]].<ref name="Latta"/><ref name="psrs"/>
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| ==Pharmacokinetics==
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| [[Image:Pethidine DOJ.jpg|frame|right]]
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| Pethidine is quickly hydrolysed in the liver to [[Pethidinic Acid|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<ref>Norpethedine half-life. 2002. Australian prescriber[http://www.australianprescriber.com/magazine/25/1/12/3/]</ref>); 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 antagonist]]s 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.
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| [[Image:Metabolism_of_pethidine.png|600px]]
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| ==Interactions==
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| Pethidine has serious interactions that can be dangerous with [[MAOI]]s (e.g. furazolidone, isocarboxazid, moclobemide, phenelzine, procarbazine, selegiline, tranylcypromine, and sibutramine). Such patients may suffer agitation, delirium, headache, convulsions, and/or [[hyperthermia]]. Fatal interactions have been reported. It is thought to be caused by an increase in cerebral serotonin concentrations. It is possible that Pethidine can also interact with a number of other medications, including muscle relaxants, some [[antidepressant]]s, [[benzodiazepine]]s, and [[alcohol]].
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| Pethidine is also relatively contraindicated for use when a patient is suffering from [[liver]], or [[kidney]] [[disease]], has a history of seizures or [[epilepsy]], has an enlarged [[prostate]] or urinary retention problems, or suffers from [[hyperthyroidism]], [[asthma]], or [[Addison's disease]].
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| ==Adverse effects==
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| {{Main|Opioid}}
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| In addition to the [[Adverse effect (medicine)|adverse effects]] common to all opioids, such as [[constipation]], dry mouth, lightheadedness, twitchiness, muscular twitches, and [[nausea]], the repeated administration of pethidine can lead to neurotoxic effects. Pethidine should ideally NOT be administered by the intravenous route as there is a serious risk of triggering histamine release.
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| == References ==
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| <references />
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| {{Analgesics}}
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| [[de:Pethidin]]
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| [[es:Meperidina]]
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| [[gl:Meperidina]]
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| [[nl:Pethidine]]
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| [[pt:Petidina]]
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| [[simple:Pethidine]]
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| [[th:เพทิดีน]]
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| [[zh:哌替啶]]
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| [[Category:Opioids]]
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| [[Category:Piperidines]]
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| [[Category:Drugs]]
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| [[tr:Petidin]]
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