|Systematic (IUPAC) name|
|Pregnancy cat.||C (AU) C (US)|
|Legal status||Controlled (S8) (AU) Schedule I (CA) Class A (UK) Schedule II (US) Class B3 (NZ)|
|Routes||oral, intravenous, intramuscular, subcutaneous|
|Bioavailability||50–60% (Oral), 80-90% (Oral, in cases of hepatic impairment)|
|Half-life||2.5-4 hours, 7-11 hours (liver disease)|
|(what is this?)|
Pethidine (INN, AAN, BAN) or meperidine (USAN) is a once popular synthetic opioid analgesic of the phenylpiperidine class. Synthesized in 1939 as a potential anticholinergic agent by the German chemist Otto Eislib, its analgesic properties were first recognized by Otto Schaumann while working for IG Farben, Germany.
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.
Compared to 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. It was later discovered that these were all myths and that it carried an at least equal risk of addiction, possessed no advantageous effects on biliary spasm or renal colic compared to other opioids and that, due to its toxic metabolite, norpethidine, it was more toxic than other opioids, especially during long-term use. It was also discovered that the norpethidine metabolite had serotonergic effects which means that pethidine could, unlike most opioids, contribute to serotonin syndrome.
Pethidine was once widely used as an analgesic in labour and delivery, but is now seldom used for this indication due to its numerous disadvantages over other opioids, namely, its potential drug interactions (especially with serotonergics) and its neurotoxic metabolite, norpethidine.
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. Overdosage 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. 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 overdosage.
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. 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
Pethidine is often employed in the treatment of postanesthetic shivering. The pharmacologic mechanism of this anti-shivering effect is not fully understood, but it may involve the stimulation of κ-opioid receptors.
Pethidine has structural similarities to atropine and other tropane alkaloids and may have some of their effects and side effects. 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. 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.
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. It has also been associated with cases of serotonin syndrome, suggesting some interaction with serotonergic neurons, but the relationship has not been definitively demonstrated.
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 4–6 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.
Like other opioid drugs, pethidine has the potential to cause physical dependence or addiction. Pethidine may be more likely to be abused than other prescription opioids, perhaps because of its rapid onset of action. 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. 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.
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); 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.
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. The number of dosage units of pethidine that were reported lost or stolen in the U.S. increased 16.2% between 2000 and 2003, from 32,447 to 37,687.
|Nitrile Precursors → Pethidine/Analogs Ki & IC50, μM|
|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.
(J. Rhoden et, al.)
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.
|R||CFT nM||Para nM||Ratio|
The N-demethyl metabolite of meperidine is toxic and accumulates upon repeat dosing.
Also, the ester in meperidine is readily hydrolyzed.
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