Pethidine

Pethidine

Systematic (IUPAC) name
Ethyl 1-methyl-4-phenylpiperidine-4-carboxylate
Clinical data
Trade names	Demerol
Pregnancy category	AU: C US: C (Risk not ruled out)
Legal status	AU: S8 (Controlled) CA: Schedule I DE: Anlage III (Prescription only) NZ: Class B UK: Class A US: Schedule II UN: Narcotic Schedule I Class B3 (NZ)
Dependence liability	High
Routes of administration	oral, intravenous, intramuscular, subcutaneous
Pharmacokinetic data
Bioavailability	50–60% (Oral), 80-90% (Oral, in cases of hepatic impairment)
Protein binding	65-75%
Metabolism	Liver
Biological half-life	2.5-4 hours, 7-11 hours (liver disease)
Excretion	Renal
Identifiers
CAS Number	57-42-1 Y
ATC code	N02AB02 (WHO)
PubChem	CID: 4058
IUPHAR/BPS	7221
DrugBank	DB00454 Y
ChemSpider	3918 Y
UNII	9E338QE28F Y
KEGG	D08343 Y
ChEMBL	CHEMBL607 Y
Chemical data
Formula	C15H21NO2
Molecular mass	247.33g/mol
SMILES O=C(C1(CCN(CC1)C)C2=CC=CC=C2)OCC
InChI 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 Y= Key:XADCESSVHJOZHK-UHFFFAOYSA-N Y=
(verify)

Pethidine (INN, AAN, BAN) or meperidine (USAN) was once a popular synthetic opioid analgesic of the phenylpiperidine class. 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.

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 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. These were later discovered to be all myths, and it carried an at least equal risk of addiction, possessed no advantageous effects on biliary spasm or renal colic compared to other opioids, and due to its toxic metabolite, norpethidine, was more toxic than other opioids, especially during long-term use. The norpethidine metabolite was found to have serotonergic effects, so pethidine could, unlike most opioids, contribute to serotonin syndrome.

Medical uses

Pethidine is the most widely used opioid in labour and delivery 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. It is still commonly used in the United Kingdom and New Zealand, and is the preferred opioid in the United Kingdom for use during labour. Pethidine is the preferred painkiller for diverticulitis, because it decreases intestinal intraluminal pressure.

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. 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.

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. 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.

Pethidine is often employed in the treatment of postanesthetic shivering. The pharmacologic mechanism of this antishivering 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– 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.

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. 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.

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); 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

Trends

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 reported lost or stolen in the U.S. increased 16.2% between 2000 and 2003, from 32,447 to 37,687.

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. In WHO usage, the first two terms replace the term "abuse" and the third term replaces the term "addiction".

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

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.

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.

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

See also

• Anileridine
• Carbetidine
• Diphenoxylate
• Furethidine
• Glutethimide
• Ketobemidone
• Methylphenidate
• Morpheridine
• Phenoperidine
• Properidine