Pethidine

Pethidine

Systematic (IUPAC) name
Ethyl 1-methyl-4-phenylpiperidine-4-carboxylate
Clinical data
Trade names	Demerol
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
Pharmacokinetic data
Bioavailability	50–60% (Oral), 80-90% (Oral, in cases of hepatic impairment)
Protein binding	65-75%
Metabolism	Liver
Half-life	2.5-4 hours, 7-11 hours (liver disease)
Excretion	Renal
Identifiers
CAS number	57-42-1 Y
ATC code	N02AB02
PubChem	CID 4058
DrugBank	DB00454
ChemSpider	3918 Y
UNII	9E338QE28F Y
KEGG	D08343 Y
ChEMBL	CHEMBL607 Y
Chemical data
Formula	C15H21NO2
Mol. 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=
Y (what is this?)  (verify)

Pethidine (INN, BAN) or meperidine hydrochloride (USAN) (commonly referred to as Demerol in the US^[1] but also referred to as: isonipecaine; lidol; pethanol; piridosal; Algil; Alodan; Centralgin; Dispadol; Dolantin; Mialgin (in Indonesia); Petidin Dolargan (in Poland);^[2] Dolestine; Dolosal; Dolsin; Mefedina is a fast-acting opioid analgesic drug.

Pethidine was the first synthetic opioid synthesized in 1932 as a potential antispasmodic agent by the chemist Otto Eislib. Its analgesic properties were first recognized by Otto Schaumann working for IG Farben, Germany.^[3]

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.^[4]

Compared to morphine, pethidine was thought to be safer and carry less risk of addiction, and to be superior in treating the pain associated with 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.^[5] Several countries, including Australia, have put strict limits on its use.^[6] Nevertheless, some physicians continue to use it as a first line strong opioid.

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. 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.^[7][8]

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.^[9] 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

Like morphine, pethidine exerts its analgesic effects by acting as an agonist at the μ-opioid receptor.^[10]

Pethidine is often employed in the treatment of postanesthetic shivering. The pharmacologic mechanism of this anti-shivering effect is not fully understood,^[11] but it may involve the stimulation of κ-opioid receptors.^[12]

Pethidine has structural similarities to atropine and other tropane alkaloids and may have some of their effects and side effects.^[13] 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.^[14] 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.^[15]

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.^[16][17] It has also been associated with cases of serotonin syndrome, suggesting some interaction with serotonergic neurons, but the relationship has not been definitively demonstrated.^{[6][15][17][18]}

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.^[15][17][18]

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.^[19] 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.^[20] 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.^[17][18]

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^[21]); 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.

Harmful use, dependence, and diversion

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.^[22] 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.^[23]

Notes

The first QSAR focused on exploring how changing the nature of the aromatic substituents alters monoamine reuptake inhibitor affinities.^[26][27]

Pethidine

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.)^[28]

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.

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.^[29]

References