Pethidine

Pethidine

Systematic (IUPAC) name
Ethyl 1-methyl-4-phenylpiperidine-4-carboxylate
Identifiers
CAS number	57-42-1
ATC code	N02AB02
PubChem	CID 4058
DrugBank	APRD00074
ChemSpider	3918
Chemical data
Formula	C15H21NO2
Mol. mass	247.33
SMILES	eMolecules & PubChem
Pharmacokinetic data
Bioavailability	50–60%
Protein binding	65–75%
Metabolism	Liver
Half-life	3–5 hours
Excretion	Renal
Therapeutic considerations
Pregnancy cat.	C(AU) C(US)
Legal status	Controlled (S8) (AU) ? (UK) Schedule II (US)
Routes	oral, IV, IM, insufflated, rectal
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Pethidine (INN) or meperidine (USAN) (commonly referred to as Demerol but also referred to as: isonipecaine; lidol; pethanol; piridosal; Algil; Alodan; Centralgin; Dispadol; Dolantin; Mialgin (in Romania); Petidin Dolargan (in Poland);^[1] Dolestine; Dolosal; Dolsin; Mefedina) 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.^[2]

Pethidine was the first synthetic opioid synthesized in 1932 as a potential anti-spasmodic 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 its hydrochloride salt in tablets, as a syrup, or by intramuscular or intravenous injection. For much of the 20th 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.^[4]

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 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.

Pharmacodynamics/mechanism of action

Pethidine's efficacy as an analgesic was discovered almost accidentally; it was synthesized in 1939 at an IG Farben laboratory as an antimuscarinic agent.^[7] Pethidine also has structural similarities to atropine and other tropane alkaloids and may have some of their effects and side effects.[1] Pethidine exerts its analgesic effects by the same mechanism as morphine, by acting as an agonist at the μ-opioid receptor. In addition to its strong 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" is due to its local anesthetic effects. It does not, contrary to popular belief, have antispasmodic effects in vivo.^[8] Pethidine also has stimulant effects mediated by its inhibition of the dopamine transporter (DAT) and norepinephrine transporter (NAT). Because of its DAT inhibitory action, pethidine will substitute for cocaine in animals trained to discriminate cocaine from saline.^[9]

Several analogues of pethidine have been synthesized that are potent inhibitors of the reuptake of the monoamine neurotransmitters dopamine and norepinephrine via DAT and NAT.^[10][11] 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][7][9][11]} 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 in 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.^[7][9][11]

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.^[12] 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.^[13] 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.^[7][14]); 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.

Interactions

Pethidine has serious interactions that can be dangerous with MAOIs (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.^[15] 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 antidepressants, benzodiazepines, and alcohol.

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 hypothyroidism, asthma, or Addison's disease.

Adverse effects

The adverse effects of pethidine administration are primarily those of the opioids as a class: nausea, vomiting, sedation, dizziness, diaphoresis, miosis, urinary retention and constipation. Overdosage can cause muscle flaccidity, respiratory depression, obtundedness, 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 serotonon 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.^{[16] [17]}

Hazardous use, 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.^[18] 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.^[19]

Notes

References