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 norpethidines anticholinergic activity probably due to its structural similarity to atropine, though its pharmacology has not been thoroughly explored. The neurotoxicity of pethidines metabolites is a unique feature of pethidine compared to other opioids. Pethidines 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". Synthesis
Pethidine can be produced in a two-step synthesis. The first step is reaction of benzyl cyanide and chlormethine in the presence of sodium amide to form a piperidine ring. The nitrile is then converted to an ester. Control
Pethidine is in Schedule II of the Controlled Substances Act 1970 of the United States as a Narcotic with ACSCN 9230 with a 6250 kilo aggregate manufacturing quota as of 2014.
Serotonin syndrome has occurred in patients receiving concurrent antidepressant therapy with selective serotonin reuptake inhibitors (SSRIs) or monoamine oxidase inhibitors, or other medication types (see Interactions below). Convulsive seizures sometimes observed in patients receiving parenteral pethidine on a chronic basis have been attributed to accumulation 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. Seizures may develop when tramadol is given intravenously following, or with, pethidine. It can interact as well with SSRIs and other antidepressants, antiparkinson agents, migraine therapy, stimulants and other agents causing serotonin syndrome. 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, benzodiazepines, and ethanol. Mechanism of action
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.