Pethidine - Pharmacodynamics/mechanism of Action

Pharmacodynamics/mechanism of Action

Like morphine, pethidine exerts its analgesic effects by acting as an agonist at the mu opioid receptor. It also has a kappa opioid receptor action, which is of unknown clinical significance. It 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" 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 (NAT). Because of its DAT inhibitory action, pethidine will substitute for cocaine in animals trained to discriminate cocaine from saline.

Several analogues of pethidine 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 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. It is also used for the treatment of postanesthetic shivering.

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.