Pethidine elimination

The biotransformation of the phenylpiperidines is primarily by hepatic phase I metabolism, catalysed by cytochrome P-450 isoenzymes. The elimination of alfentanil is significantly slowed in patients treated with erythromycin, a P-450 inhibitor, with delayed recovery and prolonged postoperative respiratory depression (Bartkowski and McDonnell 1990). Apart from pethidine and phenoperidine, none of the phenylpiperidines has pharmacologically active metabolites. 

Two main effects occur here. First, change in the pH of urine—weak bases, such as pethidine, are more easily excreted in an acid urine while alkalinisation promotes excretion of weak acids, such as salicylates and phenobarbital. Second, drugs that compete for an active excretion mechanism will reduce each other s elimination—probenecid was used in the early days of penicillin to conserve the drug, while less desirable interactions also occur, e.g. chlorpropamide and phenylbutazone interact to give increased levels of chlorpropamide and a danger of hypoglycaemia. 

Pharmacokinetic properties Pethidine (Mather and Meffin, 1978) has a faster onset and a shorter duration of action than morphine. After oral administration about 50% of the drug is eliminated by first-pass metabolism. N-demethylation yields the active metabolite nor-pethidine, and hydrolytic cleavage the inactive metabolites pethidinic and nor-pethidinic acid. The half-life of pethidine is about 3- 6 h. Nor-pethidine has a much slower elimination with a half life of up to 20 h. 

Norpethidine, a metabolite of pethidine, can cause tremor and seizures. The risk increases following repeated doses, owing to accumulation of the metabolite (longer half-life than pethidine) and resulting high plasma concentrations. Although patients with cirrhosis may have impaired formation of norpethidine, they may still be at increased risk of cumulative toxicity because of the slower elimination of the metabolite and their increased sensitivity to the effects of opioids [57]. 

GC-MS methods provide greater specificity and in many cases sensitivity when compared with more conventional techniques. They offer increased scope for the study of pharmacokinetics and of plasma concentration in relation to biological effect. SIM assay has been applied to the investigation of placental transfer of lipid soluble drugs and their subsequent elimination in the newborn (barbiturates, diphenylhydantoin, caffeine, pethidine and diazepam [122,408] diphenylhydantoin [411] amylobarbitone and 3 -hydroxyamylobarbitone [83,423]). 

Hepatic metabolism increases, though not blood flow to the liver. Consequently, there is increased clearance of drugs such as phenytoin and theophylline, whose elimination rate depends on liver enzyme activity. Drugs that are so rapidly metabolised that their elimination rate depends on their delivery to the liver, i.e. on hepatic blood flow, have unaltered clearance, e.g. pethidine. 

Renal insufficiency can result in clinically significant accumulation of pharmacologically active opioid metabolites and prolonged narcosis such patients must be monitored for signs of toxicity (SEDA-17, 79) (SEDA-21, 85) (98,99). To date, this effect has only been reported with codeine, morphine, and pethidine. Dextropropoxyphene is not recommended in renal insufficiency, as its metabolite norpropoxyphene, which is eliminated by the kidneys, accumulates, causing cardiac depression (SEDA-17, 79) (SEDA-21, 85). 

Another anomaly was described earlier where the pethidine analogue containing a cinnamic acid residue is 30 times more active than pethidine itself, whereas the same group on morphine eliminates activity. Such results strongly suggest that a simple one-receptor theory is not applicable. 

It is known that phenytoin increases the metabolism of pethidine with increased production of norpethidine, the metabolic product of pethidine that is believed to be responsible for its neurotoxicity (seizures, myoclonus, tremors etc). A study in healthy subjects found that phenytoin 300 mg daily for 9 days decreased the elimination half-life of pethidine (100 mg orally and 50 mg intravenously) from 6.4 to 4.3 hours, and the systemic clearance increased by 27%. This seems to be the only report of an adverse interaction between phenytoin and pethidine so its general importance is uncertain. Since the study cited found that pethidine given orally produced more of the toxic metabolite (norpethidine) than when given intravenously, it may be preferable to give pethidine intravenously in patients taking phenytoin, or use an alternative opioid. 

Pethidine, the active ingredient in the narcotic analgesic Demerol, was subjected to two successive exhaustive methylation-Hofmann elimination sequences, followed by ozonolysis, with the following results ... 

The dissociation behavior of the protonated molecule of pethidine (Fig. 4.3,4) was significantly different and yielded less but still informative product ions that characterize the synthetic opioid (Fig. 4.4b). ° The precursor ion at m/z 248 was predominantly de-esterified by the elimination of ethylene (-28 Da) to yield the ion at m/z 220, which subsequently released carbon dioxide ( 4 Da) or water (-18 Da) and carbon monoxide (-28 Da) to produce m/z 176 and 174, respectively. The consecutive losses resulting in the product ion at m/z 174 were... 

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