Pethidine metabolite

Gas Chromatographic Determination of Pethidine Metabolites in Urine Igaku To Seibutsugaku 75(1) 9-11 (1967) CA 68 84845u... 

Szeto HH, Inturrisi CE, Houde R, Saal S, Cheigh J and Reidenberg M (1977). Accumulation of norperidine, an active metabolite of meperidine [pethidine], in patients with renal failure or cancer. Annals of Internal Medicine, 86, 738-741. 

A similar toxic outcome can occur with pethidine in renal impairment - again not mediated through the parent drug but through a more water-soluble metabolite, nor-pethidine, which has pro-convulsant properties and may produce fits. 

Pethidine is metabolized chiefly in the liver, to mainly meperidinic acid and minor metabolite norpethidine, which are conju-... 

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. 

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. 

Tolmetin, an anti-inflammatory drug, and its metabolites were chromatographed after esterification of the carboxyl group with diazomethane [564], The extraction was performed with diethyl ether and was followed by purification and analysis on 3% of OV-17. The determination of pethidine in plasma [565] involves extraction, purification of the extract by partition chromatography and derivatization, which is performed by treatment with trichloroethyl formate in the presence of anhydrous sodium carbonate. The detection limit with an ECD was reported to be 5 pg. 

The symptoms described here resemble the 5HT toxicity syndrome (SEDA-25,16) and suggest that pethidine can provoke this reaction when combined with SSRIs, as it can with monoamine oxidase inhibitors. The report is also a useful reminder that the active metabolite of fluoxetine, norfluoxetine, has a half-life of about 1 week and would still have been present at the time of endoscopy, even though fluoxetine had been stopped 14 days before. 

The active metabolite of pethidine has a longer half life. 

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]. 

Norpethidine, a metabolite of pethidine, which has a longer half-life, may accumulate in cirrhosis, can cause tremor, and also has convulsant properties. 

PHENYTOIN ANALGESICS-OPIOIDS 1.1 efficacy of fentanyl and methadone 2. Risk of pethidine toxicity 1. t hepatic metabolism of fentanyl and methadone, and possibly an effect at the opioid receptor 2. Phenytoin induces metabolism of pethidine, which causes t levels of a neurotoxic metabolite 1. Be aware that the dose of fentanyl and methadone may need to be t 2. Co-administer with caution the effect may be 1 by administering pethidine intravenously... 

Pethidine is extensively metabolised in the liver and the parent drug and metabolites are excreted in the urine (t) 5 h). Norpethidine retains pharmacological activity and may accumulate dangerously when renal function is impaired. 

Fnrazohdone is used in the treatment of giardiasis. Its adverse effects are usually mild and transient abdominal discomfort, nausea, and vomiting. The urine may be dark-colored (SEDA-11, 597). Metabolites of furazolidone inhibit monoamine oxidase (1) and there is therefore the potential for interactions with foods containing tyramine (2) and with opioid analgesics hyperpyrexia has been reported in rabbits that were given fnrazohdone and pethidine (3). 

The use of opioids in very young patients is increasing. In a review of pain management in children, various routes of administration of opioids and their associated adverse effects have been discussed (SEDA-17, 78). Attention has been drawn to the adverse effects of intravenous codeine in children and to the risk of convulsions with pethidine in neonates, because of accumulation of its metabolite norpethidine. The risk of respiratory depression with morphine was also highlighted, and morphine is recommended for use only in neonates who are being ventilated or intensively nursed. Routine use of pulse oximetry has been recommended in all children receiving opioids (SEDA-21, 86). 

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). 

Although seizures are uncommon, several cases have been reported, including when pethidine was used in PCA. The metabolite norpethidine is considered to be of significant importance in provoking seizures. Risk factors are renal insufficiency, sickle-cell anemia, high doses of pethidine, and concurrent administration of phenothia-zines or drugs that induce hepatic enzymes (SEDA-16, 85) (SEDA-18, 82) (SEDA-19, 85). Myoclonus can occur (7). Norpethidine is twice as likely as pethidine to cause convulsions. The seizures occur at a norpethidine concentration range of 0.38-9.9 pg/ml, and only few reports have described convulsions within the first 24 hours of pethidine treatment. 

Pethidine has a rapid onset of action but its short duration (3 hours) makes it unsuitable for the control of prolonged pain. Pethidine is metabolized in the liver and at high doses a toxic metabolite (norpeiht-dine) can accumulate and cause convulsions. Pethidine interacts seriously with MAOIs (diapier 28) causing delirium, hyperpyrexia and convulsions or respiratory depression. 

Prodines and their metabolites, like the fentanyls, can be determined from body fluids only chromatographically. As no urine samples have so far been available to us for this type of analysis, Fig. 8-33 should be referred to. This shows the results of an analysis after therapeutic consumption of 25 mg pethidine, the model substance of the prodines. 

Pethidine is metabolised via several eytoehrome P450 isoenzymes. If the metabolism of pethidine is increased it ean lead to increased production of the toxic metabolite, norpethidine, and increased CNS adverse effects. 

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. 

Studies suggest that phenobarbital stimulates the liver enzymes concerned with the metabolism (A/-demethylation) of pethidine so that the production of its more toxic metabolite (norpethidine) is increased. The toxicity seen appears to be the combined effects of this compound and the directly sedative effects of the barbiturate. "... 

There is evidence that chlorpromazine can increase the activity of the liver microsomal enzymes so that the metabolism of pethidine to norpethidine and norpethidinic acid are increased. These metabolites are toxic and probably account for the lethargy and hypotension seen in one study. The effects of the phenothiazines on pethidine-induced respiratory depression may be related. Both the opioids and the phenothiazines are CNS depressants, and their effects may be additive. 

Administration of opioids for chronic arthritic pain in elderly people is effective but can be associated with problematic adverse reactions, particularly morphine and related compounds in those with chronic renal insufficiency [53 ]. There is a higher frequency of nausea, constipation, and cognitive impairment. Pethidine, dextro-propoxyphene, and pentazocine should also be avoided because they have toxic metabolites. Preferred alternatives are hydro-morphone, oxycodone, and oxymorphone. 

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