Norpethidine

Conjugate addition of norpethidine (81) to benzoylethylene gives the ketone, 93. Reduction of the carbonyl group to the alcohol affords the potent analgesic phenoperidine (94). ... 

Table 5.3. ANALGESIC ACTIVITIES OF SOME N-SUBSTITUTED NORPETHIDINES AND CORRESPONDING REVERSED ESTERS...

Janssen has linked the cyanide precursor of normethadone to norpethidine to produce diphenoxylate (XXXVIII) this complex is not an analgesic but has the... 

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

Hyperpyrexia and hypertension have been observed with the use of pethidine and MAO inhibitors. Pethidine is the opioid most commonly associated with an adverse reaction with MAOIs. Although only a small proportion of patients taking MAOIs will react adversely to pethidine, there is no sure way of predicting those in whom the combination could produce severe, life-threatening reactions. These can present in two distinct forms. The excitatory form is characterised by sudden agitation, delirium, headache, hypotension or hypertension, rigidity, hyperpyrexia, convulsions and coma. It is possibly caused by an increase in cerebral 5-HT concentrations due to inhibition of MAO. This is potentiated by pethidine, which blocks neuronal uptake of 5-HT. The depressive form, which is frequently severe and fatal, presents as respiratoiy and cardiovascular depression and coma. It is the result of a reduced breakdown of pethidine due to the inhibition of hepatic /V-demethylase by MAOIs, leading to accumulation of pethidine. The risk of adverse reactions to pethidine may be less likely with the newer, specific MAO-A inhibitors. Interactions with other opioids, such as morphine and pentazocine, have been reported, but are less common. Other opioids appear to be safe in combination with MAOIs, with the possible exception of phenoperidine, which is metabolised to pethidine, norpethidine and pethidinic acid. 

Phenobarbitai and (M)Increased production of norpethidine Increased sedation, danger... 

Table 6.1. Relative Analgesic Activities of N-Substituted Norpethidines in Ratsa...

In N-3-phenpropyl analogs of norpethidine activity is further raised when the 3-carbon chain contains a double bond (item 15) but is lost when a triple bond is present/30 An imino group placed between the aryl and alkyl portions of the N- substituent is advantageous in terms of potency, and one such derivative (item 16, piminodine, Alvodine) has been marketed in the United States/31 The related amide 1 (R = PhNHCOCH2CH2) is eighttimes as potent as codeine in mice/32 ... 

Interesting potency variations are seen in norpethidines with straight-chain alkyl substituents (N-R) activity falls to about one third that of pethidine... 

Janssen and Eddy(41) have given a semiquantitative estimate of the influence of systematic chemical modifications on analgesic potency in mice and rats of a series of N-substituted norpethidines and reversed esters of pethidine. Their estimates, based on the results of the hot-plate test obtained in three separate laboratories, are illustrated in Scheme 6.3. 

Potency relationships among a series of N-snbstituted norpethidines... 

Most attempts to design narcotic antagonists based on 4-phenylpiperidine by linking the basic center to groups such as allyl, substituted allyl, and cyclopropyl methyl (CPM) that confer such properties on fused cyclic systems as possessed by morphine and 6,7-benzomorphans have led to agonists that have no power to block opiate receptors examples include TV-allyl derivatives of norpethidine and norprodine (18)34 and the TV-3-chloroallyl reversed ester 19.(56) Essentially similar results were found for a group of TV-substituted... 

Pethidine Mean 50 40-50 3-6 0.6-27 (pH dependent, less with higher pH) No information [47] Extensive in liver via hydrolysis and N-demethylation, followed by partial conjugation. First pass metabolism of 47-61% Yes. Norpethidine which is half as potent an analgesic, but potent convulsant -causes tremor and seizures Fong half-life, up to 20 hours Cleared renally... 

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. 

High Pressure Liquid Chromatography. System HA—pethidine k 2.8 (tailing peak), norpethidine k 1.7 (tailing peak), pethidinic acid k 2.8 (tailing peak) system HC—pethidine k 0.55, norpethidine k 2.04. 

Gas Chromatography-Mass Spectrometry. In plasma or serum pethidine and norpethidine, detection limit 170 pg/ml for pethidine and 500 pg/ml for norpethidine—E. L. Todd et al., J. analyt. Toxicol., 1979, 3, 256-259. In urine pethidinic and norpethidinic acids, sensitivity 500 ng/ml—C. Lindberg et al., Acta pharm. suec., 1978,15, 327-336. 

Half-life. Plasma half-life, pethidine 3 to 10 hours (mean 5), increased in neonates and in renal impairment norpethidine about 18 hours. 

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