Meperidinic acid

It is a cleavage of drug molecule by taking up a molecule of water. The most hydrolytic enzymes are found outside the endoplasmic reticulum, and in higher concentrations in liver, kidney and plasma. The metabolism of an ester by an enzyme esterase results in the formation of an acid and alcohol. The examples are meperidine, procaina-mide, pethidine and lidocaine etc. Meperidine is catalyzed by esterases to be changed into meperidinic acid and procainamide is catalyzed by amidases. 

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

Meperidine is in part demethylated in the body appearing as normeperidine in the urine. It is, however, for the most part hydrolyzed and excreted as free and conjugated meperidinic acid. The normeperidine is also partially hydrolyzed to normeperidinic acid, which is partly conjugated. Only a small part of the drug is excreted in an unchanged form. In humans, meperidine is metabolized at the rate of about 17% per hour, so that a single dose exerts its analgesic effect for 3 to 4 h. In the dog, on the other hand, its rapid metabolism (70 to 90% per hour) makes it difficult to induce tolerance or addiction. 

Metabolism and Elimination of Other Opioid Agents. Meperidine is also metabolized in the liver. It is either hydrolyzed directly to meperidinic acid or N-demethylated to normeperidine and then hydrolyzed to normeperidinic acid. The acid forms are conjugated, then excreted (23). 

In a study by Burns et al 9 in which the plasma levels of meperidine hydrochloride were measured after intravenous injection in man, it was inferred that metabolism occurs at a rate varying from 10 to 20 per hour (17 average) in ten different subjects. No accumulation of the drug after repeated administration was found in this study and only 5 of the drug was found to be excreted unchanged in the urine. Plotnikoff et al3l determined that the biotransformation products of meperidine hydrochloride excreted in human urine are normeperidine (I), meperidinic acid (II), nor-... 

In humans, meperidine is hydrolyzed to meperidinic acid, which, in turn, is partially conjugated. Meperidine also is N-demethylated to normeperidine, which then may be hydrolyzed to normeperidinic acid and subsequently conjugated. Meperidine is metabolized chiefly in the hver, with a half-life of about 3 hours. In patients with cirrhosis, the bioavailability of meperidine is increased to as much as 80%, and the half-lives of both meperidine and normeperidine are prolonged. Approximately 60% of meperidine in plasma is protein bound. Only a small amount is excreted unchanged. 

A mixture of 23 parts of the ethyl ester of 4 phenylisonipecotic acid and 15 parts of 2,2-diphenyl-4-bromobutyronitrile in 19 parts of xylene is heated for 24 hours at 100°-120°C and then cooled and filtered to remove the precipitate of the hydrobromide of the ethyl ester of 4-phenylisonipecotic acid. The filtrate is then extracted with dilute hydrochloric acid and the extract is rendered alkaline by addition of concentrated aqueous potassium hydroxide and extracted with ether. This ether extract is treated with gaseous hydrogen chloride. The resulting precipitate is collected on a filter. The hydrochloride of the ethyl ester of 2,2 diphenyl-4-(4 -carboxy-4 -phenyl-1 -piperidino) butyronitrile thus obtained melts at about 220.5-222°C. See Meperidine hydrochloride for synthesis of 4-phenyl-isonipecotic acid ethyl ester. 

Phenylacetonitrile (p DMSO = 21.9) is considerably more acidic than acetonitrile. Dialkylation has been used in the synthesis of meperidine, an analgesic substance.78... 

The use of phenylpiperidinols rather than the meperidine-related piperidines as the basic component in antidiarrheal compounds results in retention of activity. The fact that the base is not directly related to a narcotic presumably leads to greater selectivity of action on the gut. Ring scission of butyrolactone 98 (obtainable by alkylation of a diphenylacetate ester with ethylene oxide) with hydrogen bromide gives the bromo acid 99. This is then converted to the dimethylamide by successive treatment with thionyl chloride and dimethylamine. 

One of the early syntheses of meperidine (75) starts with the double alkylation of phenylacetonitrile with the bischloro-ethyl amine, 72. The highly lachrimatory nature of this material led to the development of an alternate synthesis for the intermediate piperidine (73). Alkylation of phenylacetonitrile with two moles of 2-chloroethylvinyl ether leads to the intermediate (69). This is then hydrolyzed without prior isolation to the diol, 70. Treatment with thionyl chloride affords the corresponding dichloro compound (71). This last is then used to effect a bis alkylation on methylamine, in effect forming the piperidine (73) by cyclization at the opposite end from the original scheme. Saponification to the acid (74) followed by esterification with ethanol affords the widely used analgesic meperidine (75) substitution of isopropanol for ethanol in the esterification affords properidine (76). ... 

Meperidine Meperidine, the ethyl ester of l-methyl-4-phenylpiperidine-4-carboxyhc acid (3.1.39), is a synthetic opioid analgesic. Its synthesis is accomphshed by the alkylation of benzyl cyanide using Af,Al-fcix-(2-chlorethyl)-iV-methylamine in the presence of sodium amide, which forms l-methyl-4-phenyl-4-cyanopiperidine (3.1.38), and its subsequent acidic ethanolysis into meperidine [30-32]. 

The answers are 264-c, 263-c. (Katzung, pp 519, 535-537.) Heroin and other opioids (such as morphine and meperidine) exhibit a high degree of tolerance and physical dependence. The tolerance rate magnitudes to all of the effects of opioids are not necessarily the same. The physical dependence is quite clear from the character and severity of withdrawal symptoms, which include vomiting spasms, abdominal cramps, diarrhea, and acid-base imbalances among others. 

Meperidine (isonipecaine, Demerol , and Dolantin ) is the methyl ester of methyl-4-phenylpi-peridine-4 carboxylic acid. It is used in the form of its soluble hydrochloride. The piperidine nucleus is also present in many alkaloids, such as atropine or lobeline, which are not analgesics, as well as in morphine. 

Subsequently, Purdie and coworkers studied the CD induced in phencyclidine (and its pyrrolidine and morpholine analogues), 6-phenethylamine, phenobarbital, meperidine HC1, diazepam, and dilantin by 6-cyclodextrin [59], In this work, a method was described for the assay of meperidine in commercially available Demerol tablets. The complexation between 6-cyclodextrin and eight 5,5-disubstituted derivatives of barbituric acid was characterized on the basis of the... 

Drugs that alter the pH of urine can significantly affect the renal excretion of other drugs. Acid urine increases the effectiveness of mercurial diuretics. It also accelerates the excretion of basic drugs such as meperidine, tricyclic antidepressants, amphetamines, and antihistamines. Acidic drugs, such as aspirin, streptomycin, phenobarbital, sulfonamides, nalidixic acid, and nitrofurantoin have been shown to increase renal clearance in alkaline urine (61). The possible effects of urine pH on the renal excretion of drugs has been illustrated by the observation that if urine is rendered sufficiently alkaline, the excretion of amphetamine is markedly delayed and effective blood levels, after a single dose, can be maintained for several days (62). 

---