Pethidinic acid

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. 

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. 

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. 

Isonicotinic Acid Methochloride. To a slurry of 246 g of isonicotinic acid in 3.2 liters of methanol and 300 ml of water containing 88 g of sodium hydroxide has 355 g of methyl iodide added to it. Note Isonicotinic acid can be replaced with nicotinic acid, thus producing B-pethidine, instead of demerol. There is very little difference in potency between these two dmgs and the formula does not change Oust use an equimolar amount of nicotinic acid), so you may use either acid. Stir and reflux the above mixture for 60 hours, then remove the methanol with vacuo. Use sodium thiosulfate to reduce iodine to iodide and add water to give a volume of 1.5 liters. Use hydrochloric acid (coned) to get a ph of 2.0. 

A number of novel structures containing a quaternary diphenyl carbon centre, as in methadone, have been described. Certain basic amides (XXXV) of O-ethylbenzilic acid are active by mouth in mice and rats. The most active members are somewhat more potent than pethidine and carry [3-arylethylamino V-substituents such as phenethyl and 2- (or 4-) pyridylethyl. Detailed pharmaco-... 

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. 

Forced diuresis by furosemide, mannitol etc. and altering the urinary pH- increasing the pH of urine favours ionisation of acidic drugs like salicylates, phenobarbital etc. whereas reducing the pH favours ionisation of basic drugs like pethidine, amphetamine etc. 

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

Ionisation determines the partitioning of drugs across membranes. Unionised molecules can easily cross and reach an equilibrium across a membrane, while the ionised form cannot cross. When the pH is different in the compartments separated by the membrane the total (ionised + unionised) concentration will be different on each side. An acidic drug will become concentrated in a compartment with a high pH and a basic drug in one with a low pH. This is known as ion-trapping, and occurs in the stomach, kidneys, and across the placenta. Urinary acidification accelerates the excretion of weak bases, such as pethidine, while alkalinisation increases the excretion of acidic drugs, such as aspirin. As an example consider pethidine (pKa 8.6) with an unbound plasma concentration of 100 (arbitrary units). At pH 7.4 only 6% of the pethidine will be unionised so that at equilibrium the concentration of unionised pethidine in the urine will be 6 units. In urine at pH 6.5 only 0.8% of the pethidine will be unionised so that the total concentration in the urine will be 744 units. 

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. 

Pethidine-Intermediate-C, l-methyl-4-phenylpiperidine-4-car-boxylic acid. 

Pain research is a traditional and well established field within the pharmaceutical industry. Beginning with the isolation of morphine in a small pharmacy by Adam Serturner (1806), the next major breakthrough in pain treatment was achieved by the synthesis of acetylsalicylic acid by Felix Hoffmann in the Bayer Laboratories in Wuppertal (1897). Further outstanding contributions by the pharmaceutical industry were the first fully synthetic opioids pethidine (1939) and methadone (1946). Continued efforts up to now have resulted in many potent and clinically accepted analgesics with reasonable side effects and covering nearly all facets of pain treatment. However, pain treatment is far from being satisfactory in respect to more complex pain states, e.g. neuropathy, visceral pain or migraine. 

Verbeeck RK, Cardinal J (1985) Plasma protein binding of salicylic acid, phenytoin, chlorpromazine, propranolol and pethidine using equilibrium dialysis and ultracentrifugation. Arzneimittelforschung 35 903... 

This means that it can be used to build up heavily branched esters and carboxylic acids—the sort that are hard to make by alkylation because of the problems of hindered enolates and unreactive secondary alkyl halides. Heavily substituted acids, where CO2H is attached to a tertiary carbon atom, would be hard to make by any other method. And the Favorskii rearrangement is a key step in this synthesis of the powerful painkiller Pethidine. 

N-nitrosonormeperidinic acid for JH the sequence for pethidine is shown in Scheme 6.2.<37)... 

Complete removal of the 4-phenyl substituent of the reversed ester of pethidine results in a drastic fall in potency as judged from tests in mice (see 23, R = Et). However, certain esters of l-methyl-4-piperidinol formed from aromatic acids display antinociceptive activities in the morphine to codeine range of potency (23).<68) A QSAR study of such esters has been made and a substitution pattern of the phenyl group defined for optimal activity/69 The relevance of these compounds to morphine-type analgesics is doubtful since the more active members show marginal or no affinity for opioid receptors of rat brain homogenates and display no physical dependence in monkeys. 

Fentanyl and its analogs are made from TV-substituted-4-piperidones [i.e., from the same intermediates of the reversed esters of pethidine (p. 266)]. These ketones condense with aniline under the influence of catalysts such as toluene-p-sulfonic acid(2) and zinc chloride(18) to give Schiff bases, which are reduced to diamines 4 by NaBH4 or LAH. Recently, the direct conversion of 4-piperidones to 4-anilino derivatives 4 has been achieved by reductive amination with aniline and sodium cyanoborohydride (NaBH3CN).(19) The diamines are acylated with propionic anhydride. 

The carbinol precursor of propoxyphene is made by treating the Mannich base 21a with a benzyl Grignard reagent. The major (a) diastereoisomer 21b is separated, resolved with (+)-camphor-10-sulfonic acid, and finally acylated to yield the active drug. Pyrrolidino analogs of propoxyphene are more potent than the parent (acetate, 2 x, propionate,1 x pethidine in mice),(51) while the halogenated acetates 22 (X = F or Cl) have similar activities to morphine in mice.(58) Replacement of terminal phenyl of propoxyphene by 2-pyridyl achieves a potency rise, as occurs also in the cyclic analog 23/59 ... 

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. 

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