Codeine sources

Alkaloids are compounds that contain nitrogen in a heterocyclic ring and are commonly found in about 15-20% of all vascular plants. Alkaloids are subclassified on the basis of the chemical type of their nitrogen-containing ring. They are formed as secondary metabolites from amino acids and usually present a bitter taste accompanied by toxicity that should help to repel insects and herbivores. Alkaloids are found in seeds, leaves, and roots of plants such as coffee beans, guarana seeds, cocoa beans, mate tea leaves, peppermint leaves, coca leaves, and many other plant sources. The most common alkaloids are caffeine, theophylline, nicotine, codeine, and indole... 

Biotransformations of morphinan alkaloids have been reported for plant, fungal, and mammalian enzymatic systems with emphasis on rather specific reactions such as the reduction of ketones, N- and O-demethylation, and perox-idative transformations. Furuya et al. used immobilized tissue culture cells of Papaver somniferum to accomplish the selective reduction of codeinone (135) to codeine (136) (207) (Scheme 30). Suspension cultures of a well-established cell line of P. somniferum were grown for one week as a source of cell mass for immobilization in calcium alginate. The cells continued to live in the alginate matrix for 6 months maintaining their biological activity. The reduction of co-... 

Morphine (10) and codeine (11), constituents of opium, are the most interesting alkaloids found in nature. Morphine is also the oldest alkaloid isolated, in 1805, by the German pharmacist Sertiimer from opium, the sun dried latex of Papaver somniferum. The structure of morphine with its so-called morphinan skeleton, once called the acrobat under the alkaloids, was finally elucidated in 1952 by the first total synthesis performed by Gates and Tschudi. Many syntheses would follow [26], but all morphine used today, whether legal or illicit, originates in the natural source P. somniferum or its extract, opium. The latex may contain up to 20% morphine. Most legal morphine is converted into the anticough medicine codeine (Table 5.1) by treatment with trimethylanilinium methoxide, whereas almost all illicit morphine is acetylated to the diacetate heroin. 

Source Y. Gasche Y. Daali M. Fathi A. Chiappe S. Cottini P. Dayer and J. Desmeules. Codeine intoxication associated with uitrarapid CYP2D6 metaboiism," New England Journal of Medicine 351 (2004) 2827-2841. 

Opium, the source of morphine, is obtained from the poppy, Papaver somnlferum and P album. After incision, the poppy seed pod exudes a white substance that turns into a brown gum that is crude opium. Opium contains many alkaloids, the principle one being morphine, which is present in a concentration of about 10%. Codeine is synthesized commercially from morphine. 

Or they may be grouped according to the genus of their plant source (morphine and codeine, Section 23-2, are examples of opium alkaloids), or by their physiological effects (antimicrobials, antibiotics, analgesics), or by similarities in the route by which they are synthesized by the organism (biosynthesis). The structural and biosynthetic classifications make the most sense to the chemist and is the organization chosen here. 

Figure 1 Frequencies of codeine glucuronidation in Caucasian and Chinese populations. The data are shown in terms of the logarithms of the metabolic ratios in 149 Caucasians and 133 Chinese. Source From Ref. 35.

Alkaloids are widespread in plants and include some very well-known poisons (notably coniine and strychnine), hallucinogens (morphine, cocaine and muscimol) and other potentially lethal compounds that are nevertheless used in medical practice (e.g. atropine, codeine, colchicine and morphine). As indicated by the preliminary snap-shot above, alkaloids typically have names ending in -ine and which are often related to the plant source or properties. Thus, morphine was named after Morpheus (the God of sleep) and coniine derives from Conium maculatum (hemlock), the plant used in the judicial murder of Socrates (399 BC). Various chemical tests for alkaloids are used as preliminary indicators of alkaloid presence in crude plant extracts. Finally, it should be noted that alkaloids can also exist as jVoxides of the alkaloid base. 

Investigator Source of hair sample Morphine Codeine Other Ref. 

This chapter concentrates on some drug choices in acute rather than chronic pain, but the same principles can be used to determine the appropriateness of other types of analgesic. The drugs considered in this section are paracetamol, non-steroidal anti-inflammatories (NSAIDs specifically diclofenac, ibuprofen, indometacin, naproxen, sulindac and tenoxicam) and opioids (codeine, dihydrocodeine, morphine, pethidine and tramadol). Unless otherwise stated, all pharmacokinetic data originate from standard reference sources [1-5] and apply to adults only. 

SAFETY PROFILE Poison by ingestion. Mutation data reported. Use may lead to habituation and addiction. A narcotic, sedative, analgesic, and hypnotic. Source of morphine, codeine, papaverine, thebaine, etc. Can cause nausea, vomiting, constipation, and respiratory problems. Combustible when exposed to heat or flame, See also MORPHINE. 

The isoquinoline alkaloids include the analgesics morphine and codeine as well as the antibiotic berberine (Fig. la). Morphine and codeine are two of the most important analgesics used in medicine, and plants remain the main commercial source of the alkaloids (8). Development of plant cell cultures of Eschscholzia califomica, Papaver somniferum, and Coptis japonica has aided in the isolation and cloning of many enzymes involved in the biosynthesis of isoquinoline alkaloids (9). 

Hastier P, Buckley MJ, Peten EP, Demuth N, Dumas R, Demarquay JF, Caroli-Bosc FX, Delmont JP. A new source of drug-induced acute pancreatitis codeine. Am J Gastroenterol 2000 95(ll) 3295-8. 

Semi-Synthetic Transformations of the Morphine Alkaloids Although it has been synthesised (ref 61), (now by four distinct routes) morphine (63), a powerful analgesic is readily available from the natural source, opium obtained from Papaver somniferum as the major alkaloid present (approx. 10%) and indeed the first to be isolated by Serturner in 1803, while the methyl ether, codeine (64) which comprises only 0.5% is relatively weakly active. Thebaine (65) a third component of opium is non-analgesic but is important as an intermediate for the formation of codeine, a somewhat scarce commodity (ref. 62) but a valuable mild analgesic and anti-tussive in great demand. It is best prepared from morphine by methylation with phenyl trimethylammonium ethoxide the by-product consisting of dimethylaniline (ref.63). 

Codeine, U5P. Codeine is an alkaloid that occurs naturally in opium, but the amount present is usually too small lu he of commercial importance. Consequently, most com-nienrial codeine is prepared from morphine by methylating Ihe phenolie hydroxyl group. The mcthylation methods make use of reagents such as diazonicthane. dimethyl sulfate, and methyl iodide. Newer methods arc ha.scd on its synthesis from thebaine, which makes it possible to use Papaver brac-lealum as a natural source (see above). 

Opium poppy Papaver somniferum L., Papaveraceae) is one of the most important medicinal plants and has been cultivated since early centuries. Opium, the dried cytoplasm of a specialized internal secretory system called the laticifer, is normally collected from the unripe capsule. It is the source for the commercial production of medicinally important alkaloids, morphine, codeine, thebaine, noscapine and papaverine [130, 131], Fig. (61). Morphine, which has strong addictive property, is still the most effective analgesic for the treatment of mortal cancer patients in modem medicine. Codeine is commonly used as an antitussive. However, field cultivation of this plant has been limited since 1953 by the United Nations Opium Conference Protocol to prevent narcotic crimes. Therefore, establishing tissue culture technique for the production of morphinan alkaloids seems to be desirable not only for medicinal purpose but also for decreasing abuse of opiates. 

N ic opine was first isolated by Dobbie and Lauder from the last mother liquors from the processing of the opium alkaloids after all other bases had been eliminated [1], This remains the only source of the base. The method of isolation has since been improved and the alkaloid can ho separated from codeine through the sulphates [2], The base was first allotted the formula C18H2404N and the name hydroxycodeine it was shown to contain one —OMe, one —NMe, and to be a tertiary base. Its colour reactions and ultra-violet absorption spectrum are practically idontical with those of codeine [1]. 

A number of drugs of abuse are known substrates (e.g., codeine, hydrocodone, p-methoxyamphetamine, amphetamine) or inhibitors (e g., (-)-cocaine, pentazocine) of CYP2D6. For some of these drugs, the pharmacokinetic differences due to the polymorphism will be so profound that they are likely to exceed pharmacodynamic sources of variation in response. For other drugs (e.g., hydrocodone to hydromorphone, codeine to morphine, oxycodone to oxymorphone), CYP2D6 may not contribute importantly to the overall clearance of the drug, but may catalyze the formation of highly active metabolites. 

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