Opium, alkaloids

In modem medicine, mily the purified opium alkaloids and their derivatives are commonly employed. Although the ripe poppy capsule can contain up to 0.5 % total alkaloids, opium represents a much concentrated form and up to 25 % of its mass is composed of alkaloids. Of the many (>40) alkaloids identified, some six represent almost all of the total alkaloid content. Actual amounts vary widely, e.g., morphine (4-21 %), codeine (0.8-2.5 %), thebaine (0.5-2.0 %), papaverine (0.5-2.5 %), noscapine (narcotine) (4—8 %), and narceine (0.1-2 %). A t3q>ical commercial sample of opium would probably have a morphine content of about 12 %. Powdered opium is standardized to contain 10 % of anhydrous morphine, usually by dilution with an approved diluent, e.g., lactose or cocoa husk powder. The alkaloids are largely combined in salt form with meconic acid, opium containing some 3-5 % of this material. Meconic acid is invariably found in opium but, apart from its presence in other Papaver species, has not been detected elsewhere. It gives a deep red-colored complex with ferric chloride, and this has thus been used as a rapid and reasonably specific test for opium. Of the main opium alkaloids, only morphine and narceine display acidic properties, as well as the basic properties due to the tertiary amine. Narceine has a carboxylic acid function, while morphine is acidic due to its phenolic hydroxyl. This acidity can be exploited for the preferential extraction of these alkaloids (principally morphine) from an organic solvent by partitioning with aqueous base (Table 15.6). 

Morphine is the principal alkaloid of opium. It acts both as a base and as a phenol and reacts to form methylmorphine (codeine ) and diacetylmorphine (diamorphine or heroin). 

An opium alkaloid Although it is an excellent analgesic its use is restricted because of the potential for addiction Heroin is the diacetate ester of morphine )... 

The actions of the naturally occurring materials now known as alkaloids were probably utilized by the early Egyptians and/or Sumarians (1). However, the beginnings of recorded, reproducible isolation from plants of substances with certain composition first took place in the early nineteenth century. Then in close succession, narcotine [128-62-1] (1, now called noscopine, C22H23NOy) (2) and morphine (2, R = H) (3) (both from the opium poppy, Papaver somnijerum E.) were obtained. 

The Opiates. The International Narcotics Control Board—Vienna, tracks the tick production of narcotic dmgs and annually estimates world requkements for the United Nations. Thek most recent pubHcation (100) points out that more than 95% of the opium for Hcit medical and scientific purposes is produced by India and, in a declining trend, only about 600 t was utilized in 1988. This trend appears to be due to the fact that the United States, the largest user of opium for alkaloid extraction, reduced the amount of opium being imported from about 440 t in 1986 to 249 t in 1987 and 224 t in 1988. The United States used about 48 t of morphine (2, R = H) in 1988, most (about 90%) being converted to codeine (2, R = CH3) and the remainder being used for oral adrninistration to the terminally ill (about 2 t) and for conversion to other materials of minor commercial import which, while clearly alkaloid-derived, are not naturally occurring. 

Enkephalins and Endorphins. Morphine (142), an alkaloid found in opium, was first isolated in the early nineteenth century and widely used in patent medicines of that eta. It is pharmacologically potent and includes analgesic and mood altering effects. Endogenous opiates, the enkephalins, endorphins, and dynotphins were identified in the mid-1970s (3,51) (see Opioids, endogenous). Enkephalins and endorphins ate Hsted in Table 9. 

Opium is the dried, powdered sap of the unripe seed pod of Papaver somniferum, a poppy plant indigenous to Asia minor. Theophrastus described its medical properties in the third century BC, but the Sumerians, ca BC 4000, probably perceived its utility. Arab physicians knew of the dmg, and Arab traders carried it to the Orient where it was used as a treatment for dysentery. Paracelsus is credited with repopularizing the dmg in western Europe in the early sixteenth century by formulating opium into "laudanum", which is still in use. More than 20 different alkaloids (qv) of two different classes comprise 25% of the weight of dry opium. The benzylisoquinolines, characterized by papaverine [58-74-2] (1.0%), a smooth muscle relaxant, and noscapine [128-62-1] (6.0%), an antitussive agent, do not have any analgesic effects. The phenanthrenes, the second group, are the more common and include 10% morphine (1, = R = H), 0.5% codeine [76-57-3], C gH2 N03, (1, R = H, R = CH3), and 0.2 thebaine [115-37-7], C 2H2 N03, (2). 

Opioids. Morphine [57-27-2] C yH NO, (8) the most prevalent and analgesicaHy potent of the naturally occurring opium alkaloids (qv), has been used as an anesthetic premedication for over one hundred years (93). It has also been used as an iv analgesic for the last four decades, and, since 1969, in high doses as an anesthetic agent (117). 

The early stmctural evideace, physical properties, and aromaticity of isoquiaoline have been discussed at the beginning of this article. Two additional trivial names are encountered occasionally 2-benzaziae and leucoline. The widespread occurrence of this stmcture ia such important alkaloids as those found ia cactus, opium, and curare has created a long-standing iaterest ia its syathesis and properties (4). 

The synthesis of dextromethorphan is an outgrowth of early efforts to synthesize the morphine skeleton. /V-Methy1morphinan(40) was synthesized in 1946 (58,59). The 3-hydroxyl and the 3-methoxy analogues were prepared by the same method. Whereas the natural alkaloids of opium are optically active, ie, only one optical isomer can be isolated, synthetic routes to the morphine skeleton provide racemic mixtures, ie, both optical isomers, which can be separated, tested, and compared pharmacologically. In the case of 3-methoxy-/V-methylmorphinan, the levorotatory isomer levorphanol [77-07-6] (levorphan) was found to possess both analgesic and antitussive activity whereas the dextrorotatory isomer, dextromethorphan (39), possessed only antitussive activity. Dextromethorphan, unlike most narcotics, does not depress ciUary activity, secretion of respiratory tract fluid, or respiration. 

Noscapine [128-62-1] (45) is the second most abundant alkaloid found in opium. Unlike most opium alkaloids, however, it has an isoquinoline rather than a phenanthrene ting system. Noscapine was first isolated in 1817 but its antitussive activity was not demonstrated pharmacologically until 1952 (63). Clinical studies have confirmed its effectiveness. It is not a narcotic and has a wide margin of safety when given orally. Death could be produced in rats only with doses > 800 mg/kg (64). Noscapine is isolated from the water-insoluble residue remaining after processing opium for the manufacture of morphine. 

The alkaloid can usually be obtained from the mother liquors of hyoscyamine, but Datura Metel, in which hyoscine is the chief constituent, was the better primary source but may now prove less valuable than selected Duboisia spp. (p. 66). A process of manufacture has been described by Chemnitius, and a method for the recovery of 1-hyoscine from racemised base by Schukina et al. A method for its estimation in presence of opium alkaloids has been devised bj Wallen and Callback. 

More interesting, as regards future developments, are the eiforts now being made to dispense with opium as an intermediate in the production of morphine. The early history of experiments in the direct extraction of the alkaloid from poppy capsules and poppy straw has been recounted by Goris and by Wiiest and Frey. ... 

Estimation of Other Alkaloids in Opium. Of the other alkaloids the most important is codeine, and processes for its estimation in opium have been described by Cespari, Andrews,and Annett and co-workers methods for its assay in admixture with other drugs in tablets and other products are also available. The estimation of papaverine has been described by Issekutz,i and of narcotine by Snesarov. As to methods for the separation and estimation of two or more of these subsidiary alkaloids, codeine and narcotine have been dealt with by van der Widen,narcotine and papaverine by Annett and Bose, ( and the bromination of codeine and narceine has been studied by Vaisberg et al. with a view to estimation by this means. 

The first scheme for the separation of the six chief alkaloids of opium, VIZ., morphine, codeine, thebaine, papaverine, narcotine and narceine, is probably that of Plugge. Much later Kljatschkina investigated for each of these six bases the properties by means of which isolation and estimation could probably be effected and, on the basis of the results, devised a plan for such analyses. More recently Anneler has published a detailed account of a scheme with the same objective. l Attention had already been given to complex, systematic analyses of this kind, in connection with examination of the mixtures of opium alkaloids, which have long been in use in medicine in these at first only morphine and other alkaloids were determined, but in the more recent schemes provision is made for the estimation of each alkaloid. ... 

Mention may also be made here of some recent investigations in which comparison of physical properties of the chief opium alkaloids has been... 

The large scale on which morphine is manufactured has made it possible to conduct investigations on practically unlimited supplies of factory residues, with the result that many alkaloids have been isolated from opium, of which at present twenty-five are known. In the following table, giving their names and formulae, they have been divided into five groups —... 

The processes used in the manufacture of morphine are believed to be still based on that described by the Scottish chemist Gregory,in 1833, with improvements devised by Anderson. A description has been published by Schwyzer, who also deals with the manufactme of codeine, narcotine, cotarnine, and the commercially important morphine derivatives, diamorphine (diacetylmorphine), and ethylmorphine (morphine ethyl ether). More recently Barbier has given an account of processes, based on long experience in the preparation of alkaloids from opium. Kanewskaja has described a process for morphine, narcotine, codeine, thebaine and papaverine, and the same bases are dealt with by Chemnitius, with the addition of narceine, by Busse and Busse, and by Dott. It is of interest to note that a number of processes for the extraction and separation of opium alkaloids have been protected by patent in Soviet Russia. ... 

Apart from these methods of producing the opium alkaloids of commercial importance, processes for the minor bases have been published by Merck,Hesse, Plugge and Lohmann-Siedler. ... 

As regards general methods for distinguishing between the alkaloids of opium, mention may be made of the following Kofler and Kofler s study of the micro-sublimation of these alkaloids and the characters of the micro-sublimates the comparison by Maplethorpe and Evers of the picrates of a series of opium bases, comparison of the colour reactions of a series of opium alkaloids, and their behaviour with specific reagents and precipitants. ... 

Papaverine, C20H21O4N. This alkaloid, first obtained by Merck, occurs in the mixture precipitated by ammonia from the mother liquors of opium extract from which morphine and codeine have been separated in Gregory s process, and methods for its isolation from this mixture have been published by Hesse and others. The alkaloid may be purified by conversion into the acid oxalate, B. H2C2O4, m.p. 196° or 201-5-202°, which is nearly insoluble in alcohol. 

Papaveraldine (Xanthaline), C2oHij05N. This substance forms colourless scales, m.p. 210°, yields well-crystallised yellow salts, which are dissociated in water, and reacts as a tertiary base, forming a methiodide, m.p. 133-5°. It gives an oxime existing in two stereoisomeric forms, and contains foru methoxyl groups. The demethylated product, papaveraldoline, Ci0H,ON(OH)4, has been prepared by Oberlin. Miss Dobson and W. H. Perkin have shown that the alkaloid, Xanthaline, isolated from opium by T. and H. Smith, is identical with papaveraldine. On reduetion with... 

Narcotoline, This alkaloid, isolated from opium-poppy... 

In addition to the foregoing five phthalideisoquinoline alkaloids obtained from opium, Manske has isolated from genera of the Rhceadales six more alkaloids definitely assigned to, and three, including base F38 (p. 173), which he considers may belong to this group. Hydrastine, already dealt with (p. 162), is also a phthalidcMoquinoline derivative. 

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